Pain Medicine 2012; 13: 243–254 Wiley Periodicals, Inc.

NEUROPATHIC PAIN SECTION Original Research Articles Efficacy and Safety of Dextromethorphan/ Quinidine at Two Dosage Levels for Diabetic Neuropathic Pain: A Double-Blind, Placebo-Controlled, Multicenter Study pme_1316

243..254

rating scales applied daily using patient diaries, and another two applied at five clinic visits.

*Nerve and Muscle Center of Texas, Baylor College of Medicine, Houston, Texas;

Results. On all six scales, DMQ 45/30 mg was significantly superior to placebo, including the primary efficacy analysis, which utilized mixed-effects modeling to test all scores on an 11-point numerical Pain Rating Scale (P < 0.0001). Sensitivity analyses gave consistent results. Efficacy vs placebo was also seen for diary ratings of present pain intensity, and pain interference with sleep and with activities (all P < 0.0001). Among clinic visit assessments, DMQ 45/30 mg demonstrated greater leg pain relief (P = 0.0002) and greater reduction of leg pain intensity (P = 0.0286) vs placebo. The efficacy of DMQ 30/30 mg was numerically less than for 45/30 mg but for most outcomes remained significantly greater vs placebo. Adverse events were mostly mild or moderate and of expected types. Discontinuation for adverse events in the DMQ groups was at least twice as common as placebo.

†

Avanir Pharmaceuticals, Aliso Viejo, California;

§

University of Chicago, Chicago, Illinois, USA

Reprint requests to: Aziz I. Shaibani, MD, Nerve and Muscle Center of Texas, 6624 Fannin Street #1670, Houston, TX 77030, USA. Tel: 713-796-0033; Fax: 713-796-9302; E-mail: [email protected]. Disclosures: Dr. Shaibani was an investigator for the study, paid by the sponsor, and previously presented the results of this study in abstract form at a scientific conference. Drs. Pope and Hepner are employees of Avanir Pharmaceuticals, Inc. Dr. Thisted is a statistical consultant to Avanir Pharmaceuticals, Inc. He receives book royalties from CRC Press, and has served as an expert witness on behalf of Eli Lilly, Bayer, Pronova, Genzyme, Ameritox, Otsuka, GlaxoSmithKline, Wyeth, Novartis, and Galderma.

Abstract Objective. To evaluate dextromethorphan coadministered with quinidine as treatment of diabetic peripheral neuropathic pain. Design. In a 13-week, phase 3, randomized controlled trial, 379 adults with daily symmetric diabetic peripheral neuropathy (DPN) leg pain for ⱖ3 months received double-blind placebo, dextromethorphan/ quinidine (DMQ) 45/30 mg, or DMQ 30/30 mg, administered once daily for 7 days and twice daily thereafter. Efficacy measures included four pain

Conclusions. Throughout a 13-week trial, DMQ was effective, with an acceptable safety profile, for treatment of DPN pain. Other fixed-dose combinations of DMQ should be studied to improve overall tolerability while maintaining significant efficacy. Key Words. Clinical Trial; Dextromethorphan/ Quinidine; Diabetic Peripheral Neuropathic Pain; Numerical Pain Rating Scale; Pain Introduction Diabetic peripheral neuropathy (DPN) is a common complication of diabetes. The most frequent form, estimated to affect approximately 50% of diabetic patients [1], is a distal symmetric polyneuropathy that can involve both small and large sensory fibers [2]. The associated pain, estimated to affect approximately 25% of DPN patients [3], can be severe and disabling. Among the hypothesized 243

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Aziz I. Shaibani, MD,* Laura E. Pope, PhD,† Ronald Thisted, PhD,§ and Adrian Hepner, MD†

Shaibani et al. mechanisms, central sensitization—an abnormal hyperexcitability induced by the excitatory amino acid neurotransmitters glutamate and aspartate—is dependent on activation of N-methyl-D-aspartate—sensitive glutamate receptors (NMDA receptors) situated on dorsal horn nociceptive neurons [4].

For treatment of pseudobulbar affect, a Food and Drug Administration (FDA)-approved indication, dextromethorphan 20 mg is coadministered twice daily (b.i.d.) with a low, 10-mg dose of quinidine, a potent P450 2D6 inhibitor [21,22]. The recommended quinidine dose (10 mg b.i.d.) in the approved combination product is between 1–3% of the recommended quinidine dose for the treatment of cardiac arrhythmias (600–1,600 mg/day), but is sufficient to maintain the bioavailability of dextromethorphan [22]. In phase 1 studies of dextromethorphan/quinidine (DMQ) combinations in healthy volunteers, 30 mg of quinidine, given b.i.d., effectively blocked the metabolism of dextromethorphan administered concurrently at up to 60 mg b.i.d. [23]. In a phase 2 dose-escalation trial, 36 patients with uncontrolled DPN pain received open-label DMQ, starting at 30/30 mg once daily [24]. Among the 33 patients who completed 29 days, 23 patients (69.7%) tolerated the highest permitted dosage: 30/30 mg four times daily (120/ 120 mg/day). Statistically significant improvements were seen across a variety of pain intensity, pain relief, quality of life (QoL), and sleep rating scales. These findings provide a rationale for further evaluation of the efficacy and safety of DMQ for DPN pain. Here, we report the results of a 13-week, phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial of two dosages of DMQ: 45/30 and 30/30 mg b.i.d. 244

Patient Selection All patients were required to be ⱖ18 years old and to have diabetes mellitus (type 1 or 2) under documented glycemic control through use of established antidiabetic therapy for at least the preceding 3 months. All patients also had to have experienced a painful diabetic distal symmetric sensory/motor polyneuropathy for at least the preceding 3 months (without significant asymmetry, nondiabetic neuropathy, or any other potentially confounding pain). Exclusionary criteria included failing three or more pain medications; having required narcotics for pain control; a known sensitivity to quinidine or opiate drugs; previous treatment with coadministered dextromethorphan and quinidine; and any history of amputation, major psychiatric disturbance, sick sinus syndrome, or torsades de pointes. Patients were also excluded for electrocardiographic (ECG) findings of heart block (however, isolated right bundle branch block was acceptable) or of QT interval corrected for heart rate (QTc) prolongation (to ⱖ470 ms), sinus bradycardia (5/min). Dextromethorphan metabolizer genotype was not an inclusion consideration. Potential patients passing their initial screening were required to stop using medications that could confound pain assessment, including tricyclic antidepressants, as of 2 weeks before baseline, and selective serotonin reuptake inhibitors, analgesics, and antiepileptic drugs, as of 1 week before baseline. At baseline (day 1), potential patients scoring ⱖ2 (at least moderate leg pain) on a 5-point Pain Intensity Rating Scale (described below) were randomized to an initial capsule of DMQ 45/30 mg, DMQ 30/30 mg or identically appearing placebo. The investigators, patients, and sponsor were blinded to the treatment assignment. The study was randomized by center; randomization was blocked to ensure approximately equal representation within treatment centers. A resting ECG was obtained 1 hour following initial dosing. Patients whose QTc remained 30 ms from its initial screening value were allowed to continue on the study.

Treatments For the first week of the study’s 13-week treatment period, each patient took one capsule per day. Starting on day 8 and for the ensuing 12 weeks, patients took two capsules daily, one in the morning and one in the evening, placing the DMQ groups on a maintenance regimen of 90/60 or 60/60 mg/day. Throughout treatment, all patients were provided diaries, on which they were instructed to record the time each capsule was taken, and also any adverse events (AEs). In addition, all patients returned to their clinical center for

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Dextromethorphan hydrobromide is an NMDA receptor antagonist [5]. Its low, uncompetitive affinity for the NMDA receptor makes it neuropharmacologically attractive as an oral treatment candidate for DPN pain [6–8]. Additional actions as an agonist of the sigma-1 receptor [9], an antagonist of the N-type calcium channel [10], and an antagonist at the serotonin reuptake transporter [11–13] conceivably might also contribute to analgesic effects [14–16]. In early clinical studies of dextromethorphan in various types of neuropathic pain, such as diabetic neuropathy, postherpetic neuralgia, facial neuralgias, poststroke neuropathy, and other varieties [8,17,18], analgesia was not consistently documented: the findings included a lack of benefit vs placebo among patients receiving 81 mg/day [17], but also a report of significant benefit among recipients of a mean 381 mg/day [8]. Meanwhile, however, pharmacologic studies were suggesting that for dextromethorphan administered as monotherapy, bioavailability sufficient for any central nervous system action is difficult to achieve. In dextromethorphan-extensive metabolizers—the predominant metabolizer phenotype, found in 90% to 95% of Caucasian population samples [19,20]—dextromethorphan is rapidly and extensively metabolized by hepatic cytochrome P450 2D6. In the absence of P450 2D6 blockade, plasma dextromethorphan levels in some recipients have been undetectably low, even for oral dosage as high as 750 mg/day [21].

Methods

Dextromethorphan/Quinidine for Diabetic Neuropathic Pain assessment at days 15, 29, 50, 71, and 92 (end of treatment). Throughout the study, analgesics were disallowed, with the exception of oral acetaminophen (ⱕ650 mg/day) as rescue medication. Daily low-dose aspirin (81 mg/day) was not considered analgesic therapy. Efficacy Variables

Clinic visits included two pain assessments. On days 1, 15, 29, 50, 71, and 92, a 5-point categorical Pain Intensity Rating Scale [27] required patients to classify their leg pain for the previous 24 hours as 0 (none), 1 (mild), 2 (moderate), 3 (severe), or 4 (extreme), and a 6-point categorical Pain Relief Rating Scale [25] required patients to classify the relief of their leg pain, compared with baseline, as 4 (complete), 3 (a lot), 2 (moderate), 1 (slight), 0 (none), or -1 (worse). Additionally, on days 1 and 92, patients completed the Peripheral Neuropathy Quality of Life (PN QoL) instrument [31]. This self-administered, health-related QoL measure incorporates the 36-item Short-Form Health Survey [32], with further questions specific to peripheral neuropathy. Statistical Methods In the intent-to-treat (ITT) population, comprising all randomized patients, demographic data and baseline characteristics were tested for significant differences between treatment groups (P ⱕ 0.05) by analysis of variance (ANOVA) with a term for treatment (continuous variables), or by Pearson’s chi-square or Fisher’s exact test (categorical variables). Efficacy analyses were applied to observed-case data from the ITT population. The primary analysis compared the profile of mean daily Pain Rating Scale scores in the 45/30-mg b.i.d. group with that for the placebo group, using a mixed-effects regression model. Secondary

Among secondary efficacy variables measured at clinic visits, Pain Relief Rating Scale data were analyzed in three ways: ANOVA for evaluation of pain relief averaged across all assessment time points (days 15, 29, 50, 71, and 92); Cochran-Mantel-Haenszel test of the distribution of categorical responses at each of these time points; and chi-square test of the proportion of patients reporting substantial pain relief (either “a lot” or “complete”) at each time point. Pain Intensity Rating Scale data were tested by ANCOVA for mean change from baseline, as averaged across all time points. Change in PN QoL composite score was also tested by ANCOVA. Sample-Size Calculation Sample size was calculated using an effect size of a 0.5 standard deviation (SD) difference in the numerical Pain Rating Scale score (the primary efficacy measure) between active and control groups. A power of 90% would require 85 randomized patients in each of the treatment arms. With an expected 30% dropout rate, approximately 364 patients would be required for the study. Safety and Tolerability Assessments In the safety population, comprising all randomized patients who took at least one dose of study drug, AEs were defined as any untoward medical occurrence, as identified by interview each week in person or by telephone. Study-drug safety and tolerability were also assessed by vital sign measurements (at all clinic visits); laboratory studies (at days 29, 50, 71, and 92); ECGs (at days 15 and 92); physical examination (at day 92); and at selected clinical centers, patients underwent nerve conduction studies at the initial screening visit and at days 1, 71, and 92 or early discontinuation (about 30% of total study patients). Using standard surface-electrode procedures, the nerve conduction studies included maximal conduction velocity in segments of the peroneal motor nerve and the ulnar sensory nerve. In addition, compound sensory and motor 245

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Each patient’s daily diary keeping included four pain assessments. An 11-point numerical Pain Rating Scale, to be completed each evening, was the study’s primary assessment [25]. It asked patients to circle the number best characterizing their average pain for the preceding 12 hours, from 0 (none) to 10 (worst pain ever experienced). An 11-point numerical Sleep Rating Scale [26], to be completed each morning, asked patients to circle the number best characterizing the degree to which pain had interfered with their sleep during the preceding 24 hours, from 0 (did not interfere) to 10 (completely interfered). A 6-point categorical Present Pain Intensity Rating Scale [27–29], to be completed each morning, asked patients to circle the number best describing their present pain, as 0 (none), 1 (mild), 2 (discomforting), 3 (distressing), 4 (horrible), or 5 (excruciating). An 11-point numerical Activity Rating Scale [30], to be completed each evening, asked patients to circle the number best characterizing the degree to which pain had interfered with their general activity during the preceding 24 hours, from 0 (did not interfere) to 10 (completely interfered).

efficacy analyses of the daily Pain Rating Scale scores and other diary-based efficacy variables used the mixedeffects model to compare 45/30 mg b.i.d. and placebo at days 30, 60, and 90, and to compare 30/30 mg b.i.d. and placebo overall and at days 30, 60, and 90. Mixed-effects modeling is valid when missing data satisfy a missing-atrandom assumption. As a sensitivity analysis, a weighted generalized estimating equation (WGEE) model was applied to the primary data. This model assumes that the likelihood of obtaining a given entry would be affected by treatment assignment and by the patient’s preceding scores. In addition, observed-case Pain Rating Scale data were tested for change from baseline to week 13 using analysis of covariance (ANCOVA), with baseline and treatment as terms. Although the methods have serious limitations relative to the mixed-effects model [33], imputation of missing Pain Rating Scale data by each of two extreme approaches—last observation carried forward (LOCF) and baseline observation carried forward (BOCF)—was also explored.

Shaibani et al. N = 816 Screened N = 379 Randomized

n = 131 DMQ 45/30 mg b.i.d.

n = 79 Completed study

n = 52 Discontinued

n = 125 DMQ 30/30 mg b.i.d.

n = 74 Completed study

n = 89 Completed study

Ineligibility (3) Adverse event (25) Treatment failure (4) Subject withdrew consent (3) Investigator judgment (2) Protocol noncompliance (7) Lost to follow-up (3) Termination of study or withdrawal of subject by sponsor (1) Other (3)

n = 34 Discontinued

Ineligibility (1) Adverse event (13) Treatment failure (1) Subject withdrew consent (9) Investigator judgment (0) Protocol noncompliance (4) Lost to follow-up (2) Termination of study or withdrawal of subject by sponsor (2) Other (2)

Figure 1 Patient disposition. b.i.d. = twice daily; DMQ = dextromethorphan/quinidine. amplitudes were determined for each nerve segment. Blood samples were obtained on day 1 to determine dextromethorphan metabolizer status, and on days 15, 29, and 71 to measure plasma concentrations of dextromethorphan, its metabolite dextrorphan, and quinidine. Ethics and Good Clinical Practice The study was conducted in accordance with Good Clinical Practice and with the provisions of the Declaration of Helsinki and its amendments. Before any patients were enrolled, the study’s protocol, the informed consent form, and all protocol amendments were reviewed and approved by each center’s Institutional Review Board or Independent Ethics Committee. The study’s nature and purpose were explained to all patients, who then provided written informed consent prior to undergoing any studyrelated procedures.

Results Study Patients Of 816 potential patients, 379 were randomized. The most common reasons for screening failure were lack of compliance with the analgesic medication washout period, ECG abnormalities, lack of glycemic control, and withdrawn patient consent. The 379 patients who met the study criteria were randomized at 47 centers, 131 to the 45/30-mg b.i.d. DMQ group, 125 to the 30/30-mg b.i.d. DMQ group, and 123 to the placebo group. Their dispo246

sition throughout the study is displayed in Figure 1. Overall, 36.1% of the randomized patients (137 of 379) discontinued: 39.7% of the 45/30-mg b.i.d. group, 40.8% of the 30/30-mg b.i.d. group, and 27.6% of the placebo group. The most common reasons were AEs (in 71 patients), withdrawn consent (20 patients), and protocol noncompliance (15 patients). Diaries were returned by 358 patients (94%). Of these patients, diary entries were available for 84% at week 4, 74% at week 8, and 68% at week 13. Week-13 diary entries by treatment arm were 63% for the 45/30-mg b.i.d. group, 65% for the 30/30-mg b.i.d. group, and 76% for the placebo group. Missing diary entries were primarily due to discontinuation; 94% of patients recorded at least 90% of their diary entries prior to study discontinuation. The patients’ baseline characteristics are summarized in Table 1. Overall, most patients were male (61.7%) and Caucasian (84.4%). Their mean age was 60.9 years (range, 28 to 86 years), and they had experienced diabetes for a mean (SD) of 11.1 (9.4) years, DPN for a mean 3.8 (3.9) years, and associated daily pain for a mean 3.3 (3.9) years. Of 294 patients whose dextromethorphan metabolizer phenotype was identified, 267 (90.8%) were extensive metabolizers. Demographic and baseline clinical characteristics were similar across treatment groups, except for duration of diabetes (P = 0.046), as shown in Table 1. Common concomitant medications included principally medications for diabetes (metformin, thiazolidinediones,

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Ineligibility (1) Adverse event (33) Treatment failure (2) Subject withdrew consent (8) Investigator judgment (0) Protocol noncompliance (4) Lost to follow-up (3) Termination of study or withdrawal of subject by sponsor (0) Other (1)

n = 51 Discontinued

n = 123 Placebo

Dextromethorphan/Quinidine for Diabetic Neuropathic Pain

Table 1 Demographic and baseline clinical characteristics (intent-to-treat population) DMQ 45/30 mg b.i.d. 131

125

81 (61.8) 50 (38.2) 61.0 (10.4) 62.0 (28.0–82.0)

Placebo 123

85 (68.0) 40 (32.0) 59.8 (10.1) 58.0 (34.0–81.0)

68 (55.3) 55 (44.7) 62.0 (9.8) 62.0 (32.0–86.0)

112 15 4 97.4

(85.5) (11.5) (3.1) (23.0)

111 8 6 101.7

(88.8) (6.4) (4.8) (26.6)*

97 22 4 98.8

(78.9) (17.9) (3.3) (23.3)†

9 122 7.3 12.3 4.0 3.8 93/97

(6.9) (93.1) (1.4)‡ (10.5)‡ (4.0)‡ (4.7) (95.9)

4 121 7.2 9.4 3.6 3.0 84/99

(3.2) (96.8) (1.3)* (7.6)* (4.0)* (3.4)* (84.8)

3 120 7.4 11.5 3.8 3.2 90/98

(2.4) (97.6) (1.7) (9.6) (3.6) (3.3) (91.8)

4.9 4.0 2.1 4.1

(2.4)§ (2.8)†† (0.9)†† (2.7)§

4.7 4.2 2.0 3.9

(2.4)¶ (2.8)‡‡ (1.0)¶¶ (2.6)¶

4.4 4.0 2.0 3.7

(2.5)** (2.8)§§ (1.0)§§ (2.8)**

2.5 (0.6) 61.9 (15.7)

2.5 (0.6) 61.0 (15.1)

2.4 (0.6) 61.5 (15.8)†

* n = 124. † n = 122. ‡ n = 130. § n = 116. ¶ n = 111. ** n = 117. †† n = 112. ‡‡ n = 107. §§ n = 113. ¶¶ n = 106. b.i.d. = twice daily; DM = dextromethorphan; DMQ = dextromethorphan/quinidine; PN QoL = Peripheral Neuropathy Quality of Life; SD = standard deviation.

sulfonamides, and insulin), antihypertensives (angiotensinconverting enzyme [ACE] inhibitors, angiotensin II receptor blockers, beta-blockers, and diuretics), lipid-lowering agents (hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors), acetylsalicylic acid, and multivitamins. Prior pain medication use was comparable among the three treatment groups, with 52.0% to 55.7% having taken at least one such medication. Gabapentin had been the most commonly used, by 26.7%, 23.2%, and 28.5% of patients in the DMQ 45/30-mg, DMQ 30/30-mg, and placebo groups, respectively. Others had been used by