Impact of Disease Characteristics on the Efficacy of Duloxetine in Diabetic Peripheral Neuropathic Pain

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1 Pathophysiology/Complicatios O R I G I N A L A R T I C L E Impact of Disease Characteristics o the Efficacy of Duloxetie i Diabetic Peripheral Neuropathic Pai DAN ZIEGLER, MD, FRCP(E) 1 YILI L. PRITCHETT, PHD 2 FUJUN WANG, PHD 2 DURISALA DESAIAH, PHD 2 MICHAEL J. ROBINSON, MD 2 JERRY A. HALL, MD 2 AMY S. CHAPPELL, MD 2 OBJECTIVE To evaluate the impact of baselie disease variables related to diabetes ad diabetic europathy severity o efficacy ad safety of duloxetie i the maagemet of diabetic peripheral europathic pai. RESEARCH DESIGN AND METHODS The impact of baselie coditios was evaluated usig the data from three pooled placebo-cotrolled studies for combied duloxetie, doses of 60 mg q.d. ad 60 mg b.i.d., versus placebo. The primary efficacy measure was the weekly mea of 24-h average pai severity, ad ight pai was the secodary measure. Safety ad tolerability were assessed. RESULTS There were o sigificat (P 0.10) iteractios of treatmet by age ( 65 or 65 years), type of diabetes (type 1 or type 2), duratio of diabetes (media split 9.18 or 9.18 years), duratio of diabetic europathy ( 2,2to 6, or 6 years), severity of diabetic europathy (baselie Michiga Neuropathy Screeig Istrumet score 5 or 5), baselie A1C level (media split 7.6 or 7.6%), or baselie isuli use (yes/o). Sigificat iteractios for both pai measures were observed i baselie pai subgroups (Brief Pai Ivetory average pai, 6 ad 6). Duloxetie was more effective i the subgroup with more pai. No sigificat associatio was foud betwee ay other subgroups (P 0.10). Sigificat iteractios (P 0.1) occurred with treatmet-emerget adverse evets whe stratified by subgroups. CONCLUSIONS Pai severity but ot variables related to diabetes or europathy may predict the effects of duloxetie i diabetic peripheral europathic pai. The efficacy of duloxetie is related to the iitial pai severity ad is geeralizable across a broad spectrum of diabetic patiets, icludig those with the highest severity of diabetes or europathy. Diabetic europathy has bee reported i approximately oe-third of patiets with diabetes (1). The most commoly reported form of europathy is polyeuropathy, also called diabetic peripheral europathy, a commo ad debilitatig complicatio of diabetes (2). Pai i the feet characterized as sharp, stabbig, or burig is observed i 16 Diabetes Care 30: , % of diabetic patiets (3,4). They also may complai of pai i respose to ormally opaiful stimuli (allodyia). Serotoergic ad oradreergic euros have bee implicated i the mediatio of edogeous pai ihibitory mechaisms via descedig ihibitory pai pathways i the brai ad spial cord (5,6). I pathological pai states, From the 1 Germa Diabetes Ceter, Leibiz Istitute at the Heirich Heie Uiversity, Düsseldorf, Germay; ad 2 Lilly Research Laboratories, Eli Lilly ad Compay, Idiaapolis, Idiaa. Address correspodece ad reprit requests to Prof. Dr. Da Ziegler, FRCPE, Germa Diabetes Ceter, Leibiz Istitute at the Heirich Heie Uiversity, Auf m Heekamp 65, Düsseldorf, Germay. da.ziegler@ddz.ui-duesseldorf.de. Received for publicatio 29 September 2006 ad accepted i revised form 11 December D.Z. has received hooraria for speakig ad cosultig activities ad research grats from Eli Lilly. Y.L.P., F.W., ad A.S.C. hold stock i Eli Lilly. Y.L.P. is a full-time employee of Abbot Laboratories ad a former employee of Eli Lilly. F.W., D.D., M.J.R., ad J.A.H. are employees of Eli Lilly. Abbreviatios: DPNP, diabetic peripheral europathic pai. A table elsewhere i this issue shows covetioal ad Système Iteratioal (SI) uits ad coversio factors for may substaces. DOI: /dc Cliical trial reg. o. NCT , cliicaltrials.gov by the America Diabetes Associatio. The costs of publicatio of this article were defrayed i part by the paymet of page charges. This article must therefore be hereby marked advertisemet i accordace with 18 U.S.C. Sectio 1734 solely to idicate this fact. these edogeous pai ihibitory mechaisms may be dysfuctioal, cotributig to the cetral sesitizatio ad hyperexcitability of the spial ad supraspial pai trasmittig pathways ad maifestig as several types of persistet pai, icludig europathic pai (7). Duloxetie hydrochloride, a potet serotoi (5-HT) ad orepiephrie reuptake ihibitor (8), has bee approved for the maagemet of diabetic peripheral europathic pai (DPNP) ad for the treatmet of major depressive disorder. I all three placebo-cotrolled trials coducted i patiets with DPNP, duloxetie demostrated efficacy i reducig pai severity i patiets with DPNP at 60 mg oce daily ad twice daily (9 11). A umber of baselie diabetes/ diabetic peripheral europathy disease characteristics, as well as patiet demographics, may affect the effectiveess of pharmacological maagemet of DPNP. For istace, pharmacotherapy of chroic pai presets special problems i elderly patiets, which may be attributed, i part, to age-associated chages i the metabolism ad clearace rate of drugs (12). It is difficult to treat chroic pai adequately i elderly patiets without adverse effects (13). Studies also have show geder differeces i the perceptio of pai itesity for both acute ad chroic pai i respose to aalgesics (14). Baselie pai severity also may affect treatmet outcome. It has bee reported that greater pai severity may be associated with substatial patiet burde resultig from iterferece with daily fuctioig, especially i patiets with suboptimal pai maagemet (15). The objective of this aalysis was to evaluate the impact of various baselie disease characteristics o the efficacy ad safety of duloxetie i the maagemet of DPNP, usig pooled data from three cliical studies. RESEARCH DESIGN AND METHODS The preset aalysis was based o pooled data from three 12- week, double-blid, radomized, placebo-cotrolled, multiceter trials (studies 1 3). Etry criteria ad study desigs 664 DIABETES CARE, VOLUME 30, NUMBER 3, MARCH 2007

2 Ziegler ad Associates Table 1 Baselie characteristics of patiets i three pooled DPNP studies were early idetical for all three of these phase 3 cliical trials (9 11). For study 1, patiets ( 457) were radomly assiged to duloxetie, 20 mg q.d., 60 mg q.d., or 60 mg b.i.d., or placebo i a 1:1: 1:1 ratio for the 12-week therapy phase, as determied by a computer-geerated radom sequece usig a iteractive voice respose system. Patiets were see weekly for the first 5 weeks of treatmet ad biweekly thereafter. Studies 2 ad 3 had a idetical desig ad assessed the efficacy ad safety of 60 mg q.d. ad 60 mg b.i.d. duloxetie. I studies 2 ad 3, patiets were radomly assiged to duloxetie, 60 mg q.d. or 60 mg b.i.d., or placebo i a 1:1:1 ratio. The duratio of treatmet for studies 2 ad 3 was 12 weeks of active treatmet plus a 1-week taper phase. Patiet selectio The etry ad exclusio criteria were idetical i all three trials. Patiets were eligible for the study if they were 18 years old with type 1 or type 2 diabetes ad bilateral peripheral europathic pai of at least moderate severity. The patiets pai had to begi i the feet ad with relatively symmetrical oset. The daily pai must have bee preset for at least 6 moths, ad the diagosis of diabetic peripheral europathy was to be cofirmed by a score of 3 o the Michiga Neuropathy Screeig Istrumet (16). Patiets with axis 1 psychiatric disorders were excluded (17,18). Placebo Duloxetie Sex (M) 181 (53.4) 391 (57.1) Age (years) 61.1 ( ) 59.6 ( ) Weight (kg) 92.0 ( ) 91.0 ( ) Origi Caucasia 291 (85.8) 585 (85.4) Hispaic 29 (8.6) 64 (9.3) Africa descet 16 (4.7) 20 (2.9) Other 3 (0.9) 16 (2.3) Type of diabetes Type 1 36 (10.6) 84 (12.3) Type (89.4) 601 (87.7) Duratio of diabetes (years) 9.2 ( ) 9.2 ( ) Duratio of diabetic europathy (years) 2.7 ( ) 2.7 ( ) Michiga Neuropathy Screeig Istrumet 5.0 ( ) 5.0 ( ) Data are (%) or medias (rage). The rages for the media values i this table are 5 95% miimum ad maximum. Efficacy measures The primary efficacy measure for all three studies was the weekly mea of the 24-h average pai scores (computed from the patiet diary scores), as measured by a 11-poit (0 o pai, 10 worst possible pai) Likert scale. A secodary efficacy measure was ight pai (recorded daily by patiets i a diary ad calculated weekly), as measured by the 11-poit Likert scale. The cosistecy of the effect of duloxetie (60 mg q.d. ad b.i.d. pooled) o both 24-h average pai ad ight pai severity was assessed i subgroups of patiets stratified by age ( 65 years, oelderly, or 65 years, elderly), type of diabetes (type 1or type 2), duratio of diabetes (media split 9.18 or 9.18 years), duratio of diabetic europathy ( 2,2to 6, or 6 years), severity of europathy (baselie Michiga Neuropathy Screeig Istrumet score media split 5 or 5), baselie pai severity (Brief Pai Ivetory average pai, mea split 6 or 6), baselie A1C level (media split 7.6 or 7.6%), ad baselie isuli use (yes/o) from pooled data of the three placebo-cotrolled studies. Safety ad tolerability assessmets Safety ad tolerability were assessed by comparig differet duloxetie doses (60 mg q.d. ad b.i.d.) with placebo. Safety measures icluded discotiuatios due to adverse evets, treatmet-emerget adverse evets, vital sigs (sittig blood pressure ad heart rate), ad laboratory aalytes. Fastig glucose, lipids, A1C, ad other cliical chemistries were determied by stadard techiques at a cetral laboratory (Covace Laboratories, Priceto, NJ). Statistical aalysis All aalyses were coducted o a itetto-treat basis. Data from all three studies were pooled to gai adequate statistical power to test treatmet-by-subgroup iteractio. Duloxetie, 20 mg q.d., i study 1 was ot icluded i the aalyses because of its lack of efficacy (9). Baselie was defied as the last omissig observatio at or before radomizatio, ad ed poit was defied as the last o-missig observatio i the acute therapy phase. For the efficacy measures, chages i 24-h average pai severity ad ight pai severity from baselie to ed poit were evaluated usig the ANCOVA model with the terms of treatmet, study, ad baselie. For subgroup aalysis, the additioal terms subgroup ad treatmetby-subgroup iteractio were added to the above ANCOVA model ad tested usig the type II sum of squares. The treatmet-by-subgroup iteractio was evaluated at the sigificace level of Usig sigificace level 0.1 for the iteractio test is cosidered more covetioal tha 0.05 for testig iteractio (19). The word iteractio is to evaluate the cosistecy of respose to duloxetie treatmet betwee (or across) differet strata of a subgroup (example: age 65 vs. 65). For safety measures, chages i cotiuous measures were evaluated usig a ANOVA model with the terms of treatmet ad study. The rak-trasformed chages for laboratory data were used i the model, sice the distributio of raw data for most of the aalytes was skewed. Categorical data were aalyzed usig the Cochra-Matel-Haeszel test stratified by study. Throughout this article, the term sigificat idicates statistical sigificace, ad whe presetig efficacy results, the mea chage refers to least-squares mea chage. RESULTS Patiet demographics ad characteristics Baselie demographics ad characteristics of patiets i all three studies are summarized i Table 1. A majority of the DIABETES CARE, VOLUME 30, NUMBER 3, MARCH

3 Duloxetie efficacy ad baselie DPNP severity Table 2 Least squares mea chage of 24-h average pai severity from baselie to ed poit, overall ad by subgroups Placebo (chage) Duloxetie (chage) P Therapy by subgroup P Overall ( 1.58) ( 2.62) Age (years) ( 1.64) ( 2.66) ( 1.44) ( 2.52) Type of diabetes Type ( 1.60) ( 2.25) Type ( 1.57) ( 2.67) Duratio of diabetes (years) ( 1.60) ( 2.46) ( 1.55) ( 2.76) Duratio of diabetic europathy (years) ( 1.50) ( 2.56) to ( 1.56) ( 2.64) ( 1.78) ( 2.68) Baselie MNSI score ( 1.80) ( 2.65) ( 1.48) ( 2.60) BPI average pai ( 1.39) ( 2.12) ( 1.76) ( 3.07) Baselie A1C level ( 1.70) ( 2.60) ( 1.45) ( 2.63) Baselie isuli use No ( 1.49) ( 2.64) Yes ( 1.65) ( 2.54) Sex Female ( 1.61) ( 2.72) Male ( 1.56) ( 2.56) Origi Caucasia ( 1.48) ( 2.53) Other ( 2.73) ( 3.75) BPI, Brief Pai Ivetory; MNSI, Michiga Neuropathy Screeig Istrumet. *Mea at baselie; least squares mea chage from baselie to ed poit; compariso of mea chages betwee the two treatmets. patiets i these studies were Caucasia (85.5%), with a mea age of 59.8 years. No sigificat differeces were observed betwee the duloxetie ad placebo groups. Efficacy i 24-h average pai severity ad ight pai severity Subgroup aalyses from pooled data of all three studies showed that for the 24-h average pai severity ad ight pai scores, there were o statistically sigificat iteractios of treatmet by age, type of diabetes, duratio of diabetes, duratio of diabetic europathy, severity of europathy, baselie A1C level, ad baselie isuli use (Tables 2 ad 3). Similar results also were observed i sex ad ethicity subgroups. Treatmet-by-baselie severity iteractios were sigificat for both efficacy measures (P for 24-h average pai ad P for ight pai severity). Duloxetie s effect was sigificatly greater tha placebo for either subgroup, whereas the magitude of treatmet group differece was greater for idividuals with more severe pai at baselie (Tables 2 ad 3). Safety ad tolerability Whe the icidece of discotiuatio due to adverse evets was ivestigated i patiet subgroups stratified by age, sex, type of diabetes, ad baselie isuli use, o statistically sigificat (P 0.10) treatmet-by-subgroup iteractios were observed. The icidece of treatmet-emerget adverse evets was aalyzed from pooled data of three DPNP studies for duloxetie, 60 mg q.d. or 60 mg b.i.d., ad placebo groups, ad the results are summarized i Table 4. I patiets treated with duloxetie, treatmet-emerget adverse evets had a 5% icidece ad twice the icidece for placebo-treated patiets, ad the majority of them were sigificatly (P 0.05) differet from the placebo group. The icidece of treatmetemerget adverse evets also was aalyzed i subgroups stratified by age, sex, type of diabetes, ad baselie isuli use. Sigificat treatmet-by-subgroup iteractios were observed for the followig treatmet-emerget adverse evets: costipatio i age subgroups (P 0.085), fatigue ad diarrhea i sex subgroups (P ad P 0.053, respectively), ausea i type of diabetes subgroups (P 666 DIABETES CARE, VOLUME 30, NUMBER 3, MARCH 2007

4 Ziegler ad Associates Table 3 Least squares mea chage of ight pai severity from baselie to ed poit, overall ad by subgroups Placebo (chage) Duloxetie (chage) P Therapy by subgroup P Overall ( 1.93) ( 2.82) Age (years) ( 2.08) ( 2.86) ( 1.61) ( 2.73) Type of diabetes Type ( 1.63) ( 2.58) Type ( 1.96) ( 2.85) Duratio of diabetes (years) ( 1.90) ( 2.62) ( 1.94) ( 3.02) Duratio of diabetic europathy (years) ( 1.85) ( 2.72) to ( 1.86) ( 2.84) ( 2.30) ( 2.93) Baselie MNSI score ( 2.12) ( 2.88) ( 1.85) ( 2.79) BPI average pai ( 1.69) ( 2.23) ( 2.15) ( 3.37) Baselie A1C level ( 1.83) ( 2.69) ( 2.02) ( 2.95) Baselie isuli use No ( 1.79) ( 2.76) Yes ( 2.05) ( 2.82) Sex Female ( 2.07) ( 3.01) Male ( 1.84) ( 2.70) Origi Caucasia ( 1.78) ( 2.68) Other ( 2.76) ( 3.67) BPI, Brief Pai Ivetory; MNSI, Michiga Neuropathy Screeig Istrumet. *Mea at baselie; least squares mea chage from baselie to ed poit; compariso of mea chages betwee the two treatmets ), ad ausea i baselie isuli subgroups (P 0.042). Whe the mea chages of diastolic blood pressure ad heart rate were ivestigated i patiet subgroups stratified by age, sex, ad type of diabetes, there were o statistically sigificat treatmet-bysubgroup iteractios. For the mea chage of fastig glucose level, there was o sigificat iteractio of treatmet by age, sex, type of diabetes, or baselie isuli use. CONCLUSIONS The subgroup aalyses for both pai severity scores showed that there were few statistically sigificat (P 0.10) iteractios of treatmet by subgroups stratified by various baselie characteristics, suggestig that the effectiveess of duloxetie is i- Table 4 Icidece of treatmet-emerget adverse evets occurred at a rate of >5% ad twice the rate of placebo i duloxetie-treated patiets from pooled data of three DPNP studies Placebo Duloxetie, 60 mg q.d. Duloxetie, 60 mg b.i.d Nausea 29 (9) 84 (24)* 91 (27)* Somolece 17 (5) 53 (15)* 66 (19)* Dizziess 19 (6) 38 (11)* 43 (13)* Diarrhea 23 (7) 39 (11)* 23 (7) Fatigue 18 (5) 31 (9) 36 (11)* Costipatio 8 (2) 27 (8)* 42 (12)* Hyperhidrosis 5 (2) 28 (8)* 33 (10)* Dry mouth 10 (3) 21 (6)* 33 (10)* Vomitig 10 (3) 18 (5) 20 (6) Decreased appetite 2 (1) 10 (3)* 29 (9)* Astheia 3 (1) 12 (4)* 23 (7)* Aorexia 2 (1) 14 (4)* 20 (6)* Data are (%). *Sigificatly differet from placebo (P 0.05). DIABETES CARE, VOLUME 30, NUMBER 3, MARCH

5 Duloxetie efficacy ad baselie DPNP severity variat with respect to those baselie characteristics examied. The treatmetby-baselie severity assessmet was ot a qualitative measure. Amog the baselie variables ivestigated, sigificat treatmet-by-baselie severity (Brief Pai Ivetory average pai, 6 ad 6) iteractios were observed for both pai efficacy measures. These data suggest that duloxetie is more effective i patiets with higher baselie pai severity or that there is a larger drug-placebo differece i patiets with greater pai. We caot exclude the statistical pheomeo of a regressio toward the mea, as i both the placebo ad duloxetie groups with a higher baselie 24-h average pai; ight pai severity is reduced to a higher degree tha i idividuals with a lower baselie 24-h average pai. However, 24-h pai severity i patiets with a higher versus lower baselie 24-h average pai shows a somewhat stroger reductio i the duloxetie group tha i the placebo group, supportig the otio that the drug is particularly useful i patiets with severe 24-h europathic pai. The subgroup aalyses for the efficacy measures preseted here focused o weekly mea chages of the 24-h average pai severity ad ight pai scores. Farrar et al. (20) aalyzed the pooled results of 10 placebo-cotrolled studies ivolvig patiets with chroic pai sydromes (diabetic europathy, postherpetic euralgia, chroic low back pai, fibromyalgia, ad osteoarthritis) to corroborate the associatio betwee chage i pai itesity umeric ratig scale ad a improvemet i quatifiable measures of cliical status. The aalysis showed that, o average, a reductio of 2 poits from baselie o a 11-poit pai ratig scale (equivalet to a 30% reductio o pai severity from baselie) correspods to a cliically meaigful improvemet (20). I the preset aalysis, the mea chages of the 24-h average pai severity were reduced i the rage of poits across all the subgroups with duloxetie treatmet ad poits with placebo treatmet, thus supportig the cliical relevace of duloxetie s efficacy i the maagemet of DPNP. Sigificatly more patiets treated with duloxetie were discotiued because of adverse evets compared with patiets treated with placebo, ad o associatio betwee the baselie characteristics examied ad the tolerability of duloxetie was observed. There were statistically sigificat treatmet-by-subgroup iteractios for several treatmet-emerget adverse evets, icludig costipatio, fatigue, diarrhea, ad ausea i age, sex, type of diabetes, ad baselie isuli use subgroups, respectively. The absece of sigificat cardiovascular chages due to duloxetie therapy i the preset aalyses ad other published reports (9,10) suggests that patiets with diabetes udergoig duloxetie treatmet do ot require additioal itesive assessmet of their cardiovascular status. Duloxetie-treated patiets had a statistically sigificat decrease i A1C i these short-term studies ( 0.09%; P 0.013). It is uclear how duloxetie might affect glucose homeostasis, but some oradreergic atidepressats (e.g., desipramie) have show to modulate glucose homeostasis (21). It has bee reported that icreased oradreergic effects may be associated with elevatio of blood glucose i humas, sice catecholamies ca promote hyperglycemia through multiple mechaisms (e.g., ihibitio of isuli secretio, stimulatio of glucoeogeesis, ad decrease i isuli sesitivity) (22). The preset aalysis has several limitatios. The results are based o post hoc aalyses from pooled data of three acute treatmet trials of weeks ad may ot be geeralized to a loger duratio of treatmet of DPNP, a chroic coditio requirig maagemet for 12 weeks. Because patiets were selected from those with very limited or stable medical coditios ad stable doses of cocomitat medicatios, the applicability of these cotrolled cliical trial results to typical outpatiets is limited. I coclusio, the preset aalyses suggest that duloxetie was effective ad well-tolerated i the maagemet of DPNP, ad its effectiveess was ivariat with respect to diabetes ad/or diabetic peripheral europathy baselie coditios, except for pai severity. Diabetesrelated determiats such as duratio or type of diabetes, glycemic cotrol, ad isuli treatmet do ot predict the effects of duloxetie i DPNP. The same holds true for the duratio ad severity of the europathic process itself. Thus, the efficacy of duloxetie is ot limited to particular subgroups but rather is geeralizable across a broad spectrum of diabetic patiets, icludig those showig the highest degrees of severity of diabetes or europathy. I cotrast, efficacy may eve be ehaced i cases with relatively high pai itesity. Ackowledgmets The authors thak the Du-Flu Product Team at Eli Lilly, the may patiets for their volutary participatio i the three cliical trials, the pricipal ivestigators, ad the statistical aalysts. They also thak Jimmy Y. Xu, PhD, for the iitial draftig of this mauscript ad Elizabeth A. Agostielli, MA, for editorial review. All authors accept full resposibility for the coduct of this aalysis, were give full access to all data from the aalysis, ad participated i the decisio to publish the data. Refereces 1. Shaw JE, Zimmet PZ, Gries FA, Ziegler D: Epidemiology of diabetic europathy. I Textbook of Diabetic Neuropathy. Gries FA, Camero NE, Low PA, Ziegler D, Eds. 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