Study design:

This was a Phase 3, multinational, open-label, randomized controlled, 52-week safety study, conducted in Europe between November 2011 and February 2014 (ClinicalTrials.gov Identifier: NCT01478607). The primary objective was to evaluate the safety of repeat treatment with the capsaicin 8% patch in patients with PDPN. Secondary objectives included the evaluation of effectiveness.

Following a screening visit, patients were assigned a six-digit subject number allocated sequentially according to site and randomized to capsaicin 8% patch (with 30-minute application) plus SOC, capsaicin 8% patch (with 60-minute application) plus SOC, or SOC alone in a 1:1:1 ratio by chronological order of enrollment to receive treatment with the capsaicin 8% patch to painful areas of the feet for either 30 minutes (30-min) plus SOC, 60 minutes (60-min) plus SOC, or SOC alone. All patients were pretreated with a eutectic mixture of local anesthetics (EMLA), containing lidocaine 2.5% and prilocaine 2.5%, to limit pain or discomfort during the application period. Duration of application was selected to reflect similar durations as investigated in previous trials with capsaicin 8% patch and to ensure sufficient exposure to investigate its safety and tolerability. SOC was optimized for each patient at the discretion of each investigator and assessed at clinic visits, with no constraints imposed on the mode of treatment. The treatment area was mapped at screening and baseline visits, and re-mapped before treatment. Mapping of the treatment area(s) was identified based primarily on the patient self-report in response to specific questioning and confirmation by sensory testing. Treatment borders were defined by the most painful areas of the feet, up to a total combined surface area of 1,120 cm² (four patches) for both feet. Assessments were scheduled every 2 months; clinic visits were scheduled for Months 2, 4, 6, 8, 10, and 12, and telephone contact was scheduled for Months 1, 3, 5, 7, 9, and 11. Capsaicin 8% patch re-treatment could occur at both scheduled and unscheduled clinic visits at the investigator’s discretion, but only after at least 8 weeks had elapsed since the last treatment Figure 1. Patients could not receive more than seven capsaicin 8% patch treatments during the study.

Figure 1

*Capsaicin 8% patch treatment (Groups 1 and 2) took place at visit 2 andif warranted at scheduled visits (P) or unscheduled visits at intervals of atleast 8 weeks. EoS visit for Groups 1 and 2 took place between 8 and 12 weeksafter last patch application if patch was applied at Visit 8 (Month 12) andbetween Week 52 and 56 for patients without a patch application at Visit 8(Month 12). EoS visit for Group 3 took place between Week 52 and 56.

EoS, end of study; SOC, standard of care.

Patient disposition:

Of the 555 screened patients, a total of 468 patients were randomized at 71 centers across 11 European countries (30-min plus SOC, n=156; 60-min plus SOC, n=157; SOC alone, n=155). A total of 388 patients completed the study (30-min plus SOC, n=132; 60-min plus SOC, n=128; SOC alone, n=128); and 80 patients (17.1%) discontinued the study post baseline, most commonly due to withdrawal of consent (n=44) and adverse events (n=18;Figure 2).

SOC: standard of care.

A total of 468 patients were randomized to capsaicin 30-min plus SOC (n=156), capsaicin 60-min plus SOC (n=157), or SOC alone (n=155).

Baseline characteristics were similar and groups were comparable across age (mean 60.4 years (SD 10.52)), BMI (mean 30.44, (SD 4.836), glycated hemoglobin (mean 7.38 (SD 1.003)), average daily pain (5.6 (SD 1.32)), duration of PDPN (4.3 years (SD 3.72)), and use of prior treatments for PDPN (including pain medications and SOC) 21. The most commonly prescribed categories of pain medications at baseline and during the study were analgesics and anti-epileptics Table 2; the most commonly prescribed individual drugs for pain during the study were gabapentin and pregabalin Table 3.

Table 2

Parameter	Capsaicin 8% patch (30 min) + SOC (n=156)	Capsaicin 8% patch (60 min) + SOC (n=157)	SOC (n=155)
Pain medications before baseline, n (%)
Overall	70 (44.9)	71 (45.2)	79 (51.0)
Analgesicsa	56 (35.9)	54 (34.4)	59 (38.1)
Antiepileptics	44 (28.2)	49 (31.2)	52 (33.5)
Psycholeptics	22 (14.1)	19 (12.1)	24 (15.5)
Anti-inflammatory/antirheumatic products	14 (9.0)	12 (7.6)	17 (11.0)
Topical joint/antirheumatic products	14 (9.0)	11 (7.0)	15 (9.7)
BPI-DN Brief pain inventory diabetic neuropathy, HbA1c glycosylated haemoglobin of A1c, PDPN painful diabetic peripheral neuropathy, QOL-DN Quality-of-life questionnaire for diabetic neuropathy, SD standard deviation, SOC standard of careaAnalgesics included anilides, natural opium alkaloids, other analgesics and antipyretics, other opioids, pyrazolones and salicylic acid and derivatives Anti-inflammatory preparations, non-steroidals for topical use, preparations with salicylic acid derivatives

The average interval between each capsaicin re-treatment was 68.4 days in the capsaicin 30-min group and 68.3 days in the 60-min group. The mean number of patches used per application was similar between capsaicin groups (30-min, 1.53; 60-min, 1.42) and the mean duration of patch application was 30.2 minutes in the 30-min group and 60.2 minutes in the 60-min group.

Table 3

Pain medicationa	Capsaicin 8% patch(30 min) + SOC (n = 156)	Capsaicin 8% patch(60 min) + SOC (n = 157)	SOC (n = 155)
Overall, n (%)	98 (62.8)	105 (66.9)	107 (69.0)
Most commonly used drugs (>5% patients in any group), n (%)
Gabapentin	26 (16.7)	26 (16.6)	35 (22.6)
Pregabalin	24 (15.4)	22 (14.0)	39 (25.2)
Paracetamol	23 (14.7)	36 (22.9)	6 (3.9)
Tramadol	16 (10.3)	14 (8.9)	6 (3.9)
Diclofenac	12 (7.7)	13 (8.3)	12 (7.7)
Ibuprofen	11 (7.1)	15 (9.6)	14 (9.0)
Metamizole	10 (6.4)	10 (6.4)	5 (3.2)
Duloxetine	9 (5.8)	3 (1.9)	10 (6.5)
Carbamazepine	7 (4.5)	14 (8.9)	10 (6.5)
Alpha lipoic acid	3 (1.9)	1 (0.6)	8 (5.2)
SOC standard of careaMedication identified as ‘pain medication” YES on electronic case report from (eCRF)

Table 4

Number of patch applications	QUTENZA (30 min) + SOC (N=156) n (%)	QUTENZA (60 min) + SOC (N=157) n (%)	QUTENZA + SOC (N=313) n (%)
1 Application	7 (4.5)	6 (3.8)	13 (4.2)
2 Applications 5 (3.2) 12 (7.6) 17 (5.4)
3 Applications	15 (9.6)	8 (5.1)	23 (7.3)
4 Applications	7 (4.5)	11 (7.0)	18 (5.8)
5 Applications	14 (9.0)	10 (6.4)	24 (7.7)
6 Applications	24 (15.4)	27 (17.2)	51 (16.3)
7 Applications	84 (53.8)	83 (52.9)	167 (53.4)
N: Number of patients in the intention to treat set; n: Number of patients in the sample; SOC: Standard of care.

Over half of the patients in the capsaicin 8% patch groups received the maximum seven capsaicin treatments (167/313 [53.4%]; Table 4 ).

Efficacy :

Average pain:

Greater mean percentage reductions in average pain were seen, versus SOC alone, with both capsaicin plus SOC groups throughout the study period from Month 1, and this difference was maintained and increased by Month 12.

Figure 3

From baseline to EoS, mean percentage (standard deviation [SD]) changes in average pain were: −37.5% (32.9) for the 30-min group, −40.8% (39.7) for the 60-min group, and −13.9% (74.6) for SOC alone. The estimated mean between-group differences versus SOC alone (95% CI) were −23.7% (−35.5, −11.9) for the 30-min group and −26.9% (−38.7, −15.2) for the 60-min group.

Pain intensity:

A greater reduction in the total BPI-DN Pain Severity Index was observed for both capsaicin plus SOC groups versus SOC alone from baseline to EoS Figure 4. The mean (SD) change from baseline to EoS was −1.9 (1.8), −2. 2 (1.9), and −0.9 (1.7) with capsaicin 30-min plus SOC, capsaicin 60-min plus SOC, and SOC alone, respectively. The estimated mean difference (90% CI) between capsaicin 30-min and 60-min versus SOC was −0.9 (−1.3, −0.6) and −1.2 (−1.6, −0.9), respectively.

Greater reductions from baseline to EoS were observed in worst daily pain, least daily pain, average daily pain, and pain right now in both capsaicin plus SOC groups versus SOC Figure 4 .

Figure 4

Pain interference:

A greater reduction in total BPI-DN Pain Interference Index was also observed with both capsaicin plus SOC groups versus SOC alone from baseline to EoS Figure 4. The mean (SD) change from baseline to EoS was −1.9 (2.1), −2.0 (2.3), and −0.8 (1.9) with capsaicin 30-min plus SOC, capsaicin 60-min plus SOC, and SOC alone, respectively. The mean difference (90% CI) for capsaicin 30-min and 60-min versus SOC was −1.0 (−1.4, −0.6) and −1.2 (−1.6, −0.8), respectively. Greater reductions from baseline to EoS were observed in pain interference with general activity, mood, walking ability, normal working relations, sleep and enjoyment of life in both capsaicin plus SOC groups than in the SOC alone group (Figure 4).

Responder analyses:

A greater proportion of patients in the capsaicin plus SOC groups had ≥30% reduction in average pain (30-min, 67.3%; 60-min, 67.5%), compared with SOC alone (40.6%) Figure 5. By Month 1, 28.6% of patients in the 30-min group and 22.6% in the 60-min group achieved a 30% response, compared with 14.3% of patients receiving SOC alone. These trends were similar for the proportion of patients with ≥50% reduction in average pain (30-min, 44.8%; 60-min, 48.4%; SOC, 23.8%) (Figure 5). By Month 1, 20.0% of patients in the 30-min group and 21.1% of those in the 60-min group achieved a 50% response, compared with no patients receiving SOC alone.

Figure 5

In a post-hoc analysis of all subjects who received seven applications of 179mg capsaicin cutaneous patch (n=167), the ³30% responder rate increased steadily with each application from 32.3% to 47.0%, 50.0%, and finally to 74.1%, 2 months after the first, second, third, and seventh (i.e. last application), respectively Figure 6.

Figure 6

Patient Global Impression of Change

By EoS, greater improvements in the patients’ impression of how much they had changed since starting treatment were observed in both capsaicin plus SOC groups versus SOC alone Figure 4. More patients in both capsaicin plus SOC groups (30-min, 24.2%; 60-min, 24.5%), compared with SOC alone (9.5%) felt ‘very much improved’ or ‘much improved’ and fewer felt worse by EoS Figure 7.

Quality of life:

EQ-5D utility index:

A greater mean (SD) improvement in EQ-5D utility index from baseline to Month 12 was observed with capsaicin 8% patch 30-min plus SOC (0.12) and 60-min plus SOC (0.15) versus SOC alone (0.07).

Regarding the EQ-5D items, a greater proportion of patients at EoS in both capsaicin plus SOC arms, versus SOC alone, had no problems with mobility, self-care, usual activities, pain or discomfort, and anxiety or depression Figure 8.

EQ-5D VAS:

A greater improvement in mean (SD) EQ-5D VAS score was observed from baseline to the EoS with the capsaicin 30-min plus SOC (10.4 [18.5]) and capsaicin 60-min plus SOC (11.2 [21.4]) versus SOC alone (5.5 [18.1]) Figure 9. The mean (95% CI) difference with capsaicin 30-min and 60-min versus SOC alone was 4.9 (1.1–8.6) and 5.7 (2.0–9.4), respectively.

Figure 8

Figure 9

Self-Assessment of Treatment (SAT)

At EoS, a greater proportion of patients in both capsaicin plus SOC groups versus SOC alone reported improvements in pain level, activity level, and QoL. A greater proportion of 179mg capsaicin cutaneous patch-treated patients also indicated their willingness to undergo treatment again, and also preferred 179mg capsaicin cutaneous patch treatment over their previous treatment Figure 10. The improvements were comparable between the capsaicin groups.

Figure 10

Concomitant Pain Medication

In general, the use of concomitant pain medication remained stable in all treatment arms from baseline to EoS. The most frequently used treatments were anti-epileptic drugs by approximately one-third of the patients at baseline across treatment arms. In the 179mg capsaicin cutaneous patch arms, the proportion of patients using anti-epileptics at EoS was comparable with the proportion reported at baseline. In contrast, at EoS, the proportion of patients using anti-epileptic drugs had increased by >10% in the SOC alone arm.

Use of antidepressants and opioids was relatively low (<20%) with small increases observed from baseline to EoS – more so in the SOC alone group Table 5.

Table 5

		QUTENZA(30 min) + SOC(N = 156)	QUTENZA(60 min) + SOC(N = 157)	SOC alone (N = 155)
Baseline
		156	157	155
	Antidepressants	17 (10.9)	8 (5.1)	12 (7.7)
	Antiepiletic drugs	44 (28.2)	49 (31.2)	50 (32.3)
	Opioids	17 (10.9)	9 (5.7)	13 (8.4)
End of study
		146	147	146
	Antidepressants	16 (11.0)	10 (6.8)	22 (15.1)
	Antiepileptic drugs	43 (29.5)	53 (36.1)	63 (43.2)
	Opioids	16 (11.0)	12 (8.2)	17 (11.6)
The medication was summarized on the day before baseline visit and on the day before the end of study visit,N: Number of patients; n: Number of patients in the sample; SOC Standard of care

While the efficacy of a single capsaicin 8% treatment has been previously described in patients with PDPN in a double-blind controlled trial 19, the present study, designed primarily to assess the safety and tolerability of multiple applications of 179mg capsaicin cutaneous patch, was also the first to assess the long-term effectiveness of repeated treatment over 52 weeks in this patient population. Measuring effectiveness over a prolonged period of time has the advantage of enabling assessment of patients’ longitudinal experience of the capsaicin 8% patch, compared with the more limited experience afforded by a typical 12-week study.

Patients in the groups receiving 30-minute or 60-minute applications of the capsaicin 8% patch plus SOC had a greater reduction in average pain compared with those receiving SOC alone from Month 1 onward. Importantly, this differential treatment effect was not only sustained, but increased progressively throughout the 52 weeks of the study, as illustrated by the 30% and 50% responder rates. At EoS, the 30% responder rate was substantially higher in both capsaicin 8% patch groups (both >67%) versus SOC alone (41%). The corresponding figures for the 50% responder rate were 45% for the capsaicin 8% groups, compared with 24% for SOC alone. By Month 1, the 30% responder rates for the capsaicin 8% groups were approximately double those for SOC alone, while the 50% responder rates for the capsaicin 8% groups (20.0% and 21.1% for 30-min and 60-min groups, respectively) contrasted with no patients in the SOC alone achieving 50% response. These findings reflect substantial differences between treatment with capsaicin 8% plus SOC and SOC alone.

Compared with SOC alone, repeat treatment with the capsaicin 8% patch plus SOC over 52 weeks was also associated with greater improvements in the BPI Pain Severity Index (a composite score including pain at its worst and at its least in the last 24 hours, average pain, and pain right now) and the extent to which pain interfered with a range of activities. These findings were further supported by results from the PGIC, which demonstrated that substantially more patients in the capsaicin plus SOC groups reported very much or much improvement by EoS. Furthermore, a greater proportion of patients in the capsaicin plus SOC groups reported improvement in QoL, compared with SOC alone. Coretti et al (2014) 23 reported that the minimal clinically importance difference for the EQ-5D utility index across 18 studies, including a range of diseases, ranged from 0.03 to 0.54, with a raw average across all studies of 0.18. In the present study, the change from baseline in this index was 0.12 and 0.15 for 179mg capsaicin cutaneous patch, 30-min plus SOC and 60-min plus SOC, respectively, and 0.07 for SOC alone.In addition to the aforementioned measures of effectiveness, patient satisfaction with treatment was also assessed in this study. Pain relief and patient satisfaction are distinct concepts identified by the Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT) as central to evaluating treatment of chronic pain. Pain relief measures are used to determine whether the patient has actually benefited from an intervention and provide valuable information on how effectively pain is being managed. In contrast, patient satisfaction measures capture the personal evaluation of the intervention provided. Patient satisfaction has been shown to affect patients’ health-related decisions and treatment-related behaviors, which in turn, can substantially impact the success of treatment outcomes. Patients’ satisfaction with their treatment also predicts continuance of pharmaceutical treatment, correct medication use, and compliance with medication regimens 24. In this study, there was a noteworthy difference between treatments, with a greater proportion of patients in both capsaicin plus SOC groups versus SOC alone reporting improvements in pain level, activity level, QoL, and willingness to undergo the same treatment again. Patients indicated their preference for 179mg capsaicin cutaneous patch treatment, compared with their previous treatment, despite the inconvenience and discomfort associated with capsaicin patch application.

The use of concomitant pain medications during this study was comparable at baseline across treatment arms and remained generally stable from baseline to EoS in the 179mg capsaicin cutaneous patch arms for antidepressants, anti-epileptics, and opioids. However, a 10.9% increase in number of patients using anti-epileptic drugs was observed in the SOC alone arm from baseline to EoS with smaller increases of 7.4% and 3.2% for antidepressants and opioids, respectively. This was, perhaps, indicative of lower efficacy in the SOC alone arm, such that more patients required pain medication over time in this group.

There were a number of limitations associated with this study. Perhaps the most significant arises from the open-label study design. Although the open-label design of this study may be more representative of capsaicin 8% patch repeat treatment in clinical practice than in a double-blind design, the observed efficacy evaluations may have been biased by this approach. Differences between treatment groups in an open-label study may, at least in part, arise from the fact that patients are aware of which treatment they are receiving.

The LOCF imputation method employed in this study is a conservative method to estimate the treatment effect. The underlying assumption is that subjects who withdraw have worse efficacy than those who stay in the trial. The LOCF imputation method used the data of withdrawn patients and therefore, theoretically, gave worse results in this study than from a non-imputed analysis. As the limitations of the LOCF for missing data methodology are recognized, the data were also analyzed using the baseline observation carried forward method, and no differences in the results were observed.

In patients with PDPN, capsaicin 8% patch repeat treatment plus SOC over 52 weeks demonstrated greater effectiveness than SOC alone. 179mg capsaicin cutaneous patch provided sustained pain relief, improved HRQoL, and improved overall health status reflected by the stable number of patients using concomitant pain medication. Furthermore, our results show that the magnitude of the differential treatment effect of 179mg capsaicin cutaneous patch increases over time from the first to the last patch application.

Transparency:

Acknowledgements: The authors thank James Matthews NexGen Healthcare Communications, UK for editorial services, which was funded by Grünenthal.

Disclosure: Malcolm Stoker and J. Snijder were employees of Astellas Pharma Europe at the time of trial conduct.

Author Contributions:

Aaron I. Vinik, Serge Perrot, Etta J. Vinik, Ladislav Pazdera, Malcolm Stoker, Robert J. Snijder, Enrique Ortega, and Nathaniel Katz, were involved in the conception, design and drafting the paper. All authors provided final approval of the version to be published and agreed to be accountable for all aspects of the work.

Data Availability Statement:

The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials:

Capsaicin 8% patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy: a randomised, 52-week, open-label, safety study. BMC Neurology 2016;16:251.

Vinik A I Perrot S Vinik E J Pazdera L Stoker M Snijder R J Ortega E Katz N Capsaicin 8% patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy: a randomised, 52-week, open-label, safety study BMC Neurology 2016 16 251 251 Alleman C J Westerhout K Y Hensen M Chambers C Stoker M Long S Van Nooten F E Humanistic and economic burden of painful diabetic peripheral neuropathy in Europe: A review of the literature Diabetes Res Clin Pract 2015 109 215 225 Jensen M P Chodroff M J Dworkin R H The impact of neuropathic pain on health-related quality of life: review and implications Neurology 2007 68 1178 82 Tölle T Xu X Sadosky A B Painful diabetic neuropathy: a cross-sectional survey of health state impairment and treatment patterns J Diabetes Complicat 2006 20 26 33 Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy Clin J Pain 2002 18 350 354 Davies M Brophy S Williams R Taylor A The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes Diabetes Care 2006 29 1518 1540 Huizinga M M Peltier A Painful diabetic neuropathy: a management-centered review Clin Diabetes 2007 25 6 15 Jensen T S Backonja M M Jiménez Hernández . S New perspectives on the management of diabetic peripheral neuropathic pain Diab Vasc Dis Res 2006 3 108 127 Rudroju N Bansal D Talakokkula S T Comparative efficacy and safety of six antidepressants and anticonvulsants in painful diabetic neuropathy: a network meta-analysis Pain Physician 2013 16 705 719 Yang M Qian C Liu Y Suboptimal treatment of diabetic peripheral neuropathic pain in the United States Pain Med 2015 16 2075 2083 Zhao Y Sun P Watson P Medication adherence and healthcare costs among patients with diabetic peripheral neuropathic pain initiating duloxetine versus pregabalin Curr Med Res Opin 2004 27 785 92 Vinik A I Tuchman M Safirstein B Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies Pain 2007 128 169 79 Haanpää M Cruccu G Nurmikko T Capsaicin 8% patch versus oral pregabalin in patients with peripheral neuropathic pain Eur J Pain 2016 20 316 344 Finnerup N B Attal N Haroutounian S Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis Lancet Neurol 2015 14 162 73 Anand P Bley K Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch Br J Anaesth 2011 107 490 502 Backonja M Wallace M S Blonsky E R NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study Lancet Neurol 2008 7 1106 1118 Brown S Simpson D M Moyle G NGX-4010, a capsaicin 8% patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: integrated analysis of two phase III, randomized, controlled trials AIDS Res Ther 2013 10 5 5 Irving G A Backonja M M Dunteman E A multicenter, randomized, double-blind, controlled study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia Pain Med 2011 12 99 101 Simpson D M Brown S Tobias J for the NGX-4010 C107 Study Group. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy Neurology 2008 70 2305 2318 Simpson D M Robinson-Papp J Van J Stoker M Capsaicin 8% patch in painful diabetic peripheral neuropathy: a randomized, double-blind, placebo-controlled study J Pain 2017 18 42 53 Filipczak-Bryniarska I Krzyzewski R M Kucharz J High-dose 8% capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy: single-center experience Med Oncol 2017 34 162 162 Zelman D C Gore M Dukes E Tai K S Brandenburg N Validation of a modified version of the brief pain inventory for painful diabetic peripheral neuropathy J Pain Symptom Manage 2005 29 4 401 411 Coretti S Ruggeri M Mcnamee P The minimum clinically important difference for EQ-5D index: a critical review Expert Rev Pharmacoecon Outcomes Res 2014 14 2 221 254