Effect of Bismuth Subsalicylate on Gastrointestinal Tolerability in Healthy Volunteers Receiving Oral Delayed-release Dimethyl Fumarate: PREVENT,a Randomized,Multicenter, Double-blind,Placebo-controlled Study

Purpose

Flushing and gastrointestinal (GI) events are commonly associated with the use of delayed-release dimethyl fumarate (DMF) treatment for relapsing multiple sclerosis.

A Multicenter,Randomized, Double-Blind,Controlled Dose Finding Study of NGX-4010, a High-Concentration Capsaicin Patch,for the Treatment of Postherpetic Neuralgia

Postherpetic neuralgia (PHN) is a painful complication of acute herpes zoster. This multicenter, double-blind, controlled study randomized 299 PHN patients to receive either NGX-4010, a high-concentration capsaicin (8%) patch, or a low-concentration capsaicin (0.04%) control patch for 30, 60, or 90 minutes. The mean percent reductions in NPRS score from baseline to weeks 2 through 8 were significantly greater in the total NGX-4010 group (26.5%, P = .0286) and the 90-minute NGX-4010 group (27.8%, P = .0438) compared to the pooled control group (17.3%). After review of the data suggested a difference between genders in reporting of pain scores and a higher proportion of males (61%) in the 60-minute NGX-4010 group, post hoc gender-stratified analyses were performed and showed that the 60-minute NGX-4010 group also had a significantly larger mean percent reduction in average pain scores (28.0%, P = .0331). Pain reduction in the 30-minute NGX-4010 group, although similar in magnitude to the other doses, was not significantly different from control in either of these analyses. Similar results were observed during weeks 2 through 12. Most treatment-emergent adverse events were application-site specific, transient and mostly mild to moderate in severity.     

Lower Placebo Responses After Long-Term Exposure to Fibromyalgia Pain

Knowledge about placebo mechanisms in patients with chronic pain is scarce. Fibromyalgia syndrome (FM) is associated with dysfunctions of central pain inhibition, and because placebo analgesia entails activation of endogenous pain inhibition, we hypothesized that long-term exposure to FM pain would negatively affect placebo responses. In our study we examined the placebo group (n = 37, mean age 45 years) from a 12-week, randomized, double-blind, placebo-controlled trial investigating the effects of milnacipran or placebo. Twenty-two patients were classified as placebo nonresponders and 15 as responders, according to the Patient Global Impression of Change scale. Primary outcome was the change in pressure pain sensitivity from baseline to post-treatment. Secondary outcomes included ratings of clinical pain (visual analog scale), FM effect (Fibromyalgia Impact Questionnaire), and pain drawing. Among placebo responders, longer FM duration was associated with smaller reductions in pressure pain sensitivity (r = .689, P = .004), but not among nonresponders (r = ?.348, P = .112). In our study we showed that FM duration influences endogenous pain regulation, because pain levels and placebo-induced analgesia were negatively affected. Our results point to the importance of early FM interventions, because endogenous pain regulation may still be harnessed at that early time. Also, placebo-controlled trials should take FM duration into consideration when interpreting results.

Results of a Double-Blind,Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain

Context

Prior Phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain.

Patient and Health Care Provider Responses from a Prospective,Double-Blind,Randomized Controlled Trial Comparing Vapocoolant Spray versus Placebo Spray in Adults Undergoing Venipuncture in the Emergency Department

Background: Painful medical procedures are common. Topical anesthetics are easily applied, rapid onset, inexpensive, and avoid injection pain and needlestick injury. The aims of this study, using patient and health care provider questionnaires, were to answer the following questions: (1) Does vapocoolant spray decrease venipuncture pain? (2) Would patients be satisfied with and use a vapocoolant spray in the future? (3) Would providers be satisfied with and use a vapocoolant spray in the future? Design: Adults (18-80 years) in a hospital emergency department (ED) were randomly assigned to sterile water placebo spray (S) (N = 50) or vapocoolant spray (V) (N = 50) before venipuncture. Questionnaires were completed by patients undergoing venipuncture (N = 100) and the health care providers (N = 100) who performed the venipuncture (total questionnaires = 200) as part of a prospective, double-blind, randomized controlled trial comparing the efficacy and safety of vapocoolant spray compared with placebo spray in patients undergoing venipuncture in the ED. Results: Patient and venipuncture variables were not significantly different for the two groups (S vs. V). Responses to the questionnaires were significantly different for the S versus V groups for both the patients and the health care providers. Patient questionnaires: Did you have less pain with spray? S 14%, V 76% (p < .001). Compared with previous blood draws, the spray was much more painful/more painful: S 10%, V 6%; same: S 76%, V 16%; less painful/much less painful: S 14%, V 78% (p < .001). How satisfied were you with the spray? Satisfied/very satisfied: S 20%, V 74% (p < .001). Would you use this spray in future? Yes S 20%, V 80% (p < .001). Provider results: The patient had less pain with the use of the spray: S 14%, V 78% (p < .001). How satisfied were you with the use of the spray? Satisfied/very satisfied: S 12%, V 82% (p < .001). Would you use this spray in the future? Yes S 24%, V 84% (p < .001). Conclusions: The use of a vapocoolant spray in adult ED patients undergoing venipuncture significantly decreased venipuncture pain, was associated with high patient and provider satisfaction, and both patients and providers would use a vapocoolant spray in the future for venipuncture and other painful procedures.     

Post-Zoster-Neuralgie des linken Trigeminusastes V1

A 68-year-old patient suffered from postzoster neuralgia with severe pain of the left trigeminal nerve V1. Despite medication with gabapentin 1800?mg/d, oxacarbazepine 600?mg, tapentadol 500?mg/d, amitriptyline 20?mg as well as ambroxol 20% ointment and lidocaine patch topically, the pain reached an intensity of 8–10 on the numeric rating scale (NRS). Wearing a CPAP (continuous positive airway pressure) mask at night to treat a sleep apnea was impossible or the mask was leaking under lidocaine patch, only topical ambroxol 20% brought a certain pain relief. Lack of sleep, a strongly reduced quality of life and massive exhaustion followed quickly. Due to a fall the systemic medication could not be increased. Also lidocaine infusions with dexamethasone and supraorbitalis blockades were unsuccessful, and a ganglionic local opioid analgesia (GLOA) was anatomically not feasible. Therefore, 8 weeks after the onset of the disease, treatment with capsaicin 8% for 60?min on the face was performed. After only one week, 20–30% pain relief was achieved, sometimes even freedom from pain. Six weeks after application, the average pain during the day was only NRS 3/10 despite a considerable reduction in oral medication. Three months after the second treatment, the patient was almost pain-free during the day. Topical capsaicin 8% patch is, in our opinion, also safe and successful to use on the face with appropriate experience of the user.     

Analgesic Effects of Alcohol: A Systematic Review and Meta-Analysis of Controlled Experimental Studies in Healthy Participants

Despite the long-standing belief in the analgesic properties of alcohol, experimental studies have produced mixed results. This meta-analysis aimed to clarify whether alcohol produces a decrease in experimentally-induced pain and to determine the magnitude of any such effect. PubMed, PsycINFO, and Embase databases were searched from inception until April 21, 2016 for controlled studies examining the effect of quantified dosages of alcohol on pain response to noxious stimulation. Eighteen studies involving 404 participants were identified providing alcohol versus no-alcohol comparisons for 13 tests of pain threshold (n = 212) and 9 tests of pain intensity ratings (n = 192). Random effects meta-analysis of standardized mean difference (SMD) provided robust support for analgesic effects of alcohol. A mean blood alcohol content (BAC) of approximately .08% (3–4 standard drinks) produced a small elevation of pain threshold (SMD [95% CI] = .35 [.17–.54], P = .002), and a moderate to large reduction in pain intensity ratings (SMD [95% CI] = .64 [.37–.91], P < .0001), or equivalently, a mean reduction of 1.25 points on a 0- to 10-point pain rating scale. Furthermore, increasing BAC resulted in increasing analgesia, with each .02% BAC increment producing an increase of SMD = .11 for pain threshold and SMD = .20 for reduced pain intensity. Some evidence of publication bias emerged, but statistical correction methods suggested minimal impact on effect size. Taken together, findings suggest that alcohol is an effective analgesic that delivers clinically-relevant reductions in ratings of pain intensity, which could explain alcohol misuse in those with persistent pain despite its potential consequences for long-term health. Further research is needed to corroborate these findings for clinical pain states.

Bolus remifentanil for chest drain removal in ICU: a randomized double-blind comparison of three modes of analgesia in post-cardiac surgical patients

Purpose

We compared 1 versus 0.5 μg/kg bolus remifentanil versus placebo in alleviating pain due to chest drain removal. Effects on sedation, respiratory rate (RR), oxygen saturation, heart rate (HR) and blood pressure were also evaluated.

Methods

Sixty patients following cardiac surgery were enrolled in this prospective, randomized, double-blind clinical trial. Patients were randomized to 1 or 0.5 μg/kg remifentanil or placebo. All received standardized analgesia. Visual analog scale (VAS) pain scores and cardio-respiratory data were recorded pre-procedure, at drain removal and at 2 min intervals post procedure.

Results

Patients receiving remifentanil had statistically significantly less pain than placebo at drain removal [median (25–75%) VAS: 0.5 μg/kg remifentanil 1 (0–2) versus placebo 5 (3–6), P = 0.001; 1.0 μg/kg remifentanil 0 (0–2) versus placebo 5 (3–6), P = 0.0001]. VAS scores between remifentanil groups were equivalent. Remifentanil 1 μg/kg versus placebo at drain removal revealed significant reductions in HR [mean ± standard deviation (SD): 76 ± 15 versus 92 ± 10, P = 0.01], blood pressure [mean ± SD: 103 ± 22 versus 131 ± 14, P = 0.01] and RR [median (25–75%): 10 (8–12) versus 16 (14–18), P = 0.001]. Remifentanil 0.5 μg/kg versus placebo at drain removal revealed significant reductions in blood pressure [mean ± SD: 116 ± 19 versus 131 ± 14, P = 0.02] and RR [median (25–75%): 12 (10–13) versus 18 (16–18), P = 0.001]. SpO₂ at drain removal was significantly reduced when comparing 1 μg/kg remifentanil versus placebo [median (25–75%): 94 (88–97) versus 97 (96–98), P = 0.049] but not 0.5 μg/kg remifentanil versus placebo. Two patients became apnoeic following 1 μg/kg remifentanil, necessitating respiratory support. Sedation scores in all groups were similar.

Conclusions

Bolus remifentanil at the tested doses delivers excellent analgesia, but 1 μg/kg remifentanil results in respiratory depression. Remifentanil bolus at 0.5 μg/kg is safe and effective for chest drain removal after heart surgery in ICU.     

Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy

A length-dependent neuropathy with pain in the feet is a common complication of diabetes (painful diabetic neuropathy). It was hypothesized that pain may arise from sensitized-hyperactive cutaneous nociceptors, and that this abnormal signaling may be reduced by topical administration of the α₂-adrenergic agonist, clonidine, to the painful area. This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Nociceptor function was measured by determining the painfulness of 0.1% topical capsaicin applied to the pretibial area of each subject for 30 minutes during screening. Subjects were then randomized to receive 0.1% topical clonidine gel (n = 89) or placebo gel (n = 90) applied 3 times a day to their feet for 12 weeks. The difference in foot pain at week 12 in relation to baseline, rated on a 0–10 numerical pain rating scale (NPRS), was compared between groups. Baseline NPRS was imputed for missing data for subjects who terminated the study early. The subjects treated with clonidine showed a trend toward decreased foot pain compared to the placebo-treated group (the primary endpoint; P = 0.07). In subjects who felt any level of pain to capsaicin, clonidine was superior to placebo (P < 0.05). In subjects with a capsaicin pain rating ?2 (0–10, NPRS), the mean decrease in foot pain was 2.6 for active compared to 1.4 for placebo (P = 0.01). Topical clonidine gel significantly reduces the level of foot pain in painful diabetic neuropathy subjects with functional (and possibly sensitized) nociceptors in the affected skin as revealed by testing with topical capsaicin. Screening for cutaneous nociceptor function may help distinguish candidates for topical therapy for neuropathic pain.     

Longitudinal and Temporal Associations Between Daily Pain and Sleep Patterns After Major Pediatric Surgery

Approximately 20% of children develop persistent pain after major surgery. Sleep disruption has been implicated as a predictor of children's acute postsurgical pain. However, perioperative sleep patterns have not been longitudinally assessed, and the role of sleep in persistence of postsurgical pain has not been explored. We aimed to examine sleep patterns over 4 months in children having major surgery, and temporal relationships between daily sleep and pain. Sixty children age 10 to 18 (mean = 14.7) years having major surgery completed 7 days of actigraphy sleep monitoring (sleep duration, efficiency), twice daily electronic diaries (sleep quality, pain intensity, medication use), and validated questionnaires at presurgery, 2 weeks, and 4 months postsurgery. Generalized linear models, controlling for age, sex, naps, and medication, showed sleep quality (β [B] = ?.88, P < .001) and efficiency (B = ?1.50, P = .036) were significantly reduced at 2 weeks compared with presurgery, and returned to baseline by 4 months. Poorer night-time sleep quality was significantly associated with greater next day pain intensity (B = ?.15, P = .005). Sleep duration and efficiency were not associated with subsequent pain; daytime pain was not associated with subsequent sleep. Findings suggest sleep quality may be an important target for intervention after surgery in children; research is needed to understand how other sleep parameters may relate to recovery.

Cranial Electrotherapy Stimulation for the Management of Depression,Anxiety, Sleep Disturbance,and Pain in Patients With Advanced Cancer: A Preliminary Study

Context

Cranial electrotherapy stimulation (CES) is a safe modulation of brain activity for treating depression, anxiety, insomnia, and pain. However, there are no published studies in patients with advanced cancer (ACPs).

An open-label pilot study of high-concentration capsaicin patch in painful HIV neuropathy

Peripheral neuropathy is the most frequent neurological complication of human immunodeficiency virus (HIV)-1 infection and is commonly associated with the development of chronic pain. This open-label, 12-week pilot study assessed the efficacy, tolerability, and safety of a high-concentration capsaicin dermal patch (NGX-4010; capsaicin, 640microg/cm2, 8% w/w) to treat painful HIV-associated distal sensory polyneuropathy (DSP). Eligible patients had moderate-to-severe pain in both feet due to HIV-associated DSP or antiretroviral toxic neuropathy. Patients received a single 60-minute application of the investigational high-concentration capsaicin patch to the affected areas. The primary outcome measure was the mean percent change in numeric pain rating scale (NPRS) during weeks two to 12 postadministration. After a single 60-minute NGX-4010 application, the mean percent change from baseline in "average pain for past 24 hours" NPRS scores during weeks two to 12 was -40% (95% CI: -61%, -19%; P=0.0020). Similar results were observed for "worst pain for past 24 hours" and "pain now" scores. Eight of 12 patients (67%) were treatment responders (> or =30% pain decrease). Four of 12 patients (33%) experienced a > or =50% reduction in pain. Treatment was generally well tolerated. Treatment-associated pain was self-limited and could be managed with short-acting opioids. This study demonstrates that treatment of painful HIV-associated neuropathy with a single application of NGX-4010, a high-concentration capsaicin patch, was feasible, well tolerated, and associated with significant reduction in pain over the 12 weeks studied. No safety concerns were identified. Controlled studies of NGX-4010 for the treatment of painful HIV-associated neuropathy are warranted.     

Safety and efficacy of pregabalin in patients with central post-stroke pain

Pregabalin has demonstrated efficacy in several forms of neuropathic pain, but its long-term efficacy in central post-stroke pain (CPSP) is unproven. We evaluated the efficacy and safety of pregabalin versus placebo in patients with CPSP. A 13-week, randomized, double-blind, multicenter, placebo-controlled, parallel group study of 150 to 600 mg/day pregabalin was conducted in patients aged ?18 years with CPSP. The primary efficacy endpoint was the mean pain score on the Daily Pain Rating Scale over the last 7 days on study drug up to week 12 or early termination visit. Secondary endpoints included other pain parameters and patient-reported sleep and health-related quality-of-life measures. A total of 219 patients were treated (pregabalin n = 110; placebo n = 109). A mean pain score at baseline of 6.5 in the pregabalin group and 6.3 in the placebo group reduced at endpoint to 4.9 in the pregabalin group and 5.0 in the placebo group (LS mean difference = -0.2; 95% CI = -0.7, 0.4; P = 0.578). Treatment with pregabalin resulted in significant improvements, compared with placebo, on secondary endpoints including MOS-sleep, HADS-A anxiety, and clinician global impression of change (CGIC) P < 0.05. Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 9 (8.2%) of pregabalin patients versus 4 (3.7%) of placebo patients. Although pain reductions at endpoint did not differ significantly between pregabalin and placebo, improvements in sleep, anxiety, and CGIC suggest some utility of pregabalin in the management of CPSP.     

Efficacy and safety of empagliflozin in type 2 diabetes mellitus: a meta-analysis of randomized controlled trials

Objectives: The prevalence of diabetes has increased in the recent decades and optimum glycemic control is required to reduce morbidity and mortality. We meta-analyzed randomized controlled trials in order to assess the efficacy and safety of empagliflozin compared to placebo in type 2 diabetes mellitus patients.

Methods: We included double-blind, placebo controlled trials of empagliflozin that evaluated glycemic efficacy and safety (10 mg or 25 mg) either as monotherapy or as add-on to existing diabetes pharmacotherapy.

Results: The results demonstrated significant improvements in HbA1c (SMD ?0.929%, 95 % CI ?1.064 to ?0.793, for 10 mg and ?1.064%, 95 % CI ?1.184 to ?0.944, for 25 mg) and FPG (SMD ?0.929%, 95 % CI ?1.064 to ?0.793, for 10 mg and ?1.064%, 95 % CI ?1.184 to ?0.944, for 25 mg) with empagliflozin monotherapy (n = 609) compared to placebo. Significant improvements in HbA1c [SMD ?1.582%, 95% CI ?2.164 to ?1.000, for 10 mg (n = 1079) and ?1.668%, 95% CI ?2.260 to ?1.077, for 25 mg (n = 1070)] and FPG [SMD ?0.865 mmol/L, 95 % CI ?1.309 to ?0.420, for 10 mg (n = 854) and ?0.996 mmol/L, 95% CI ?1.456 to ?0.536, for 25 mg (n = 854)] were also observed in empagliflozin add-on therapy trials. Reductions in blood pressure and body weight were also seen in both monotherapy and add-on therapy. Empagliflozin was associated with increased risk of hypoglycemia, genital and urinary tract infections (OR 1.043, 2.814, 1.119 respectively).

Conclusion: This meta-analysis shows empagliflozin is safe and effective for the treatment of T2DM along with existing diabetes pharmacotherapy.     

Das 8 %ige Capsaicin-Pflaster bei Phantomschmerz

Background

Post amputation pain presents a challenge for pain physicians and is often detrimental to the patient’s quality of life.

Patients and methods

A prospective 12-week non-interventional study (NIS) was conducted in Germany to obtain data on the effectiveness and safety of capsaicin 8?% cutaneous patches from real life use in patients with peripheral neuropathic pain. For the first time in a subgroup of amputees data on post amputation pain were collected. This article presents the results for patients who suffered from phantom limb pain (PLP), stump pain (SP) and combined phantom limb/stump pain (PLP/SP).

Results

The analyses included 21 patients with post amputation pain (PLP: n?=?10, SP: n?=?4, PLP/SP: n?=?7). The mean duration of pain (± standard deviation) was 12.8?±?13.0 years for PLP, 23.1?±?29.9 years for SP and 11.0?±?15.8 years for PLP/SP. A single treatment with capsaicin 8?% cutaneous patches significantly reduced the average pain intensity over the observational period of 12 weeks. The mean numeric pain rating scale (NPRS) baseline score changed by ??2.4 for PLP with a standard error of the mean (SEM) of 0.4 (median: ??2.9, Q1: ??3.5, Q3: ??1.0), ??1.7 for SP (SEM: 0.8, median: ??1.1, Q1: ??2.9, Q3: ??0.5) and ??1.5 for PLP/SP (SEM: 0.6, median: ??2.0, Q1: ??2.3, Q3: 0) during weeks 1–12. The 30 % responder rates (i.e. ≥?30?% reduction in pain, day 7/14 to week 12) were 70.0?% (PLP), 50.0?% (SP) and 28.6?% (PLP/SP). PLP and PLP/SP patients in particular, benefited from improvements in pain attacks, sleep duration and sleep quality and one patient (PLP/SP) reported an adverse drug reaction (increase of pain). Physicians rated the tolerability of the patch as very good or good in 90.5?% of patients. A poor tolerability was stated for none of the 21 amputees. Of the patients 80 % for PLP and 50?% for both SP and PLP/SP expressed the wish to receive retreatment with capsaicin 8?% patches.

Conclusion

Capsaicin 8?% cutaneous patches seem to be effective and safe for the treatment of post amputation pain, notably in patients suffering from phantom limb pain.     

Comparison of cooling and EMLA to reduce the burning pain during capsaicin 8% patch application: A randomized,double-blind,placebo-controlled study

Topical capsaicin 8% was developed for the treatment of peripheral neuropathic pain. The pain reduction is associated with a reversible reduction of epidermal nerve fiber density (ENFD). During its application, topical capsaicin 8% provokes distinct pain. In a randomized, double-blind study analyzed with a block factorial analysis of variance, we tested whether cooling the skin would result in reliable prevention of the application pain without inhibiting reduction of ENFD. A capsaicin 8% patch was cut into 4 quarters and 2 each were applied for 1 hour on the anterior thighs of 12 healthy volunteers. A randomization scheme provided for 1 of the application sites of each thigh to be pretreated with EMLA and the other with placebo, whereas both application sites of 1 thigh, also randomly selected, were cooled by cool packs, resulting in a site temperature of 20°C during the entire treatment period. The maximum pain level given for the cooled sites (visual analogue scale [VAS] 1.3 ± 1.4) proved to be significantly lower than for the non-cooled sites (VAS 7.5 ± 1.9) (P < .0001). In contrast, there was no significant difference in application pain between the sites pretreated with EMLA or with placebo (VAS 4.1 ± 3.6 vs 4.8 ± 3.5, P = .1084). At all application sites, ENFD was significantly reduced by 8.0 ± 2.8 (ENF/mm ± SD, P < .0001), that is, 70%, with no significant differences between the sites with the different experimental conditions. In conclusion, cooling the skin to 20°C reliably prevents the pain from capsaicin 8% patch application, whereas EMLA does not. ENFD reduction is not inhibited by cooling.     

A Randomized,Controlled, Open-Label Study of the Long-Term Effects of NGX-4010, a High-Concentration Capsaicin Patch,on Epidermal Nerve Fiber Density and Sensory Function in Healthy Volunteers

Desensitization of nociceptive sensory nerve endings is the basis for the therapeutic use of capsaicin in neuropathic pain syndromes. This study evaluated the pharmacodynamic effects of a single 60-minute application of NGX-4010, a high-concentration (8% w/w) capsaicin patch, on both thighs of healthy volunteers. Epidermal nerve fiber (ENF) density and quantitative sensory testing (QST) using thermal, tactile, and sharp mechanical-pain (pinprick) stimuli were evaluated 1, 12 and 24 weeks after capsaicin exposure. After 1 week, there was about an 80% reduction of ENF density compared to unexposed sites. In addition, there was about an 8% increase in tactile thresholds compared to baseline and the proportion of stimuli reported as sharp mechanical pain decreased by about 15 percentage points. Twelve weeks after exposure to capsaicin, ENF regeneration was evident, but not complete, and sharp mechanical-pain sensation and tactile thresholds did not differ from unexposed sites. Nearly full (93%) ENF recovery was observed at 24 weeks. No statistically significant changes in heat- or cold-detection thresholds were observed at any time point. NGX-4010 was generally well tolerated. Transient, mild warming or burning sensations at the site of application were common adverse effects.PerspectiveThis article evaluates the effect of a single 60-minute NGX-4010 application on ENF density and QST in healthy volunteers followed for 24 weeks. The results help predict the long-term safety of NGX-4010 applications in patients.     

Are Geriatric Patients Placed in an Emergency Department Observation Unit on a Chest Pain Pathway More Likely Than Non-Geriatric Patients to Re-Present to the Hospital within 30 Days?

Background

Emergency department observation units (EDOUs) are used frequently for low-risk chest pain evaluations.

Empagliflozin Monotherapy in Japanese Patients with Type 2 Diabetes Mellitus: a Randomized, 12-Week,Double-Blind,Placebo-Controlled,Phase II Trial

Introduction

This study was designed to determine the efficacy and tolerability of empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus (T2DM).

Methods

Patients with glycosylated hemoglobin (HbA1c) ≥7.0–≤10% were randomized via an interactive web response system, and treated double-blind with empagliflozin 5, 10, 25, 50 mg, or placebo once daily for 12 weeks. The primary endpoint was change from baseline in HbA1c at week 12. Other endpoints included percentage of patients with HbA1c <7.0% and changes from baseline in fasting plasma glucose (FPG), body weight, and systolic blood pressure (SBP) at week 12.

Results

A total of 547 patients were randomized and treated with empagliflozin 5 mg (n = 110), 10 mg (n = 109), 25 mg (n = 109), 50 mg (n = 110), or placebo (n = 109) for 12 weeks. Adjusted mean [95% confidence interval (CI)] differences vs. placebo in changes from baseline in HbA1c were ?0.72% (?0.87, ?0.57) with empagliflozin 5 mg, ?0.70% (?0.85, ?0.55) with 10 mg, ?0.95% (?1.10, ?0.80) with 25 mg, and ?0.91 (?1.06, ?0.76) with 50 mg (all p < 0.001). More patients with HbA1c ≥7.0% at baseline reached HbA1c <7.0% with empagliflozin (19–33%) than placebo (3%). Compared with placebo, empagliflozin reduced FPG, body weight (p < 0.001 for all doses for both endpoints) and SBP (p = 0.001, p = 0.014 and p = 0.003 for empagliflozin 10, 25, and 50 mg, respectively). Adverse events were reported by 42% of patients receiving placebo and 33–38% of patients receiving empagliflozin. There were few reports of confirmed hypoglycemic adverse events or events consistent with urinary tract infection or genital infection in any treatment group.

Conclusions

Empagliflozin monotherapy for 12 weeks in Japanese patients with T2DM reduced HbA1c, FPG, body weight and SBP, and was well tolerated.