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.     

Randomized,Double-Blind,Dose-Ranging Study of TAK-875, a Novel GPR40 Agonist,in Japanese Patients With Inadequately Controlled Type 2 Diabetes

OBJECTIVE

Assessment of the efficacy and safety of TAK-875 (a novel GPR40 agonist) in Japanese patients with type 2 diabetes inadequately controlled by diet/exercise.

RESEARCH DESIGN AND METHODS

This was a phase II, multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week dose-ranging evaluation of TAK-875 (6.25–200 mg once daily) with the primary end point of change in A1C at week 12. A nonblinded group received 1 mg glimepiride once daily as an active control.

RESULTS

A total of 396 patients were randomized to receive TAK-875 (n = 299), placebo (n = 48), or glimepiride (n = 49). The least square mean changes in A1C at week 12 from baseline were as follows: 0.09% in the placebo group; −0.54, −0.67, −0.88, −1.27, −1.29, and −1.40% in the 6.25-, 12.5-, 25-, 50-, 100-, and 200-mg TAK-875 groups, respectively; and −1.32% in the 1-mg glimepiride group. All TAK-875 groups had statistically significant reductions in A1C compared with placebo (P < 0.0001), and those receiving ≥50 mg TAK-875 achieved reductions in A1C equivalent to those with glimepiride. Results for other glycemic parameters, including improvements during a meal tolerance test, mirrored these positive findings with TAK-875. There were no significant differences in incidence of adverse events among the groups and no dose-dependent changes in tolerability. Hypoglycemic episodes were reported in 0.7% of patients in the TAK-875 groups and in 4.1% of the glimepiride group.

CONCLUSIONS

TAK-875 produced clinically and statistically significant improvements in glycemic control in patients with type 2 diabetes inadequately controlled by diet and exercise, and it was well tolerated with a lower propensity to cause hypoglycemia.Free fatty acids (FFAs) are not only an important nutritional source—they also act as signaling molecules for a number of cellular processes including insulin secretion (1). There is accumulating evidence that long-chain fatty acids amplify glucose-stimulated insulin secretion from pancreatic β cells, and this effect is mediated through activation of the G-protein–coupled receptor (GPR)40, also known as free fatty acid receptor 1 (2). GPR40, as a potential target for the treatment of diabetes, is receiving much attention, since it is highly expressed in pancreatic β cells (3–5).TAK-875 is an orally bioavailable GPR40 agonist that was chosen as a lead compound for clinical evaluation (6). An initial clinical study of single oral doses of 25–800 mg TAK-875 in healthy volunteers in the U.S. showed no glucose-lowering effects or dose-dependent safety/tolerability changes (7). The authors concluded that these pharmacological properties support the notion that TAK-875, if effective in patients with type 2 diabetes, would have a low risk of provoking hypoglycemia. Recently, results were published from an exploratory randomized, double-blind study in 65 Japanese patients with type 2 diabetes who were treated with placebo or 100 or 400 mg TAK-875 once daily for 2 weeks (8). TAK-875 produced marked dose-dependent glucose-lowering effects and improvements in other indices of glycemic control. TAK-875 was well tolerated, and importantly, no hypoglycemia occurred.Based on the above, the current placebo-controlled study was designed to evaluate the glycemic effects of a range of dosages of TAK-875 (6.25–200 mg) administered once daily for 12 weeks in Japanese patients with type 2 diabetes inadequately controlled by diet/exercise. Glimepiride (1 mg) once daily was administered in an open-label fashion to one of the randomized groups as an active control.     

A Randomized,Double-Blind,Placebo-Controlled Study of Fentanyl Buccal Tablets for Breakthrough Pain: Efficacy and Safety in Japanese Cancer Patients

ContextRapid-onset opioids for treating breakthrough pain (BTP) in patients with cancer are needed in the Japanese care setting.ObjectivesTo examine the efficacy and safety of fentanyl buccal tablets (FBTs) for treating BTP in Japanese cancer patients.MethodsThis was a randomized, double-blinded, placebo-controlled study. In subjects receiving around-the-clock (ATC) opioids at doses of 30 mg or more to less than 60 mg or 60–1000 mg of oral morphine equivalents (low and high ATC groups), dose titration was started from 50 to 100 μg FBT, respectively. Subjects whose effective dose was identified were randomly allocated to a prearranged administration order of nine tablets (six FBTs and three placebos), one tablet each for nine episodes of BTP (double blinded). Efficacy and safety of FBT were assessed for patients overall, and also for the low and high ATC groups.ResultsA significant difference was observed between FBT and placebo for the primary endpoint of pain intensity difference at 30 minutes. The analgesic onset of FBT was observed from 15 minutes in several secondary variables (e.g., pain relief). Adverse events were somnolence and other events associated with opioids were mostly mild or moderate. Of the low and high ATC group subjects, an effective FBT dose was identified in 72.2% and 73.1%, respectively.ConclusionThe safety of FBT and its analgesic effect on BTP were confirmed in Japanese cancer patients receiving opioids. Our findings suggest that analgesic onset may occur from 15 minutes after FBT, and that FBT can be administered to patients with low doses of ATC opioids.     

A Randomized, Double-Blind, Placebo-Controlled Evaluation of the Efficacy and Safety of Intravenously Administered Dofetilide in Patients with Wolff-Parkinson-White Syndrome

KRAHN, A.D., et al. : A Randomized, Double-Blind, Placebo-Controlled Evaluation of the Efficacy and Safety of Intravenously Administered Dofetilide in Patients with Wolff-Parkinson-White Syndrome. Pharmacological conversion of arrhythmias in Wolff-Parkinson-White (WPW) syndrome is often frequently undertaken. Current antiarrhythmic drugs used for conversion can be associated with significant side effects and variable efficacy. Fifteen male patients (mean age 34, range 18–63 years) with WPW syndrome and atrial fibrillation or AVRT induced in the electrophysiology laboratory were enrolled in a prospective, randomized, placebo-controlled crossover study. Patients were randomized to one of two doses of intravenous dofetilide or placebo. Patients who failed to respond to this initial infusion received a second higher dose infusion of dofetilide. With the initial infusion, six of ten dofetilide patients converted to sinus rhythm compared to one of five placebo patients. After a second infusion of dofetilide for placebo patients and higher dose dofetilide for low dose dofetilide patients, the overall conversion rate was 71% with dofetilide compared with 20% for placebo (  P = 0.046  ). Atrial fibrillation converted to sinus rhythm in 82% of patients who received dofetilide. Intravenous dofetilide was safe and effective at converting induced atrial fibrillation in patients with WPW syndrome.     

Allogeneic Mesenchymal Precursor Cells in Type 2 Diabetes: A Randomized,Placebo-Controlled,Dose-Escalation Safety and Tolerability Pilot Study

OBJECTIVE

To assess the safety, tolerability, and feasibility of adult allogeneic bone marrow–derived mesenchymal precursor cells (MPCs) in type 2 diabetes inadequately controlled with metformin either alone or with one additional oral antidiabetic agent.

RESEARCH DESIGN AND METHODS

The study was a dose-escalating randomized placebo-controlled trial assessing one intravenous (IV) infusion of MPCs (rexlemestrocel-L; Mesoblast Inc.) 0.3 × 10⁶/kg (n = 15), 1.0 × 10⁶/kg (n = 15), or 2.0 × 10⁶/kg (n = 15) or placebo (n = 16). Study duration was 12 weeks.

RESULTS

Subjects (21 women, 40 men) with a mean ± SD baseline HbA_1c 8.3 ± 1.0% (67 ± 10.9 mmol/mol), BMI 33.5 ± 5.5 kg/m², and diabetes duration 10.1 ± 6.0 years were enrolled at 18 U.S. sites. No acute adverse events (AEs) were associated with infusion. No serious AEs, serious hypoglycemia AEs, or discontinuations due to AEs over 12 weeks were found. No subjects developed donor-specific anti-HLA antibodies or became sensitized. The safety profile was comparable among treatment groups. Compared with placebo, a single IV infusion of rexlemestrocel-L reduced HbA_1c at all time points after week 1. The adjusted least squares mean ± SE dose-related differences in HbA_1c from placebo in the rexlemestrocel-L groups ranged from −0.1 ± 0.2% (−1.1 ± 2.2 mmol/mol) to −0.4 ± 0.2% (4.4 ± 2.2 mmol/mol) at 8 weeks and from 0.0 ± 0.25% to −0.3 ± 0.25% (−3.3 ± −2.7 mmol/mol) at 12 weeks (P < 0.05 for 2.0 × 10⁶/kg dose at 8 weeks). The clinical target HbA_1c <7% (53 mmol/mol) was achieved by 33% (5 of 15) of the subjects who received the 2.0 × 10⁶/kg dose vs. 0% of those who received placebo (P < 0.05).

CONCLUSIONS

This short-term study demonstrates the safety and feasibility of up to 246 million MPCs in subjects with type 2 diabetes.     

Liberty Asthma QUEST: Phase 3 Randomized,Double-Blind,Placebo-Controlled,Parallel-Group Study to Evaluate Dupilumab Efficacy/Safety in Patients with Uncontrolled,Moderate-to-Severe Asthma

Introduction

Dupilumab, a fully human anti-IL-4Rα monoclonal antibody, inhibits signaling of both interleukin (IL)-4 and IL-13, which are key drivers of type 2-mediated inflammation. Dupilumab is approved in the EU, USA, and other countries for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis. Following positive phase 2 results in asthma, the phase 3 Liberty Asthma QUEST trial was initiated to provide further evidence for dupilumab efficacy and safety in patients with uncontrolled, moderate-to-severe asthma.

Methods

Liberty Asthma QUEST is a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (NCT02414854) in patients with persistent asthma who are receiving continuous treatment with inhaled corticosteroids (ICS) plus one or two other asthma controller medicines. A total of 1902 patients (aged?≥?12 years) were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on therapy with subcutaneously administered dupilumab 200 or 300 mg every 2 weeks or matched placebo. The study consisted of a 4?±?1-week screening period, 52-week randomized treatment period, and 12-week post-treatment follow-up period. All patients continued to receive their prescribed ICS plus up to two additional controller medications. The primary efficacy endpoints were annualized rate of severe exacerbation events during the 52-week treatment period and absolute change from baseline in pre-bronchodilator FEV₁ at week 12.

Conclusion

Uncontrolled asthma patients with persistent symptoms represent a population of significant unmet need, for whom new treatments are required. Patients with severe asthma are at high risk of asthma exacerbations, and face an accelerated decline in lung function and impaired quality of life. QUEST examines the efficacy of dupilumab in this at-risk patient population; it is the largest placebo-controlled study in uncontrolled, moderate-to-severe asthma with a biologic agent to date, and the only phase 3 study of a biologic therapy of asthma that enrolled patients irrespective of baseline type 2 inflammatory biomarker levels.

Funding

Sanofi and Regeneron Pharmaceuticals, Inc.

Clinical Trials.gov Identifier

NCT02414854.

     

Ropinirole in Patients With Restless Legs Syndrome and Baseline IRLS Total Scores ≥24: Efficacy and Tolerability in a 26-Week,Double-Blind,Parallel-Group,Placebo-Controlled Study Followed by a 40-Week Open-Label Extension

Background

As with studies of other dopamine agonists, previously reported studies of ropinirole in restless legs syndrome (RLS) recruited patients with baseline International Restless Legs Scale (IRLS) total scores ≥15. The reported pooled analyses of clinical trials data suggest benefits of ropinirole in patients with IRLS total scores ≥24, but the effects of ropinirole have not been prospectively evaluated in this patient population.

Objective

The goal of this study was to evaluate the efficacy and tolerability of ropinirole in patients with RLS and baseline IRLS total scores ≥24. This study was conducted in part to fulfill a postlicensing commitment between the maker of ropinirole and the European Union’s Committee for Medicinal Products for Human Use.

Methods

The protocol for this study comprised a randomized, double-blind, placebo-controlled, parallel-group, 26-week phase during which adults with baseline IRLS total scores ≥24 received a ropinirole dose from 0.25 to 4 mg (n = 197) or placebo (n = 207) followed by a 40-week, open-label phase during which all patients (n = 269) received ropinirole. The primary efficacy end point was the change from baseline in the IRLS total score at week 12. Tolerability measures included the incidence of adverse events, augmentation, and early morning rebound. Due to the possibility of a treatment-by–center group interaction (P = 0.04) in the IRLS analysis, further efficacy exploratory analyses were performed to assess the impact of the interaction on the overall assessment of efficacy.

Results

Demographic characteristics were comparable between groups (mean [SD] age: placebo, 56.1 [11.38] years; ropinirole, 56.5 [11.92] years; 63% female in both groups). All of the patients in the ropinirole group were white; 99% of the placebo group was white. Ropinirole was significantly better than placebo for change from baseline in the IRLS total score during both short- and long-term treatment, with mean treatment differences of –2.1 (P = 0.039) and –2.5 (P = 0.023) for weeks 12 and 26, respectively. A statistically significant treatment by center group interaction was observed (P = 0.040) for the change from baseline in IRLS total score, indicating variation of treatment effects among center groups; however, all center groups showed an improvement from baseline at both week 12 and week 26 for the ropinirole immediate-release group and the placebo group. The incidences of augmentation and early morning rebound were ≤4% for ropinirole. The adverse event profile of ropinirole was consistent with that reported in previous clinical trials.

Conclusions

In this subset of patients with RLS and a baseline IRLS total score ≥24, ropinirole was effective and well tolerated compared with placebo. The incidence of augmentation and early morning rebound in this study was low. Clinicaltrials.gov identifier: NCT00329602.     

Pharmacokinetics and Safety of DS-8500a,an Antidiabetic Drug,in Japanese Subjects with Hepatic or Renal Impairment: A Single-Center,Open-Label,Single-Dose Study

Introduction

The pharmacokinetics, safety, and tolerability of DS-8500a (a G protein receptor 119 agonist) up to 100 mg have been investigated in healthy Japanese adults. The objective of this study was to evaluate the effects of hepatic or renal impairment on the pharmacokinetics of a single 25-mg oral dose of DS-8500a.

Methods

This single-center, open-label study enrolled subjects into eight groups according to hepatic function (normal; mild or moderate impairment) and renal function [normal; mild, moderate, or severe impairment; and end-stage renal disease (ESRD)]. Drug concentrations were measured by liquid-chromatography tandem mass spectrometry. Pharmacokinetic parameters were evaluated by non-compartmental analysis. Adverse events (AEs) were evaluated for safety.

Results

The hepatic and renal groups enrolled 15 and 30 subjects, respectively. Pharmacokinetic parameters of DS-8500a were comparable between the normal hepatic function and mild hepatic impairment groups, but the mean area under the concentration–time curve (AUC) was 1.37-fold higher, and the half-life was longer in the moderate hepatic impairment group compared with the normal hepatic function group. The maximum concentration (C_max) and AUC values were 0.704- and 0.609-fold lower, respectively, in the ESRD group compared with the values in the other renal impairment groups; no clear differences in AUC and time to C_max were observed in the normal function and mild, moderate, and severe renal impairment groups. There was no relationship between apparent total body clearance and estimated glomerular filtration rate. The incidence of AEs was similar among all groups.

Conclusion

DS-8500a exposure in the mild hepatic impairment and mild to severe renal impairment groups was similar to that in the corresponding normal hepatic and renal function groups, but dose adjustments may be required in those with moderate hepatic impairment and ESRD.

Trial registration

Japic CTI-No. 163135.

Funding

Daiichi Sankyo Co. Ltd., Tokyo, Japan.

     

Duloxetine Versus Placebo in Patients With Chronic Low Back Pain: A 12-Week,Fixed-Dose,Randomized, Double-Blind Trial

This randomized, double-blind, placebo-controlled study assessed efficacy and safety of duloxetine in patients with chronic low back pain (CLBP). Adults (n = 401) with a nonneuropathic CLBP and average pain intensity of ≥4 on an 11-point numerical scale (Brief Pain Inventory [BPI]) were treated with either duloxetine 60 mg once daily or placebo for 12 weeks. The primary measure was BPI average pain. Secondary endpoints included Patient's Global Impressions of Improvement (PGI-I), Roland Morris Disability Questionnaire (RMDQ-24), BPI-Severity (BPI-S), BPI-Interference (BPI-I), and response rates (either ≥30% or ≥50% BPI average pain reduction at endpoint). Health outcomes included Short Form-36, European Quality of Life–5 Dimensions, and the Work Productivity and Activity Impairment questionnaire. Safety and tolerability were assessed. Compared with placebo-treated patients, duloxetine-treated patients reported a significantly greater reduction in BPI average pain (P ≤ .001). Similarly, duloxetine-treated patients reported significantly greater improvements in PGI-I, BPI-S, BPI-I, 50% response rates, and some health outcomes. The RMDQ and 30% response rate showed numerical improvements with duloxetine treatment. Significantly more patients in the duloxetine group (15.2%) than patients in the placebo group (5.4%) discontinued because of adverse events (P = .002). Nausea and dry mouth were the most common treatment-emergent adverse events with rates significantly higher in duloxetine-treated patients.     

Botulinum Toxin Type B in the Spastic Arm: A Randomized,Double-Blind,Placebo-Controlled,Preliminary Study

Objective

To determine the efficacy and safety of 2 doses of botulinum toxin type B (rimabotulinumtoxinB, BoNT/B) in spastic upper limb muscles.

Design

Randomized, double-blind, placebo-controlled trial with a 3-month follow-up.

Setting

Tertiary care center.

Participants

Referred sample of adult hemiparetic patients (N=24) with disabling elbow flexor overactivity after stroke or traumatic brain injury.

Interventions

Injection of 10,000U of rimabotulinumtoxinB (fixed 2500U dose into elbow flexors; n=8), 15,000U (5000U into elbow flexors; n=8), or placebo (n=8) into overactive upper limb muscles selected as per investigator's discretion.

Main Outcome Measures

At 1 month postinjection, active range of elbow extension (goniometry; primary outcome); active upper limb function (Modified Frenchay Scale [MFS]); subjective global self-assessment (GSA) of arm pain, stiffness, and function; rapid alternating elbow flexion-extension movement frequency over the maximal range; elbow flexor spasticity grade and angle (Tardieu), and tone (Ashworth).

Results

No adverse effects were associated with either BoNT/B dose. Both doses improved active elbow extension versus placebo (+8.3°; 95% confidence interval, 1.1°–15.5°; analysis of covariance, P=.028). The high dose of BoNT/B also improved subject-perceived stiffness (P=.005) and the composite pain, stiffness, and function GSA (P=.017), effects that persisted 3 months from injection. No MFS change was demonstrated, although subjects with a baseline MFS <70/100 seemed more likely to benefit from BoNT/B.

Conclusions

In this short-term study, BoNT/B up to 15,000U into spastic upper limb muscles, including the elbow flexors, was well tolerated and improved active elbow extension and subject-perceived stiffness.     

Metabolic,Intestinal, and Cardiovascular Effects of Sotagliflozin Compared With Empagliflozin in Patients With Type 2 Diabetes: A Randomized,Double-Blind Study

OBJECTIVEInhibiting sodium–glucose cotransporters (SGLTs) improves glycemic and cardiovascular outcomes in patients with type 2 diabetes (T2D). We investigated the differential impact of selective SGLT2 inhibition and dual inhibition of SGLT1 and SGLT2 on multiple parameters.RESEARCH DESIGN AND METHODSUsing a double-blind, parallel-group design, we randomized 40 patients with T2D and hypertension to receive the dual SGLT1 and SGLT2 inhibitor sotagliflozin 400 mg or the selective SGLT2 inhibitor empagliflozin 25 mg, with preexisting antihypertensive treatment, for 8 weeks. In an in-house testing site, mixed-meal tolerance tests (MMTTs) and other laboratory and clinical evaluations were used to study metabolic, intestinal, cardiovascular, and urinary parameters over 24 h.RESULTSChanges from baseline in glycemic and blood pressure control; intestinal, urine, and metabolic parameters; and cardiovascular biomarkers were generally similar with sotagliflozin and empagliflozin. During the breakfast MMTT, sotagliflozin significantly reduced incremental area under the curve (AUC) values for postprandial glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) and significantly increased incremental AUCs for postprandial glucagon-like peptide 1 (GLP-1) relative to empagliflozin, consistent with sotagliflozin-mediated inhibition of intestinal SGLT1. These changes waned during lunch and dinner MMTTs. Both treatments significantly lowered GIP incremental AUCs relative to baseline over the 14 h MMTT interval; the most vigorous effect was seen with sotagliflozin soon after start of the first meal of the day. No serious or severe adverse events were observed.CONCLUSIONSChanges from baseline in glycemic and blood pressure control, cardiovascular biomarkers, and other parameters were comparable between sotagliflozin and empagliflozin. However, sotagliflozin but not empagliflozin inhibited intestinal SGLT1 after breakfast as shown by larger changes in postprandial glucose, insulin, GIP, and GLP-1 AUCs, particularly after breakfast. Additional study is warranted to assess the clinical relevance of transient SGLT1 inhibition and differences in incretin responses ({"type":"clinical-trial","attrs":{"text":"NCT03462069","term_id":"NCT03462069"}}NCT03462069).     

Efficacy of Preventive Analgesia with Tramadol or Lornoxicam for Percutaneous Nephrolithotomy: A Prospective, Randomized, Double-Blind, Placebo-Controlled Study

Background: Prevention of postoperative pain provides better and more rapid convalescence for patients.Objective: The aim of this study was to compare the preventive analgesic effect of tramadol and lornoxicam in the early postoperative period in patients undergoing percutaneous nephrolithotomy (PCNL).Methods: Patients who were scheduled for elective PCNL at the Cumhuriyet University Hospital, Sivas, Turkey, were enrolled in this prospective, double-blind, placebo-controlled study. The patients were randomly assigned to 1 of 3 groups: tramadol, lornoxicam, and normal saline (NS). Ten minutes before induction of anesthesia, the tramadol group received tramadol 100 mg IV, the lornoxicam group received lornoxicam 8 mg IV, and the NS group received NS 2 mL IV. Anesthesia was induced using fentanyl 1 μg/kg and thiopental sodium 4 to 7 mg/kg. Vecuronium 0.1 mg/kg was used for muscle relaxation. Desflurane 4% to 6% and 50%:50% oxygen/nitrous oxide were used for maintenance. Oxygen saturation, heart rate, and mean blood pressure were recorded before induction and during the postoperative period. During the postoperative period, visual analogue scale O/AS) scores, time to first analgesic (TFA), total analgesic consumption (TAC), and patient satisfaction scores were determined. Data about postoperative nausea and vomiting and other adverse events and complications were also collected.Results: Seventy-three patients were assessed for enrollment and 60 (33 women, 27 men; mean [SD] age, 44.69 [11.27] years; age range, 20-62 years) were included in the study. The baseline demographic characteristics and duration of surgery were similar in all 3 groups. The mean (SD) VAS scores in the tramadol group were significantly lower than in the NS group at 15 and 30 minutes and 1, 2, 4, and 12 hours after surgery (all, P < 0.05). The VAS scores in the lornoxicam group were significantly lower than in the NS group at 15 and 30 minutes and 1 hour (all, P < 0.05). The VAS score at 1 hour after surgery was significantly lower in the tramadol group than in the lornoxicam group (18 [8] vs 32 [16]; P < 0.05); however, there were no other significant differences in VAS scores between the active groups. A significantly shorter TFA was associated with the NS group when compared with the tramadol and lornoxicam groups (46 [27] vs 354 [187] and 180 [118], respectively; both, P < 0.05). TFA was significantly shorter in the lornoxicam group when compared with the tramadol roup (180 [118] vs 354 [187]; P < 0.05). TAC was significantly higher in the NS group than in the tramadol and lornoxicam groups (270 [47] vs 115 [74] and 145 [72], respectively; both, P < 0.05). Patient satisfaction score (range) was significantly lower in the NS group when compared with the tramadol and lornoxicam groups (0 [0-1] vs 3 [0-3] and 2 [0-3], respectively; both, P < 0.05). There were no other significant between-group differences observed.Conclusions: Tramadol and lornoxicam were more effective than NS in preventing early postoperative pain. The preventive analgesic effect of tramadol was comparable with that of lornoxicam, except at 1 hour when tramadol was more effective among these patients undergoing PCNL. Both drugs were well tolerated.     

Multicenter,Double-Blind,Randomized, Placebo-Controlled,Parallel-Group Study of the Efficacy,Safety, and Tolerability of THC:CBD Extract and THC Extract in Patients with Intractable Cancer-Related Pain

This study compared the efficacy of a tetrahydrocannabinol:cannabidiol (THC:CBD) extract, a nonopioid analgesic endocannabinoid system modulator, and a THC extract, with placebo, in relieving pain in patients with advanced cancer. In total, 177 patients with cancer pain, who experienced inadequate analgesia despite chronic opioid dosing, entered a two-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial. Patients were randomized to THC:CBD extract (n = 60), THC extract (n = 58), or placebo (n = 59). The primary analysis of change from baseline in mean pain Numerical Rating Scale (NRS) score was statistically significantly in favor of THC:CBD compared with placebo (improvement of ?1.37 vs. ?0.69), whereas the THC group showed a nonsignificant change (?1.01 vs. ?0.69). Twice as many patients taking THC:CBD showed a reduction of more than 30% from baseline pain NRS score when compared with placebo (23 [43%] vs. 12 [21%]). The associated odds ratio was statistically significant, whereas the number of THC group responders was similar to placebo (12 [23%] vs. 12 [21%]) and did not reach statistical significance. There was no change from baseline in median dose of opioid background medication or mean number of doses of breakthrough medication across treatment groups. No significant group differences were found in the NRS sleep quality or nausea scores or the pain control assessment. However, the results from the European Organisation for Research and Treatment of Cancer Quality of Life Cancer Questionnaire showed a worsening in nausea and vomiting with THC:CBD compared with placebo (P = 0.02), whereas THC had no difference (P = 1.0). Most drug-related adverse events were mild/moderate in severity. This study shows that THC:CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids.     

Efficacy and Safety of 30-Mg Fimasartan for the Treatment of Patients With Mild to Moderate Hypertension: An 8-Week,Multicenter, Randomized,Double-Blind,Phase III Clinical Study

Purpose

The standard 60-mg dose of fimasartan, a newly developed selective angiotensin II receptor blocker, is effective and safe for use in patients with mild to moderate hypertension. This study aimed to compare the efficacy and safety of low-dose (30 mg) fimasartan and placebo or valsartan (80 mg) for 8 weeks in patients with mild to moderate hypertension.

Methods

In this randomized trial, 293 patients (219 men; mean age, 54.24 [9.77] years) with mild to moderate hypertension were enrolled. After randomization to receive 30-mg fimasartan (n = 115), placebo (n = 117), or 80-mg valsartan (n = 61), the treatment dose was kept constant without dose escalation for 8 weeks. The primary end point was improvement in sitting diastolic blood pressure (SiDBP) from baseline to 8 weeks that was compared between treatments with low-dose fimasartan and placebo. The secondary end point was the overall efficacy and safety of low-dose fimasartan compared with that of placebo or valsartan.

Findings

At week 8, SiDBP changed by –9.93 (8.86) mm Hg in the fimasartan group and by –2.08 (9.47) mm Hg in the placebo group, which indicated significant antihypertensive efficacy (P < 0.0001). Efficacy was shown at week 4 as measured by SiDBP (–9.96 [7.73] vs –2.27 [7.85] mm Hg; P < 0.0001) or sitting systolic blood pressure (SiSBP) (–16.18 [14.44] vs –1.95 [13.48] mmHg; P < 0.0001) and at week 8 as determined by SiSBP (–15.35 [16.63] vs –2.30 [14.91] mm Hg; P < 0.0001). The fimasartan group exhibited more potent antihypertensive efficacy than the valsartan group both at week 4 (SiDBP, –9.96 [7.73] vs –6.53 [9.58] mm Hg [P = 0.0123]; SiSBP, –16.18 [14.4] vs –7.65 [12.89] mm Hg [P = 0.0002]) and at week 8 (SiDBP, –9.93 [8.86] vs –5.47 [8.96] mm Hg [P = 0.0021]; SiSBP, –15.35 [16.63] vs –7.49 [13.68] mm Hg [P = 0.0021]). Most treatment-emergent adverse events (TEAEs) were mild (89 of 95), and there were no serious TEAEs. The incidence of TEAEs was 19.1% in the fimasartan group, 22.6% in the placebo group, and 13.6% in the valsartan group, with no significant differences.

Implications

Low-dose fimasartan (30 mg) was well tolerated during the study period with no significant TEAEs. Low-dose fimasartan had an effective blood pressure–lowering effect that was greater than that of 80-mg valsartan in patients with mild to moderate hypertension. ClinicalTrials.gov identifier: NCT01672476.     

Efficacy and Safety of Mulberry Twig Alkaloids Tablet for the Treatment of Type 2 Diabetes: A Multicenter,Randomized, Double-Blind,Double-Dummy,and Parallel Controlled Clinical Trial

OBJECTIVEThis study aimed to evaluate the efficacy and safety of mulberry twig alkaloids (Sangzhi alkaloids [SZ-A]) in the treatment of type 2 diabetes (T2D).RESEARCH DESIGN AND METHODSThis was a multicenter, randomized, double-blind, double-dummy, and parallel controlled noninferiority clinical trial that was conducted for 24 weeks. A total of 600 patients were randomly allocated to the SZ-A group (n = 360) or acarbose group (n = 240). The primary efficacy end point was the change of glycosylated hemoglobin (HbA_1c) compared with baseline. In addition, adverse events (AEs), severe AEs (SAEs), treatment-related AEs (TAEs), and gastrointestinal disorders (GDs) were monitored.RESULTSAfter treatment for 24 weeks, the change in HbA_1c was –0.93% (95% CI –1.03 to –0.83) (–10.2 mmol/mol [–11.3 to –9.1]) and –0.87% (–0.99 to –0.76) (–9.5 mmol/mol [–10.8 to –8.3]) in the SZ-A and acarbose groups, respectively, and the least squares mean difference was –0.05% (95% CI –0.18 to 0.07) (–0.5 mmol/mol [–2.0 to 0.8]) between the two groups, with no significant difference on the basis of covariance analysis (P > 0.05). The incidence of TAEs and GDs was significantly lower in the SZ-A group than the acarbose group (P < 0.01), but no differences for AEs or SAEs between the two groups were observed (P > 0.05).CONCLUSIONSSZ-A exhibited equivalent hypoglycemic effects to acarbose in patients with T2D. Nevertheless, the incidence of TAEs and GDs was lower following SZ-A treatment than acarbose treatment, suggesting good safety.     

Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind,Randomized, Placebo-Controlled Phase IIb Trial

OBJECTIVETo evaluate the efficacy of aluminum-formulated intralymphatic glutamic acid decarboxylase (GAD-alum) therapy combined with vitamin D supplementation in preserving endogenous insulin secretion in all patients with type 1 diabetes (T1D) or in a genetically prespecified subgroup.RESEARCH DESIGN AND METHODSIn a multicenter, randomized, placebo-controlled, double-blind trial, 109 patients aged 12–24 years (mean ± SD 16.4 ± 4.1) with a diabetes duration of 7–193 days (88.8 ± 51.4), elevated serum GAD65 autoantibodies, and a fasting serum C-peptide >0.12 nmol/L were recruited. Participants were randomized to receive either three intralymphatic injections (1 month apart) with 4 μg GAD-alum and oral vitamin D (2,000 IE daily for 120 days) or placebo. The primary outcome was the change in stimulated serum C-peptide (mean area under the curve [AUC] after a mixed-meal tolerance test) between baseline and 15 months.RESULTSPrimary end point was not met in the full analysis set (treatment effect ratio 1.091 [CI 0.845–1.408]; P = 0.5009). However, GAD-alum–treated patients carrying HLA DR3-DQ2 (n = 29; defined as DRB1*03, DQB1*02:01) showed greater preservation of C-peptide AUC (treatment effect ratio 1.557 [CI 1.126–2.153]; P = 0.0078) after 15 months compared with individuals receiving placebo with the same genotype (n = 17). Several secondary end points showed supporting trends, and a positive effect was seen in partial remission (insulin dose–adjusted HbA_1c ≤9; P = 0.0310). Minor transient injection site reactions were reported.CONCLUSIONIntralymphatic administration of GAD-alum is a simple, well-tolerated treatment that together with vitamin D supplementation seems to preserve C-peptide in patients with recent-onset T1D carrying HLA DR3-DQ2. This constitutes a disease-modifying treatment for T1D with a precision medicine approach.     

The SimpliciT1 Study: A Randomized,Double-Blind,Placebo-Controlled Phase 1b/2 Adaptive Study of TTP399, a Hepatoselective Glucokinase Activator,for Adjunctive Treatment of Type 1 Diabetes

OBJECTIVEDespite advances in exogenous insulin therapy, many patients with type 1 diabetes do not achieve acceptable glycemic control and remain at risk for ketosis and insulin-induced hypoglycemia. We conducted a randomized controlled trial to determine whether TTP399, a novel hepatoselective glucokinase activator, improved glycemic control in people with type 1 diabetes without increasing hypoglycemia or ketosis.RESEARCH DESIGN AND METHODSSimpliciT1 was a phase 1b/2 adaptive study. Phase 2 activities were conducted in two parts. Part 1 randomly assigned 20 participants using continuous glucose monitors and continuous subcutaneous insulin infusion (CSII). Part 2 randomly assigned 85 participants receiving multiple daily injections of insulin or CSII. In both parts 1 and 2, participants were randomly assigned to 800 mg TTP399 or matched placebo (fully blinded) and treated for 12 weeks. The primary end point was change in HbA_1c from baseline to week 12.RESULTSThe difference in change in HbA_1c from baseline to week 12 between TTP399 and placebo was −0.7% (95% CI −1.3, −0.07) in part 1 and −0.21% (95% CI −0.39, −0.04) in part 2. Despite a greater decrease in HbA_1c with TTP399, the frequency of severe or symptomatic hypoglycemia decreased by 40% relative to placebo in part 2. In both parts 1 and 2, plasma β-hydroxybutyrate and urinary ketones were lower during treatment with TTP399 than placebo.CONCLUSIONSTTP399 lowers HbA_1c and reduces hypoglycemia without increasing the risk of ketosis and should be further evaluated as an adjunctive therapy for the treatment of type 1 diabetes.     

Comparison of the Efficacy and Safety of Insulin Detemir and Insulin Glargine in Hospitalized Patients with Type 2 Diabetes: A Randomized Crossover Trial

Introduction

Previous studies comparing insulin detemir versus insulin glargine showed conflicting results, and included only outpatients. This study compared the two insulin analogs once daily in hospitalized patients with type 2 diabetes (T2D).

Methods

A total of 55 patients aged 18–80 years with hyperglycemia admitted to the endocrinology wards were screened between June 2014 and February 2015. Forty-two enrolled patients were randomly assigned to receive either insulin detemir followed by insulin glargine once daily (n = 21), or vice versa (n = 21). The two insulin analogs were titrated 0.1 U/kg once daily based on fasting blood glucose (FBG). After achieving FBG <7.8 mmol/L (the first period), subjects were switched from one analog to the other (the second period) with no change in the dose. The second period lasted for 3 days. When hypoglycemia occurred in the second period, the observation was discontinued. Six-point blood glucose including FBG, 2 h after breakfast, lunch, dinner, bedtime, and at 3:00 am was tested every day. The glucose profiles of the final days in the two periods were compared.

Results

At the end of the first period, days for achieving FBG target (4.0 ± 0.5 days vs. 3.3 ± 0.4 days, t = 1.079, P = 0.286) and total daily dose (30.1 ± 2.4 U vs. 30.1 ± 2.9 U, t = 0.002, P = 0.999) between insulin detemir and insulin glargine were similar. There was no significant difference in the 24-h glucose control between the two analogs. No hypoglycemia occurred with both analogs in the first period. However, in the second period, when insulin glargine was switched to insulin detemir, two, three and, one patients had hypoglycemia events on day 1, day 2 and day 3 of the second period, respectively. One patient had severe hypoglycemia on day 1.

Conclusion

When both basal insulin analogs were given once daily in T2D, insulin detemir achieved similar efficacy to insulin glargine. On the other hand, there may be differences in action of the compared basal insulins. Further studies with larger patient samples are necessary to support evidence and reveal possible mechanisms.