50-mg Group Research Articles

Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease

New therapeutic approaches for Alzheimer disease (AD) are needed. To assess whether idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild to moderate AD. Three randomized clinical trials that included 2525 patients aged 50 years or older with mild to moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites). The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017. Idalopirdine (10, 30, or 60 mg/d) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3). Primary end point in all 3 studies: change in cognition total score (range, 0-70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog); key secondary end points: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores. Dose group efficacy required a significant benefit over placebo for the primary end point and 1 or more key secondary end points. Safety data and adverse event profiles were recorded. Among 2525 patients randomized in the 3 trials (mean age, 74 years; mean baseline ADAS-Cog total score, 26; between 62% and 65% of participants were women), 2254 (89%) completed the studies. In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, -0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, -0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, -0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, -0.55 [95% CI, -1.45 to 0.36]). Treatment-emergent adverse events occurred in between 55.4% and 69.7% of participants in the idalopirdine groups vs between 56.7% and 61.4% of participants in the placebo groups. In patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment. These findings do not support the use of idalopirdine for the treatment of AD. clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654.

Canagliflozin in Conjunction With Sulfonylurea Maintains Glycemic Control and Weight Loss Over 52 Weeks: A Randomized, Controlled Trial in Patients With Type 2 Diabetes Mellitus

PurposeOur aim was to investigate the long-term efficacy and safety of canagliflozin, a sodium−glucose co-transporter 2 inhibitor, added to background sulfonylurea (SU) monotherapy for patients with type 2 diabetes mellitus. MethodsThe CANagliflozin cardioVascularAssessment Study (CANVAS) was a double-blind, placebo-controlled cardiovascular outcomes study that randomly assigned participants to receive placebo or canagliflozin 100 or 300 mg once daily in addition to routine therapy. CANVAS included a prespecified SU substudy of patients taking background doses of SU monotherapy; data from the primary efficacy evaluation at 18 weeks have been published previously. We performed a retrospective analysis of the SU substudy at 52 weeks to measure long-term efficacy and safety of canagliflozin used with an SU. The primary objective of the long-term extension was to assess the change from baseline to 52 weeks in glycosylated hemoglobin (HbA1c). FindingsA total of 215 patients were included in the 52-week extension study. Patients receiving both 100-mg and 300-mg doses of canagliflozin achieved a sustained reduction in HbA1c relative to patients receiving placebo (−0.61% [95% CI, −0.941% to −0.282%] and −0.66% [95% CI, −0.993% to −0.332%], respectively), regardless of baseline HbA1c, duration of diabetes, SU dose, estimated glomerular filtration rate, or body mass index. A sustained reduction in fasting plasma glucose was also found in both 100-mg and 300-mg groups, relative to the placebo group (−2.04 mmol/L [95% CI, −2.778 to −1.299 mmol/L] and −1.88 mmol/L [95% CI, −2.623 to −1.146 mmol/L], respectively). Weight was reduced significantly at 52 weeks in both 100-mg and 300-mg groups, relative to placebo (−1.9% [95% CI, −3.2% to −0.7%] and −2.0% [95% CI, −3.2% to –0.7%], respectively). Reduction in systolic blood pressure was also reported for both dose groups relative to the placebo group, but there was no clear difference in HDL-C, LDL-C, or triglyceride levels. Canagliflozin was generally well tolerated. While documented hypoglycemia occurred in 14% of patients on placebo, the frequency of hypoglycemia with the addition of canagliflozin was similar. There was an increased frequency of genital mycotic infections in both men (5.1%) and women (10.4%) in both canagliflozin groups combined, relative to the placebo group (0%), and their frequency increased in the higher-dose group. There was a slightly higher rate of renal impairment in those treated with canagliflozin versus placebo (2.1% vs 0%). ImplicationsAfter 52 weeks, patients receiving canagliflozin added to background SU had sustained reductions in HbA1c and fasting plasma glucose, without increasing hypoglycemia and body weight; safety findings were generally consistent with the known safety profile of the drug. ClinicalTrials.gov identifier: NCT01032629.

Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease

BackgroundPatients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype may benefit from treatment with mepolizumab, a monoclonal antibody directed against interleukin-5.MethodsWe performed two phase 3, randomized, placebo-controlled, double-blind, parallel-group trials comparing mepolizumab (100 mg in METREX, 100 or 300 mg in METREO) with placebo, given as a subcutaneous injection every 4 weeks for 52 weeks in patients with COPD who had a history of moderate or severe exacerbations while taking inhaled glucocorticoid-based triple maintenance therapy. In METREX, unselected patients in the modified intention-to-treat population with an eosinophilic phenotype were stratified according to blood eosinophil count (≥150 per cubic millimeter at screening or ≥300 per cubic millimeter during the previous year). In METREO, all patients had a blood eosinophil count of at least 150 per cubic millimeter at screening or at least 300 per cubic millimeter during the previous year. The primary end point was the annual rate of moderate or severe exacerbations. Safety was also assessed.ResultsIn METREX, the mean annual rate of moderate or severe exacerbations in the modified intention-to-treat population with an eosinophilic phenotype (462 patients) was 1.40 per year in the mepolizumab group versus 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P=0.04); no significant between-group differences were found in the overall modified intention-to-treat population (836 patients) (rate ratio, 0.98; 95% CI, 0.85 to 1.12; adjusted P>0.99). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100-mg mepolizumab group, 1.27 per year in the 300-mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100-mg and 300-mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P=0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P=0.14), respectively. A greater effect of mepolizumab, as compared with placebo, on the annual rate of moderate or severe exacerbations was found among patients with higher blood eosinophil counts at screening. The safety profile of mepolizumab was similar to that of placebo.ConclusionsMepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations. (Funded by GlaxoSmithKline; METREX and METREO ClinicalTrials.gov numbers, NCT02105948 and NCT02105961.)

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

BackgroundExperimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved.MethodsWe conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.ResultsAt 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31).ConclusionsAntiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.)

DIFFERENCES IN 24-H AMBULATORY BLOOD PRESSURE MONITORING (ABPM) IN PATIENTS SWITCHED BETWEEN DIFFERING EXTENDED-RELEASE FORMULATIONS OF NIFEDIPINE: DOSE SCALING BETWEEN 30-MG VS. 60-MG DOSES

Pharmacies frequently switch patients between the two once-daily osmotic pump formulations of nifedipine-extended-release (nifedipine-XL) deemed to be bioequivalent in Canada. We recently demonstrated statistically significant and clinically important differences in 24-h systolic blood pressures (SBP) when patients are switched between the two 60-mg versions of nifedipine-XL (the original two-compartment pump sold under the brand name Adalat XL = AdN and the newer one-compartment pump sold as Mylan-nifedipine-XL = MyN). We report the comparison of SBP results from ABPM studies on patients switched between the two 30-mg versions of nifedipine-XL (AdN and MyN), and contrast with the 60-mg results using the same protocol. Using a randomized-block, cross-over design, 40 patients receiving morning-dosed AdN or MyN 30 mg were studied using 24-h ABPM at the end of each 2-wk daily dosing period. We compared 24-h SBP (06:00 h - 06:00 h) and terminal 8-h SBP (22:00 h - 06:00 h) for each formulation. Mean ± SE 24-h SBP was 132.6 ± 1.6 mmHg with AdN, and 133.5 ± 1.6 mmHg with MyN (p=0.16). For the terminal 8 h, mean ± SE nocturnal SBP was 123.7 ± 2.0 mmHg with AdN and 125.4 ± 1.9 mmHg with MyN (p=0.18). Plots of the SBP 30-mg curves followed the same pattern as the 60-mg formulations. Some patients had terminal 8-h SBP 22 mmHg higher while taking MyN than while receiving AdN. Patients taking the MyN version of 30-mg nifedipine tended to have less blood pressure control. Although this difference was not statistically significant for the 30-mg group as a whole, some individuals experienced large differences when switched. The lesser overall difference seen when switching between the 30-mg versions (vs. with the 60-mg versions) could be due to: a halving of dose effects on SBP at the lower dose; or improvements in the MyN formulation characteristics made in the interval following the prior release of the 60-mg tablet. However, differences in the release pattern between the first vs. zero-order delivery technologies are conserved in the new MyN tablet, although less apparent at the smaller dose size. While not important on a population basis, switching between the 30-mg formulations of nifedipine-XL by pharmacies can still cause unexplained variability in SBP control in some patients, with unintended management consequences. Both nifedipine formulations work, but given the lack of cost differential, avoiding potential SBP inconsistencies from switches between different delivery technologies remains a reasonable precaution.

Pharmacokinetics, Safety, and Tolerability of Tedizolid Phosphate After Single-dose Administration in Healthy Korean Male Subjects

PurposeTedizolid phosphate is a next-generation oxazolidinone prodrug that is transformed into the active moiety tedizolid. Its indication is acute bacterial skin and skin structure infections caused by gram-positive species, including methicillin-resistant Staphylococcus aureus. Although tedizolid phosphate has been marketed in Korea, no data on the pharmacokinetic (PK) properties or tolerability of tedizolid phosphate in Korean subjects are available. This study was designed to evaluate the PK properties, oral bioavailability, and tolerability with a single-dose oral and intravenous administration of tedizolid phosphate in healthy Korean male subjects. MethodsA block-randomized, double-blind, placebo-controlled, single-dose study was conducted in 3 groups (200, 400, and 600 mg; 10 subjects in each group). In the second part of the study, subjects from the 200-mg group received administration orally and intravenously (1-hour infusion) via 2-way crossover for the evaluation of absolute bioavailability. There was a 7-day washout period between treatments in the absolute bioavailability part of the study. Serial blood samples for PK analysis were collected for up to 72 hours. Tolerability was assessed by analysis of adverse events. FindingsThirty healthy Korean subjects completed the study and were included in the PK and tolerability analyses. Tedizolid phosphate was rapidly converted into tedizolid. After a single oral dose, the Tmax of tedizolid was observed to be 1.5 to 2.5 hours, and the plasma concentration–time curve of tedizolid showed a 2-phase elimination pattern, with a half-life of ~11 hours. Dose-dependent increases were observed in the AUClast value (29,441–78,062 μg · h/L) and in the Cmax value (2679–6980 μg/L) with the administration of tedizolid phosphate 200 to 600 mg PO. The absolute bioavailability of tedizolid was 95.2% (90% CI, 92.7%–97.8%) in the 200-mg administration group. There were no serious adverse events or clinically significant changes in the tolerability assessment. ImplicationsTedizolid phosphate at doses of up to 600 mg was well-tolerated in these healthy Korean male subjects. Tedizolid shows dose linearity with oral administration, and no dose adjustment of tedizolid phosphate 200 mg would be needed when switching administration routes. ClinicalTrials.gov identifier: NCT02097043.

Determining an optimal clinical dose of elobixibat, a novel inhibitor of the ileal bile acid transporter, in Japanese patients with chronic constipation: a phase II, multicenter, double-blind, placebo-controlled randomized clinical trial

BackgroundElobixibat is an oral treatment candidate for chronic constipation with a novel mechanism of action via inhibition of the ileal bile acid transporter. We performed this randomized, double-blind, placebo-controlled, dose-finding phase IIb study in Japanese patients with chronic constipation to determine the optimal clinical dose of elobixibat.MethodsJapanese patients with chronic constipation were randomized to receive elobixibat (5, 10, or 15 mg) or placebo once daily for 2 weeks. The primary efficacy endpoint was the change from baseline in frequency of spontaneous bowel movements at Week 1 of treatment. Secondary endpoints and adverse events were also examined.ResultsAmong 226 patients who provided informed consent, 163 patients were randomized and included in the full analysis set. In the 10- and 15-mg groups, frequency of spontaneous bowel movements (±standard deviation) were significantly higher than baseline (5.7 ± 4.2 and 5.6 ± 3.5 times per week, respectively, compared with 2.6 ± 2.9 times per week in the placebo group [P = 0.0005, P = 0.0001, respectively]). Subgroup analysis indicated that elobixibat was equally effective in patients with or without constipation-predominant irritable bowel syndrome. Common adverse events included mild abdominal pain and diarrhea in the elobixibat groups; no serious or severe adverse events occurred. Elobixibat was well tolerated at once-daily oral doses up to 15 mg for 2 weeks.ConclusionsOur study results suggest that 10 mg of elobixibat is a clinically optimal dose for Japanese patients with chronic constipation.Clinical trial registration numberJapicCTI-142608.

Low-dose tolvaptan PK/PD: comparison of patients with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion to healthy adults

PurposeTolvaptan (TLV) is indicated to treat hyponatremia due to syndrome of inappropriate diuretic hormone (SIADH) in Europe. Treatment is to be initiated at 15 mg QD but post-approval reporting indicates increasing use of 7.5 mg as the starting dose. Physicians believe 7.5 mg is effective and has a lower incidence of overly rapid correction of serum sodium.MethodsSingle TLV doses of 3.75, 7.5, and 15 mg were administered to 14 healthy adults in a crossover design and to 29 subjects ≥18 years with SIADH and serum sodium between 120 and 133 mmol/L in a parallel-group design. Pharmacodynamics and TLV plasma concentrations were assessed for 24 h post-dose.ResultsIn SIADH subjects, corrections of serum sodium (Δ of ≥8 mmol/L in the first 8 h or ≥12 mmol/L in the first 24 h) were observed in one, one, and two subjects in the 3.75-, 7.5-, and 15-mg dose groups. Fluid balance (FB) for 0–6 h post-dose was correlated (r2 = 0.37) with maximum increases in serum sodium; subjects with large corrections had large (~1 L) negative FB. Compared to healthy adults, subjects with SIADH did not drink in response to their negative FB and had larger increases in serum sodium at 24 h. Median time of maximum increase in healthy adults was 6 h, with no rapid corrections, and FB was near 0 mL by 24 h.ConclusionStarting titration with 7.5 mg TLV will not eliminate the risk of rapid corrections in serum sodium. Monitoring FB may indicate that a subject is at risk for over correction.

An up-down determination of the required seated duration after intrathecal injection of bupivacaine and fentanyl for the prevention of hypotension during Cesarean delivery

A prolonged seated time after intrathecal injection of hyperbaric bupivacaine and morphine is related to the incidence of hypotension during Cesarean delivery, but results in a high incidence of pain during peritoneal closure. We conducted this study to determine the effect of the addition of intrathecal fentanyl on the relationship between seated time and hypotension and intraoperative analgesia requirements. Women undergoing Cesarean delivery were randomized to receive an intrathecal injection of either 11.25 or 15 mg of hyperbaric bupivacaine with morphine 150 µg and fentanyl 15 µg using a combined spinal-epidural technique. The seated duration following intrathecal injection was assigned using up-down methodology. If the preceding patient was hypo- or normotensive, the next patient sat for 15 sec more or less, respectively. A systolic blood pressure < 80% of the preoperative value was defined as hypotension; a standardized anesthetic was administered, and the presence of pain during the procedure was recorded. Isotonic regression of pooled adjacent violators was used to determine the time at which 50% of each group would avoid hypotension (i.e., the median effective seated time). There were 15 patients in each group. The median seated time was 129 sec (95% confidence interval [CI], 116 to 150) for the 11.25-mg group and 459 sec (95% CI, 444 to 471) for the 15-mg group. Only one (3%) of the 30 patients in the study had pain on peritoneal closure, and this was successfully treated with intravenous fentanyl. We have determined the seated time required following intrathecal injection of hyperbaric bupivacaine, morphine, and fentanyl to prevent hypotension in 50% of patients undergoing Cesarean delivery. www.clinicaltrials.gov , NCT01896960. Registered 2 July 2013.

Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis

BackgroundHereditary angioedema with C1 inhibitor deficiency is characterized by recurrent, unpredictable swelling episodes caused by uncontrolled plasma kallikrein generation and excessive bradykinin release resulting from cleavage of high-molecular-weight kininogen. Lanadelumab (DX-2930) is a new kallikrein inhibitor with the potential for prophylactic treatment of hereditary angioedema with C1 inhibitor deficiency.MethodsWe conducted a phase 1b, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients with hereditary angioedema with C1 inhibitor deficiency were randomly assigned in a 2:1 ratio to receive either lanadelumab (24 patients) or placebo (13 patients), in two administrations 14 days apart. Patients assigned to lanadelumab were enrolled in sequential dose groups: total dose of 30 mg (4 patients), 100 mg (4 patients), 300 mg (5 patients), or 400 mg (11 patients). The pharmacodynamic profile of lanadelumab was assessed by measurement of plasma levels of cleaved high-molecular-weight kininogen, and efficacy was assessed by the rate of attacks of angioedema during a prespecified period (day 8 to day 50) in the 300-mg and 400-mg groups as compared with the placebo group.ResultsNo discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group.ConclusionsIn this small trial, administration of lanadelumab to patients with hereditary angioedema with C1 inhibitor deficiency reduced cleavage of high-molecular-weight kininogen and attacks of angioedema. (Funded by Dyax; ClinicalTrials.gov number, NCT02093923.)

Quantifying Barriers to Improvement of Treatment Satisfaction in Men With Erectile Dysfunction: Use of Person-Item Maps

IntroductionPatient-reported outcomes are a valuable tool used to gauge treatment satisfaction in different conditions, including erectile dysfunction (ED). AimTo use person-item maps to quantify barriers to improvement of treatment satisfaction in men with ED. MethodsMen 18 to 65 years old with documented ED received sildenafil 50 mg, sildenafil 100 mg, or placebo for 8 weeks in a double-blinded manner. Post hoc analyses were conducted on Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) data (11 items rating treatment satisfaction; each item score range = 0–4). Main Outcome MeasuresPerson-item maps were developed based on Rasch models. To quantify barriers to improvement of treatment satisfaction, responses to the 11 items of the EDITS questionnaire were dichotomized to indicate improvement (responses of 3 or 4 were combined to a score of 1) vs no change or worsening (responses of 0, 1, or 2 were combined to a score of 0). ResultsAnalyses were conducted using data from 278 men who completed the EDITS questionnaire at the end of double-blinded treatment. The person-item map indicated that EDITS item 4 (ease of use of treatment) was the easiest barrier to overcome, whereas the most difficult barrier to improvement of treatment satisfaction was EDITS item 2 (degree to which treatment met expectations). Most men in the sildenafil 100-mg group endorsed most EDITS items, consistent with substantial improvement. The sildenafil 50-mg group was similar, but with smaller frequencies for endorsing improvement of the more difficult EDITS items. In contrast, men receiving placebo endorsed mainly the easiest EDITS items, with only a small number of men endorsing the difficult items. ConclusionA person-item map is a useful means for quantifying barriers to improvement of treatment satisfaction represented by EDITS items in patients with ED.

Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial

Nonsteroidal anti-inflammatory drugs are used extensively for the management of acute and chronic pain, with ketorolac tromethamine being one of the most frequently used parenteral analgesics in the emergency department (ED). The drugs may commonly be used at doses above their analgesic ceiling, offering no incremental analgesic advantage while potentially adding risk of harm. We evaluate the analgesic efficacy of 3 doses of intravenous ketorolac in ED patients with acute pain. We conducted a randomized, double-blind trial to assess the analgesic efficacy of 3 doses of intravenous ketorolac (10, 15, and 30 mg) in patients aged 18 to 65 years and presenting to the ED with moderate to severe acute pain, defined by a numeric rating scale score greater than or equal to 5. We excluded patients with peptic ulcer disease, gastrointestinal hemorrhage, renal or hepatic insufficiency, allergies to nonsteroidal anti-inflammatory drugs, pregnancy or breastfeeding, systolic blood pressure less than 90 or greater than 180 mm Hg, and pulse rate less than 50 or greater than 150 beats/min. Primary outcome was pain reduction at 30 minutes. We recorded pain scores at baseline and up to 120 minutes. Intravenous morphine 0.1 mg/kg was administered as a rescue analgesic if subjects still desired additional pain medication at 30 minutes after the study drug was administered. Data analyses included mixed-model regression and ANOVA. We enrolled 240 subjects (80 in each dose group). At 30 minutes, substantial pain reduction was demonstrated without any differences between the groups (95% confidence intervals 4.5 to 5.7 for the 10-mg group, 4.5 to 5.6 for the 15-mg group, and 4.2 to 5.4 for the 30-mg group). The mean numeric rating scale pain scores at baseline were 7.7, 7.5, and 7.8 and improved to 5.1, 5.0, and 4.8, respectively, at 30 minutes. Rates of rescue analgesia were similar, and there were no serious adverse events. Secondary outcomes showed similar rates of adverse effects per group, of which the most common were dizziness, nausea, and headache. Ketorolac has similar analgesic efficacy at intravenous doses of 10, 15, and 30 mg, showing that intravenous ketorolac administered at the analgesic ceiling dose (10 mg) provided effective pain relief to ED patients with moderate to severe pain without increased adverse effects.

Effects of Increasing Hydrocortisone to 300 mg Per Day in the Treatment of Septic Shock: a Pilot Study.

The Surviving Sepsis Campaign guidelines recommend hydrocortisone in septic shock only when fluid resuscitation and vasopressors fail to restore hemodynamic stability. Hydrocortisone administration modalities are supported only by low-grade recommendations. Our main objective here was to determine differences in 28-day mortality between two low-dose hydrocortisone regimens for the treatment of septic shock. We performed a multicenter, prospective, randomized, double-blind, pilot study in four adult medical intensive care units. Patients presenting septic shock were rapidly administered one of two regimens of hydrocortisone, either a 50-mg intravenous bolus every 6 h during 7 days (200-mg group; n = 59) or a 100-mg initial bolus followed by a continuous infusion of 300 mg daily for 5 days (300-mg group; n = 63). Hydrocortisone was stopped abruptly at the end of treatment. There were no significant differences between the 200-mg and 300-mg groups as concerns 28-day mortality (respectively 52.5% vs. 44.4% [RR 0.84, 95% CI, 0.58-1.22, P = 0.47]), refractory shock incidence or delay from shock to vasopressor cessation. There were also no differences in adverse events between the groups. Shock relapse after hydrocortisone cessation was independent of hydrocortisone regimens, but it was associated with the persistence of infection and the use of etomidate. The resumption of hydrocortisone due to shock relapse was significantly more frequent in the 300-mg group. We found no differences in mortality or adverse events between the two hydrocortisone administration regimens. Shock relapse was significantly associated with the persistence of infection and the use of etomidate.

TRPV1 antagonist JNJ-39439335 (mavatrep) demonstrates proof of pharmacology in healthy men: a first-in-human, double-blind, placebo-controlled, randomized, sequential group study.

This double-blind, randomized, placebo-controlled, sequential group, phase 1 study was designed to assess in healthy men, the safety, tolerability, pharmacokinetics, and translational pharmacodynamics of JNJ-39439335 (mavatrep), a transient receptor potential vanilloid subtype 1 antagonist; it was preceded by a translational preclinical study which assessed the ability of JNJ-39439335 to block capsaicin-induced flare in rats, providing predictive pharmacokinetic and pharmacodynamic data that informed the subsequent phase 1 clinical study. The clinical study consisted of 2 parts: part 1 assessed pharmacokinetics and pharmacodynamics, including heat pain detection threshold and heat pain tolerance, of JNJ-39439335, and part 2 assessed pharmacodynamic effect of JNJ-39439335 on capsaicin-induced flare and sensory testing on naïve and UVB-sensitized skin in humans. Plasma concentrations of JNJ-39439335 peaked at approximately 2 to 4 hours postdose, then declined multiexponentially, with a prolonged terminal phase (half-life: 30-86 hours). Renal clearance of JNJ-39439335 was negligible. JNJ-39439335 treatment resulted in clear, consistent dose-related increases in heat pain detection threshold, heat pain tolerance, and heat pain latency. JNJ-39439335 reduced the capsaicin-induced flare area and flare intensity, with complete blocking observed in the 50-mg dose group at 144 hours postdose. This was consistent with the capsaicin flare results observed with JNJ-39439335 in rats. The most common adverse events observed in the clinical study were related to increases in body temperature after JNJ-39439335 treatment; these were predominately mild to moderate in severity with no evidence of exposure dependence up to 225 mg. JNJ-39439335 was well tolerated at single doses up to 225 mg, recommending its suitability for further clinical development.

A Randomized, Double-blind, Active-Controlled, Multi-center Study of Ilaprazole in the Treatment of Reflux Esophagitis

Proton pump inhibitors (PPIs) are the main drugs for the treatment of reflux esophagitis. Previous studies have indicated ilaprazole to be safer and more effective in treating duodenal ulcers as compared with omeprazole. Being a novel PPI, ilaprazole may be used in the treatment of reflux esophagitis. The purpose of this study was to evaluate the safety and efficacy of ilaprazole tablets in the treatment of reflux esophagitis. This study used a randomized, double-blind, multi-center, active-comparison design. The patients were randomly divided into an ilaprazole group (10mg once daily and 15mg once daily) and an esomeprazole group (40mg once daily). Both the groups were treated for 8weeks. Heartburn and reflux symptoms prior to treatment, and 4 and 8weeks after the treatment were assessed. Gastroscopy was performed after 4 and 8weeks. The healing rate after 4weeks treatment was compared. If esophagitis was healed at the end of 4weeks, patients did not undergo gastroscopy at the end of 8weeks. Three hundred and twenty-five patients were enrolled in this study. The 4-week full analysis set (per-protocol set) healing rates in the esomeprazole 40-mg group, the ilaprazole 10-mg group, and the ilaprazole 15-mg group were: 71.43% (78.89%), 81.31% (86.73%), and 71.70% (81.40%), respectively, p=0.1595 (0.4122); the 8-week healing rates were 84.76% (93.33%), 88.79% (94.90%), and 85.85% (97.67%), respectively, p=0.6689 (0.4049). Drug-related adverse events rate were 10.48%, 14.02%, and 15.09%, respectively, in the three groups (p=0.6114). The efficacy and safety of ilaprazole (10mg/day, 15mg/day) in treating reflux esophagitis was similar to esomeprazole (40mg/day). Ilaprazole (10mg/day) has a smaller dosage, hence it should be considered more in clinical uses. ClinicalTrials.gov NCT01107938.

Effect of Bevacizumab Nasal Spray on Epistaxis Duration in Hereditary Hemorrhagic Telangectasia: A Randomized Clinical Trial.

Epistaxis is the most frequent and disabling manifestation of hereditary hemorrhagic telangiectasia (HHT). The efficacy of intravenous bevacizumab (an anti-vascular endothelial growth factor monoclonal antibody) for epistaxis has been shown. However, the efficacy of intranasal bevacizumab has yet to be evaluated. To evaluate the efficacy of 3 different doses of bevacizumab administered as a nasal spray in a repeated manner for the duration of nosebleeds in patients with HHT. Randomized, multicenter, placebo-controlled, phase 2/3 clinical trial with dose selection at an intermediate analysis and prespecified stopping rules (nonbinding stopping for futility). Patients aged 18 years or older with a diagnosis of HHT were recruited from 5 French centers from April 2014 to January 2015 with a 6-month follow-up after the end of treatment. Participants had a history of self-reported nosebleeds with a monthly duration of more than 20 minutes in at least the 3 months prior to inclusion corroborated by epistaxis grids completed during the same preinclusion period. Eighty consecutive HHT patients were randomized and treated in the phase 2 study, with 4 parallel groups in a 1:1:1:1 ratio. One group received placebo (n = 21); the other 3 received bevacizumab nasal spray. Each bevacizumab group received a different dose of the drug (25 mg [n = 20], 50 mg [n = 20], or 75 mg [n = 19] per treatment) in 3 doses 14 days apart for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, and 225 mg in each treatment group. Mean monthly epistaxis duration for 3 consecutive months immediately after the end of the treatment. Of the 80 patients who were randomized (mean age, 60.47 [SD, 10.61] years; 37 women [46.25%]), 75 completed the study. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 59 patients receiving bevacizumab in comparison with the placebo group (P = .57) or between the bevacizumab groups. The mean monthly epistaxis duration was 259.2 minutes (95% CI, 82.1-436.3 minutes) in the 25-mg group, 244.0 minutes (95% CI, 81.8-406.2 minutes) in the 50-mg group, 215.0 minutes (95% CI, 102.8-327.2 minutes) in the 75-mg group, and 200.4 minutes (95% CI, 109.3-291.5 minutes) in the placebo group. Toxicity was low and no severe adverse events were reported. This study was terminated prior to phase 3 for treatment futility after interim analysis on the recommendations of an independent data monitoring committee. In patients with HHT, a bevacizumab nasal spray treatment of 3 administrations at 14-day intervals with doses of 25 mg, 50 mg, or 75 mg per spray, compared with a placebo, did not reduce monthly epistaxis duration in the 3 consecutive months immediately after the end of treatment. clinicaltrials.gov Identifier: NCT02106520.

Optimal Dose of Calcium for Treatment of Nutritional Rickets: A Randomized Controlled Trial.

Calcium supplementation is indicated for the treatment of nutritional rickets. Our aim was to determine the optimal dose of calcium for treatment of children with rickets. Sixty-five Nigerian children with radiographically confirmed rickets were randomized to daily supplemental calcium intake of 500 mg (n = 21), 1000 mg (n = 23), or 2000 mg (n = 21). Venous blood, radiographs, and forearm areal bone density (aBMD) were obtained at baseline and at 8, 16, and 24 weeks after enrollment. The primary outcome was radiographic healing, using a 10-point radiographic severity score. The radiographic severity scores improved in all three groups, but the rate of radiographic healing (points per month) was significantly more rapid in the 1000-mg (-0.29; 95% confidence interval [CI] -0.13 to -0.45) and 2000-mg (-0.36; 95% CI -0.19 to -0.53) supplementation groups relative to the 500-mg group. The 2000-mg group did not heal more rapidly than the 1000-mg group. Of those who completed treatment for 24 weeks, 12 (67%), 20 (87%), and 14 (67%) in the 2000-mg, 1000-mg, and 500-mg groups, respectively, had achieved a radiographic score of 1.5 or less (p = 0.21). Serum alkaline phosphatase decreased and calcium increased similarly in all groups. Forearm diaphyseal aBMD improved significantly more rapidly in the 2000-mg group than in the 500-mg and 1000-mg groups (p < 0.001). Daily calcium intakes of 1000 mg or 2000 mg produced more rapid radiographic healing of rickets than 500 mg, but 2000 mg did not have greater benefit than 1000 mg. Some children require longer than 24 weeks for complete healing of nutritional rickets. © 2016 American Society for Bone and Mineral Research.

Dose-ranging effect of systemic diphenhydramine on postoperative quality of recovery after ambulatory laparoscopic surgery: a randomized, placebo-controlled, double-blinded, clinical trial

Study objectiveDiphenhydramine is an antihistamine with previously demonstrated analgesic and antiemetic properties. However, it is unknown if the beneficial perioperative properties of diphenhydramine can translate to a better quality of postsurgical recovery. The main objective of the current investigation was to investigate dose-ranging effects of diphenhydramine on quality of recovery after surgery. SettingTertiary hospital in the United States. DesignA prospective, randomized, double-blind trial. InterventionSaline, diphenhydramine 25 >mg, or diphenhydramine 50 mg given intravenously before induction. MeasurementsThe primary outcome was global Quality of Recovery–40 at 24hours. Postoperative pain, nausea, opioid consumption, and discharge time were also evaluated. Main resultsNinety subjects were randomized, and 75 completed the study. The median (interquartile range) Quality of Recovery–40 scores were not different among study groups: 164 (151-189), 169 (159-181), and 172 (157-185) for the saline, 25-mg diphenhydramine, and 50-mg diphenhydramine groups, respectively (P=.74). Postoperative nausea was decreased in the 50-mg group, 3 of 24 (12.5%), compared with the saline group, 12 of 27 (44%), P=.01. There was an inverse linear association between postoperative opioid consumption and quality of recovery (R2=0.37, P<.001). ConclusionsDiphenhydramine does not provide dose-ranging improvements on postoperative quality of recovery after ambulatory laparoscopic gynecologic surgery. Our results support a recent concept that not all postoperative nausea and vomiting symptoms are clinically important. Future studies evaluating postoperative nausea and vomiting should include patient-centered outcomes to validate the clinical importance of the examined interventions.

Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical and MRI findings

ObjectiveTo assess early effects on joint structures of VX-509 in combination with stable disease-modifying antirheumatic drug (DMARD) therapy using MRI in adults with rheumatoid arthritis (RA).MethodsThis phase II, placebo-controlled, double-blind,...

Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia

BackgroundNew treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells.MethodsWe conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day.ResultsThe majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%.ConclusionsSelective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.)