Efficacy and safety of tamsulosin 0.4 mg single pills for treatment of Asian patients with symptomatic benign prostatic hyperplasia with lower urinary tract symptoms: a randomized,double-blind,phase 3 trial

Objective: To verify the efficacy and safety of tamsulosin 0.4?mg and tamsulosin 0.2?mg compared with those of placebo in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

Methods: A total of 494 patients from multiple centers participated in this double-blind, randomized, phase 3 trial. Eligible patients were randomly assigned to the tamsulosin 0.4?mg group, tamsulosin 0.2?mg group or placebo group. The International Prostate Symptom Score (IPSS), maximum flow rate (Qmax), post-void residual (PVR) urine volume, blood pressure, heart rate and adverse events were compared among the three groups at 4, 8 and 12 weeks.

Results: A total of 494 BPH patients were analyzed. There were no differences in the baseline characteristics among the three groups. After 12 weeks of treatment, total IPSS was improved in the 0.2?mg and 0.4?mg tamsulosin groups; however, the extent of improvement was greater in the 0.4?mg group than in the 0.2?mg group (0.4?mg: ?9.59 vs. 0.2?mg: ?5.61; least-squares mean difference [95% confidence interval]: ?3.95 [?5.01, ?2.89], p?p?Qmax and PVR were improved in the 0.4?mg and 0.2?mg groups; however, the differences were not statistically significant between treatment groups. No patients experienced any serious adverse effects in any of the three groups.

Conclusions: Tamsulosin 0.4?mg and 0.2?mg appear to be superior to placebo treatment, and tamsulosin 0.4?mg is more effective than 0.2?mg in terms of total IPSS improvement. Tamsulosin 0.4?mg has favorable efficacy and tolerability in Asian men with symptomatic BPH.

ClinicalTrials.gov Identifier: NCT02390882.     

A randomized,double-blind,placebo-controlled study of escitalopram in patients with social anxiety disorder in Japan

Objective This randomized, double-blind placebo-controlled study compared the efficacy and tolerability of escitalopram (10 and 20?mg/day) in Japanese patients with social anxiety disorder (SAD).

Research design and methods Patients aged 18–64 years with a primary diagnosis of DSM-IV-TR defined SAD, a Liebowitz Social Anxiety Scale Japanese version (LSAS-J) total score ≥60 and a Clinical Global Impression–Severity (CGI-S) score ≥4 at baseline were randomly assigned (1:1:1) to placebo, escitalopram 10?mg or escitalopram 20?mg. The primary endpoint was change from baseline to Week 12 in the LSAS-J total score for both escitalopram 10?mg and 20?mg versus placebo (ANCOVA, FAS, LOCF), using a hierarchical testing procedure. Pre-specified secondary endpoints included LSAS-J sensitivity analyses.

Clinical trial registration This study has the www.japic.or.jp identifier: JapicCTI-121842.

Results For the primary efficacy endpoint, the difference from placebo in the LSAS-J was ?3.9 (p?=?0.089) for escitalopram 10?mg. Since the superiority of escitalopram 10?mg over placebo was not confirmed, an analysis without multiplicity adjustment was made, which showed a difference for escitalopram 20?mg versus placebo of ?9.8 (p?<?0.001). In pre-specified sensitivity analyses, the difference versus placebo was ?4.9 (p?=?0.035) (ANCOVA, FAS, OC) and ?5.0 (p?=?0.028) (MMRM, FAS) (escitalopram 10?mg) and ?10.1 (p?<?0.001) (ANCOVA, FAS, OC) and ?10.6 (p?<?0.001) (MMRM, FAS) (escitalopram 20?mg). Common adverse events (incidence ≥5% and significantly different from placebo) were somnolence, nausea and ejaculation disorder.

Conclusion Escitalopram was efficacious, safe and well tolerated by patients with SAD in Japan. Study limitations are discussed including patient characteristics.     

Clinical acceptability study of micronized purified flavonoid fraction 1000 mg tablets versus 500 mg tablets in patients suffering acute hemorrhoidal disease

Objective: To compare the clinical acceptability of micronized purified flavonoid fraction (MPFF) 1000?mg with MPFF 500?mg tablets, administered at the same daily dose in patients suffering non-complicated acute hemorrhoids.

Background: MPFF is an established treatment for hemorrhoidal disease.

Methods: This was a double-blind, multi-center, randomized study. Patients took either MPFF 1000?mg or 500?mg tablets for 7 days (daily dose; 3?g over 4 days followed by 2?g over 3 days). Adverse events were recorded in a patient diary. On day 7, anal pain and bleeding were assessed (visual analog scale [VAS] and Dimitroulopoulos scale, respectively).

Results: Patients (162) were randomized to MPFF 1000?mg (79) and MPFF 500?mg (83). No serious adverse events (AEs) occurred; 10 emergent AEs were considered treatment-related (6 for MPFF 1000?mg and 4 for 500?mg). Both regimens were associated with significant reduction in anal pain (VAS); ?2.37?cm MPFF 1000?mg (P?<?0.001) and ?2.17?cm 500?mg (P?<?0.001), with a slight trend in favor of MPFF 1000?mg (mean global reduction ?2.27?cm, P?<?0.001). Bleeding improved significantly in both groups of patients, 56% of patients on MPFF 1000?mg versus 61% on MPFF 500?mg. Bleeding ceased after treatment in 47% patients on MPFF 1000?mg versus 54% on 500?mg.

Conclusion: After 7 days of treatment with MPFF at the same daily dose, both regimens reduced anal pain and bleeding. MPFF 1000?mg had a comparable safety profile to MPFF 500?mg, with the advantage of fewer tablets.

Key limitations: Safety study.     

LDL cholesterol levels after switch from atorvastatin to rosuvastatin

Objective: Initial statin therapy may not always adequately reduce elevated low-density lipoprotein cholesterol (LDL-C) levels. Although alternative therapies are available, switching to another statin may be beneficial, especially for those at highest risk of cardiovascular disease and events. This study examined changes in LDL-C levels following a switch from 40/80?mg of atorvastatin (ATV) to 20/40?mg of rosuvastatin (RSV).

Methods: This retrospective cohort study used data from the MarketScan administrative claims databases linked to laboratory values. Patients with or at risk for atherosclerotic cardiovascular disease (ASCVD) who switched from ATV 40/80?mg to RSV 20/40?mg and had LDL-C values measured within 90 days before and 30–180 days after the switch were included. The change in LDL-C was quantified for each patient and summarized across all patients and within each switch pattern (e.g. ATV40 to RSV20).

Results: There was a significant mean (SD) decrease in LDL-C of 21% (30%) across the whole sample (N?=?136) after switching from ATV to RSV. The greatest decrease occurred in patients who switched from ATV40 to RSV40 (N?=?20; ?29% [19%]; p?N?=?112; ?24% [24%]; p?Conclusions: Switching from ATV to RSV was associated with a significant decrease in LDL-C among high-risk patients. Switching between these two high-intensity statins may offer a viable alternative to other treatment modifications aimed at lowering LDL-C in this population.     

Blood pressure reduction with olmesartan in mild-to-moderate essential hypertension:a planned interim analysis of an open label sub-study in German patients

ABSTRACT

Objective: To present the baseline characteristics and open-label treatment phase results for German patients in OLMEBEST, a European, multinational, partially randomized, partially double-blind study in patients with mild-to-moderate essential hypertension.

Research design and methods: After a 2‐week placebo run-in, patients received olmesartan 20?mg for 8 weeks. Controlled patients (mean sitting diastolic blood pressure [sDBP] < 90?mmHg) continued on olmesartan 20?mg/day for a further 4 weeks. Non-controlled patients (sDBP > 90?mmHg) were randomized to olmesartan 40?mg/day or olmesartan 20?mg/day plus 12.5?mg hydrochlorothiazide for 4 weeks. Of 823 patients included, 558 continued olmesartan 20?mg treatment and 228 patients were randomized to olmesartan 40?mg/day or combination therapy. Efficacy variables included the change from baseline in mean sitting DBP and systolic blood pressure [sSBP] at Week 8 (and Week 12 for controlled patients), and the proportion of controlled patients and responders (mean sDBP < 90?mmHg or improvement of > 10?mmHg from baseline at Week 8).

Results: After 8 weeks of olmesartan medoxomil 20?mg, mean reduction from baseline in sDBP was 11.8?mmHg and in sSBP was 17.1?mmHg. In controlled patients continuing open-label olmesartan medoxomil 20?mg, mean reduction from baseline at 12 weeks in sDBP was 14.9?mmHg and in sSBP was 20.1?mmHg. At Week 8, the response rate was 76% and the control rate was 70%. Olmesartan medoxomil 20?mg/day was well tolerated; 30.9% of patients experienced an adverse event, and the majority of these events were judged by the investigators to be mild.

Conclusion: Olmesartan medoxomil monotherapy at the recommended dosage of 20?mg once daily is effective and well tolerated in patients with mild-to-moderate hypertension.     

Real-world utilization of methotrexate or prednisone co-therapy with etanercept among Canadian patients with rheumatoid arthritis: a retrospective cohort study

Objective: To evaluate whether initiation of etanercept therapy among patients with rheumatoid arthritis (RA) impacts use of co-therapy with methotrexate or prednisone, and to describe etanercept dosing dynamics compared to product monograph in the Canadian real-world setting.

Methods: A retrospective cohort study was conducted using claims-level data from IQVIA Private Drug Plan database, Ontario Public Drug Plan database and Régie de l’assurance maladie du Québec database. Bio-naïve RA patients initiating etanercept between July 2014 and June 2015 were identified and their claims for methotrexate or prednisone were analyzed. Utilization of methotrexate or prednisone was calculated as average weekly dose in milligrams, and compared in the 6?months pre-initiation versus 12?months post-initiation of etanercept. Weekly etanercept dosing of each patient was calculated and analyzed to determine whether patients had at least 20% higher or lower average dose than monograph recommended dose (50?mg/week), and were then flagged as above-monograph or below-monograph, respectively.

Results: A total of 2876 patients with RA (66% female, 76% aged 18–65) were included; 62% (n?=?1,140) used methotrexate and 27% used prednisone (n?=?498) both pre- and post-initiation of etanercept. In methotrexate patients, the average weekly dose dispensed was 25.4?mg in the 6?months pre-etanercept, and 25.0?mg in the 12?months post-etanercept initiation (p?=?.5282). In prednisone patients, the average weekly dose dispensed reduced from 122.6?mg pre-etanercept to 107.1?mg post-etanercept initiation (p?=?.2173). Among patients who were already on methotrexate or prednisone, after initiating on etanercept 16% (n?=?213) and 34% (n?=?254) of patients stopped methotrexate and prednisone, respectively. When compared to the recommended dose, 12% (n?=?168) of patients were below-monograph and 7.1% of patients were above-monograph during their first year of etanercept therapy. Average etanercept dosing was consistently lower than product monograph during the follow-up year.

Conclusions: Patients had a modest but not statistically significant decrease in prescribed doses of co-therapy with methotrexate and prednisone when etanercept was added to patients’ therapy. In addition, 12–14% of patients stopped their co-therapy with methotrexate or prednisone. Further study is needed to understand the impact on patient outcomes and safety.     

Clinical implications of 750 mg, 5-day levofloxacin for the treatment of community-acquired pneumonia

SUMMARY

Objective: To evaluate the time to symptom resolution and IV-to-PO transition in community-acquired pneumonia (CAP) patients treated with 750?mg or 500?mg levofloxacin.

Research Design: A retrospective, subset analysis of a multicenter, randomized, double-blind, controlled trial comparing 750?mg levofloxacin for 5 days to 500?mg levofloxacin for 10 days for the treatment of CAP.

Patients and Methods: A total of 528 CAP patients were included. Baseline symptoms were re-evaluated on Day 3 of therapy, and time to IV-to-PO transition was recorded for inpatients.

Results: For the overall population, 67.4% of patients receiving 750?mg levofloxacin had resolution of fever by Day 3 of therapy, compared to 54.6% of 500?mg treated patients (?P = 0.006). Patients who started on 750?mg levofloxacin IV (?N = 108) transitioned to PO in an average of 2.68 days while those starting on 500?mg IV (?N = 124) transitioned in 2.95 days (?P = 0.144). The median time for IV-to-PO switch was 2.35 days and 2.75 days for patients receiving 750?mg and 500?mg levofloxacin, respectively (?P = 0.098, log rank test). By Day 3 of therapy, 68% of patients receiving the 750?mg dose had transitioned from IV to PO levofloxacin, compared with 61% of the 500?mg group (?P = 0.280). The safety profiles were comparable for the two regimens.

Conclusions: The 750?mg levofloxacin dose resulted in a greater proportion of patients with resolution of CAP symptoms by Day 3 when compared with 500?mg therapy. Consequently, the 750?mg regimen trended toward more rapid transition to PO, potentially resulting in lower overall drug costs. Time to switch from IV to PO was determined by the investigators’ discretion rather than a set protocol. Additionally, length of stay data was not collected in this study, which can significantly impact overall healthcare costs. Further research is required to fully understand the economic impact of the 750?mg, 5-day levofloxacin regimen.     

Effect on blood pressure control of switching from valsartan monotherapy to losartan/hydrochlorothiazide in Asian patients with hypertension: results of a multicentre open-label trial

ABSTRACT

Study design: An open-label, multicentre study was conducted to evaluate the antihypertensive efficacy of a 4-week course of losartan 50?mg plus hydrochlorothiazide 12.5?mg in Asian patients with essential hypertension whose blood pressure had previously been treated with but not controlled by valsartan 80?mg.

Methods: A total of 237 eligible patients with mean trough sitting diastolic blood pressure (SiDBP) 95–115?mmHg and a mean trough sitting systolic blood pressure (SiSBP) < 190?mmHg entered the baseline period of treatment with valsartan 80?mg/day for 4 weeks. Those (n = 165) whose SiDBP remained > 90?mmHg and who were not excluded for other reasons were then switched to a single-tablet formulation of losartan 50?mg/hydrochlorothiazide 12.5?mg combination once daily for a further 4 weeks.

Results: Mean SiDBP (study primary endpoint) at the end of combination therapy was reduced to 86.9 mmHg from 95.2 mmHg. SiSBP (study secondary endpoint) was reduced to 132.6 mmHg from 140.7 mmHg. Mean reductions after switching from valsartan 80?mg to losartan 50?mg/hydrochlorothiazide 12.5?mg were thus 8.3 and 8.1 mmHg for SiDBP and SiSBP, respectively (?p ≤ 0.001 for both outcomes). The goal of SiDBP ≤ 90 mmHg was attained in 72% of the patients previously not controlled to the same level by valsartan 80?mg/day. Combination therapy with losartan 50?mg/hydrochlorothiazide 12.5?mg was generally well tolerated. Mean compliance with the losartan 50?mg/hydrochlorothiazide 12.5?mg combination was > 99%.

Conclusion: These results demonstrate that in Asian patients who do not reach the goal of mean trough SiDBP ≤ 90?mmHg with valsartan monotherapy at 80?mg once-daily, switching to a single-tablet combination of losartan 50?mg/hydrochlorothiazide 12.5?mg once-daily is well tolerated, provides effective control of blood pressure and is an excellent choice to achieve blood pressure reduction goals.     

Treatment of Overactive Bladder with Once-daily Extended-release Tolterodine or Oxybutynin: The Antimuscarinic Clinical Effectiveness Trial (ACET)

Summary

Treatment with the antimuscarinic agents tolterodine and oxybutynin is the mainstay of therapy for overactive bladder, a chronic and debilitating condition characterized by urinary urgency with or without urge incontinence, usually in combination with urinary frequency and nocturia. This study consisted of two trials; in one, patients with overactive bladder were randomized to 8 weeks of open-label treatment with either 2?mg or 4?mg of once-daily extended-release tolterodine (TER), and in the other to 5?mg or 10?mg of extended-release oxybutynin (OER). The study protocol and design were identical for the two trials and site selection ensured that there was no bias in either trial for the tendency of investigators to prescribe one drug rather than the other, or for geographical location. A total of 1289 patients were enrolled, 669 in the tolterodine trial (TER 2?mg, n?=?333; TER 4?mg, n?=?336) and 620 in the oxybutynin trial (OER 5?mg, n?=?313; OER 10?mg, n?=?307). Fewer patients prematurely withdrew from the trial in the TER 4?mg group (12%) than either the OER 5?mg (19%; p?=?0.01) or OER 10?mg groups (21%; p?=?0.002). More patients in the OER 10?mg group than the TER 4?mg group withdrew because of poor tolerability (13% vs 6%; p?=?0.001). After 8 weeks, 70% of patients in the TER 4?mg group perceived an improved bladder condition, compared with 60% in the TER 2?mg group, 59% in the OER 5?mg group and 60% in the OER 10?mg group (all p?<?0.01 vs TER 4?mg). Response to therapy was greater in a subgroup of patients whose perception of bladder condition was moderate to severe at baseline (TER 4?mg 77% vs OER 10?mg 65%; p?<?0.01). Dry mouth was dose-dependent with both agents, although differences between doses only reached statistical significance in the oxybutynin trial (OER 5?mg vs OER 10?mg; p?=?0.05). Patients treated with TER 4?mg reported a significantly lower severity of dry mouth compared with OER 10?mg. In conclusion, the greater efficacy and tolerability of tolterodine ER 4?mg suggests improved clinical effectiveness compared with oxybutynin ER 10?mg.     

Use of almotriptan in triptan-experienced and triptan-naïve patients

ABSTRACT

Objective: To evaluate the efficacy of oral almotriptan 12.5?mg as an acute treatment for migraine with a focus on triptan-experienced versus triptan-naïve patients.

Research design and methods: Four recent Almirall-sponsored clinical trials of oral almotriptan 12.5?mg in acute migraine, in which data regarding previous acute therapy were collected, are reviewed. The results and conclusions are limited by the open-label and post hoc design of some of these trials and analyses.

Results: In two trials, almotriptan 12.5?mg was used to treat migraine sufferers who were dissatisfied with or were receiving inadequate results with their previous therapy. One of these trials enrolled only patients whose dissatisfaction with their current therapy was confirmed by a validated questionnaire; the other looked at almotriptan 12.5?mg efficacy in patients with previous poor response to sumatriptan. In the other two trials, patients had been achieving satisfactory results with their migraine therapy; one was a randomized, double-blind clinical trial of almotriptan 12.5?mg and zolmitriptan 2.5?mg, the other was an open-label almotriptan 12.5?mg satisfaction trial. Almotriptan 12.5?mg is shown to be effective, well-tolerated, and preferred to previous agents in both patients who were satisfied with, and those who were dissatisfied with, their previous therapy.

Conclusions: Almotriptan should, therefore, not only be considered as first-line therapy for acute migraine but should also be considered for patients who are not satisfied with or not receiving optimal relief from their current acute therapy.     

Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week,randomized, double-blind,placebo-controlled,Phase III study

Objective: To examine the efficacy and safety of canagliflozin monotherapy, a sodium/glucose co-transporter 2 inhibitor, in Japanese type 2 diabetes patients.

Methods: In this double-blind, multi-centre Phase III study, patients aged ≥ 20 years with hemoglobin A1c (HbA1c) 7.0 – 10.0% on diet/exercise therapy alone received placebo or canagliflozin (100 or 200 mg) once daily for 24 weeks. The main outcome measure was the change in HbA1c from baseline to Week 24.

Results: The changes in HbA1c (?0.74 and ?0.76 vs + 0.29%), fasting plasma glucose (1 mg/dl = 0.0555 mmol/l; ?31.6 and ?31.9 vs + 3.7 mg/dl), 2-h plasma glucose after 75-g glucose load (?84.9 and ?79.0 vs ?0.5 mg/dl), body weight (percent change: ?3.76 and ?4.02 vs ?0.76%) and systolic blood pressure (?7.88 and ?6.24 vs ?2.72 mmHg) were significantly greater with 100 and 200 mg canagliflozin than with placebo (all, p < 0.05). Genital infections in females (6.5, 6.3 and 0%) and asymptomatic hypoglycemia (4.4, 5.6 and 2.2%), but not symptomatic hypoglycemia (2.2, 1.1 and 1.1%), were more frequent in the 100- and 200-mg groups than in the placebo group.

Conclusion: Canagliflozin significantly improved glycemic control and was well tolerated.     

Section 3 The activity and tolerance of ibuprofen in patients with rheumatism and associated conditions

Summary

Ibuprofen, in a daily dosage range of 600?mg. to 1200?mg., was given to 100 patients suffering from a variety of rheumatic conditions for periods ranging from 1 to 3 months. The drug was found to be effective and well-tolerated by the majority of patients, even by those with associated conditions such as gastro-intestinal disorders which often make treatment difficult with other antirheumatic agents. Side-effects were reported in only 4 patients.     

Etoricoxib versus naproxen in patients with rheumatoid arthritis: a prospective,randomized, comparator-controlled 121-week trial

ABSTRACT

Background: Etoricoxib is a cyclooxygenase-2 (COX?2) selective inhibitor effective in the treatment of rheumatoid arthritis. An initial 12-week treatment study found that etoricoxib (90?mg once daily) was more effective than naproxen (500?mg twice daily) or placebo in treating rheumatoid arthritis. The present two-part extension of that study was performed to monitor tolerability and examine long-term efficacy of etoricoxib 90?mg or 120?mg compared with naproxen.

Methods: Patients completing the initial 12-week study and those discontinuing due to lack of efficacy, were eligible for the Extension Study Part I (12–52 weeks) and assigned (2?:?1?:?2 ratio) to receive etoricoxib (90?mg or 120?mg daily) or naproxen (500?mg twice daily); these patients remained on the same therapy for Extension Study Part II (52–121 weeks). Primary outcome measures included investigator and patient assessment of disease activity, and tender and swollen joint counts.

Results: Of 816 patients enrolled in the initial 12-week trial, 717 continued into the Extension Study Part I; 505 patients completed and 390 entered the Extension Study Part II, with 283 patients completing 121 weeks. Patients receiving etoricoxib (90?mg) or naproxen throughout the study experienced sustained efficacy in all outcomes, as did patients transitioning to etoricoxib (120?mg) following the initial 12-week trial. Patients transitioning from placebo to etoricoxib (90?mg) experienced rapid, sustained improvements in all outcome measures.

Conclusion: In conclusion, etoricoxib provided sustained efficacy throughout the 121-week study, with efficacy comparable to naproxen.     

Section 3 Clinical evaluation of ibuprofen given orally and rectally,in degenerative arthroses

Summary

In an open assessment in 46 patients with chronic arthritic and allied disorders, ibuprofen was administered in both oral and suppository form for an average of 10 days. Total daily dosage ranged from 1300?mg. to 1700?mg. ibuprofen depending on the weight of the patient. Pain relief was assessed as very good or good in 56.5 % and moderate in 26 % of patients. General side-effects were reported by 10 patients and 6 were withdrawn. Poor local tolerance of the suppository was reported by 19 patients, 9 of whom stopped treatment.     

Bisoprolol/amlodipine combination therapy improves blood pressure control in patients with essential hypertension following monotherapy failure

Objective: The efficacy of a bisoprolol/amlodipine fixed-dose combination (FDC) in patients with essential hypertension who had not responded to bisoprolol or amlodipine monotherapy was investigated.

Research design and methods: In an 18 week, multicenter, randomized, comparative phase III study (ClinicalTrials.gov identifier: NCT01977794), patients with blood pressure uncontrolled by bisoprolol or amlodipine monotherapy (5?mg OD) began treatment with bisoprolol/amlodipine FDC 5/5?mg OD. Patients with controlled blood pressure (BP) at week 6/12 continued at current FDC strength, and patients with uncontrolled BP received FDC dose uptitration (maximum dose: 10/10?mg). The primary efficacy endpoint was change in systolic blood pressure (SBP) at week 18 versus baseline (corresponding to SBP under monotherapy), and secondary endpoints included change from baseline in SBP after week 6/12 and percentage of BP-controlled patients at week 6, 12 and 18. Safety was assessed by number/types of adverse events (AEs).

Results: Two hundred patients were randomized to treatment (100 with uncontrolled BP under bisoprolol and 100 under amlodipine monotherapy). Overall, 196 patients were eligible for analysis. The patient groups displayed similar mean SBP reductions from baseline by study end (bisoprolol monotherapy failure: 25.9?±?12.82?mmHg reduction; amlodipine monotherapy failure: 24.7?±?11.67?mmHg reduction; p?<?0.001 for both). Overall mean SBP decreased by 25.3?±?12.25?mmHg (p?<?0.001). Mean heart rate reductions were also observed (bisoprolol monotherapy failure: 6.6?±?9.67 bpm reduction; amlodipine monotherapy failure: 11.5?±?8.65 bpm reduction; p?<?0.001 for both). Most patients (83.2%) displayed BP control with bisoprolol/amlodipine 5/5?mg at 6 weeks. Treatment was well tolerated at all dose levels; treatment-related AEs (mostly of mild/moderate intensity) were reported by 52.5% of patients, with no severe or serious treatment-related AEs reported. As the study focused on hypertension, total cardiovascular risk was not assessed.

Conclusions: Bisoprolol/amlodipine FDC therapy is associated with significant BP improvements in patients with essential hypertension following monotherapy failure.     

Section 2 Long-term ibuprofen therapy of rheumatic disease in patients with a past history of peptic Ulceration

Summary

Thirty patients with chronic rheumatic conditions and a known history of peptic ulceration were treated with ibuprofen, 600?mg. to 1200?mg. daily. Six patients withdrew from the study. In the remaining 24 patients, ibuprofen gave effective relief of symptoms and did not aggravate the gastro-intestinal pathology.     

Clinical efficacy of once-daily micronized purified flavonoid fraction 1000 mg tablet in patients with symptomatic chronic venous disease

Aim: To investigate the clinical efficacy of micronized purified flavonoid fraction (MPFF) 1000?mg given as a single 1000?mg tablet once daily in patients suffering from chronic venous disease (CVD) vs MPFF 500?mg twice daily.

Methods: In an international, randomized, double-blind, parallel-group study, patients classified C0s to C4 according to Clinical Etiological Anatomic Pathophysiologic [CEAP] classification and with leg pain graded as superior to 4?cm on a 10-cm visual analog scale (VAS), were treated for 8 weeks with either MPFF 1000?mg once daily or MPFF 500?mg twice daily. The present post-hoc analysis focuses on the effect of treatment over time in patients randomized to the MPFF 1000?mg group. Leg pain was assessed at each follow-up visit by VAS. VAS scores over time were compared between each visit using paired Student t-tests.

Results: In total, 87 patients out of 174 were randomized to the MPFF 1000?mg group. Mean age?±?SD was 49.1?±?12.2 years, most of the patients were female (81.6%), the main CEAP classes of the most affected leg were C1 (20.7%), C2 (39.1%), C3 (33.33%), and the mean duration of CVD was 14.6?±?10.9 years. Patients with previous CVD treatment represent 27.6% of the patients. A MPFF 1000?mg tablet once daily was associated with a significant and continuous reduction in leg pain throughout the treatment period: –1.54?cm (±1.45) from baseline to week 2 (p?<?.01), –1.11?cm (±1.06) from week 2 to week 4 (p?<?.01), –1.57?cm (±1.05) from week 4 to week 8 (p?<?.01).

Conclusions: The new MPFF 1000?mg dose regimen in once daily tablets was associated with a rapid and continuous reduction in leg pain throughout the 8-week treatment period.     

Pharmacokinetic model and simulations of dose conversion from immediate- to extended-release tramadol*

ABSTRACT

Objective: Extended-release tramadol (tramadol ER) is a once-daily formulation of tramadol approved in the United States for moderate to moderately severe chronic pain in adults. This modeling and simulation analysis was conducted to support dosing recommendations for switching patients receiving immediate-release tramadol (tramadol IR) to tramadol ER.

Research design and methods: Monte Carlo simulations based on steady-state data from three Phase 1 studies predicted minimum plasma concentration (C_min), maximum plasma concentration (C_max), and area under the plasma-concentration-versus-time curve (AUC).

Main outcome measures: Pharmacokinetic parameters were compared between 100?mg daily increments of tramadol ER every 24?h (Q24H) and corresponding 25?mg increments of tramadol IR every 6?h (Q6H), such as tramadol ER 200?mg Q24H versus tramadol IR 200, 225, 250, and 275?mg daily.

Results: Tramadol ER and IR were predicted to provide similar exposure (AUC) at a total daily dose of 100, 200, or 300?mg. Estimated exposure was comparable between tramadol IR 125-, 225-, and 325?mg and tramadol ER 100-, 200-, and 300?mg, respectively. Estimated exposure was 30–41% lower with tramadol ER 100?mg versus tramadol IR 150 and 175?mg daily, 15–26% lower with tramadol ER 200?mg versus tramadol IR 250 and 275?mg daily, and 8–19% lower with tramadol ER 300?mg versus tramadol IR 350 and 375?mg daily.

Conclusions: This pharmacokinetic analysis supports switching patients from a total daily dose of tramadol IR 200 or 300?mg directly to tramadol ER 200 and 300?mg once daily, respectively. Patients who take other doses of tramadol IR may switch to the next lower 100?mg increment of tramadol ER (e.g., from tramadol IR 225, 250, or 275?mg daily in divided doses to tramadol ER 200?mg once daily). Confirmation of these findings would require clinical studies comparing the systemic exposure of tramadol upon switching from the IR to the ER formulation.     

Clinical effectiveness of low-dose chlorthalidone (6.25 mg) + atenolol combination in stage I hypertensive patients: a multicenter,randomized, controlled study

ABSTRACT

Objective: To compare the efficacy and safety of low-dose chlorthalidone + atenolol combination with atenolol and atenolol + amlodipine combination in stage I hypertensive patients uncontrolled on active run-in monotherapy.

Methods: Newly diagnosed stage I hypertensive patients were randomized to active run-in monotherapy either with atenolol 25?mg (98/300) or chlorthalidone 6.25?mg (100/300) or amlodipine 2.5?mg (102/300). A total of 282/300 patients (atenolol 92, chlorthalidone 91, amlodipine 99) completed the active run-in phase successfully. Patients uncontrolled on active run-in monotherapy (atenolol 33, chlorthalidone 45, amlodipine 47) received the study treatment, namely atenolol 50?mg alone, chlorthalidone 6.25?mg + atenolol 25?mg and atenolol 25?mg + amlodipine 2.5?mg, respectively. Efficacy of the therapy was evaluated by BP measurement at weeks 12 and 20 post-therapy.

Results: Post-active run-in monotherapies, the study treatment groups showed a significant fall in mean SBP and DBP from baseline (p?<?0.05). The mean fall in SBP and DBP was comparable for study treatments (atenolol 50?mg, atenolol 25?mg + chlorthalidone 6.25?mg and atenolol 25?mg + amlodipine 2.5?mg) (p = 0.337 for SBP and p = 0.054 for DBP) at week 12 and (p = 0.744 for SBP and p = 0.855 for DBP) at week 20; also, the percentage of responders was comparable for the three study treatment groups (p = 0.799) indicating that the low-dose chlorthalidone + atenolol combination is non-inferior to the high-dose atenolol alone and atenolol + amlodipine combination. No serious laboratory/clinical adverse events were reported in this study.

Conclusion: Chlorthalidone 6.25?mg in combination with atenolol 25?mg is effective and safe in stage I (JNC 7) essential hypertensive patients. This low dose of chlorthalidone could reduce dose-related concerns over metabolic adverse effects and may lead to wider usage of this proven antihypertensive agent in combination therapy.     

Efficacy and safety of low-dose SoluMatrix meloxicam in the treatment of osteoarthritis pain: a 12-week,phase 3 study

Objective:

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as meloxicam are commonly used to treat osteoarthritis (OA) but are associated with potentially serious dose-related adverse events (AEs). SoluMatrix meloxicam has been developed with the goal of enabling effective treatment at low doses. This phase 3 study evaluated the efficacy and safety of low-dose SoluMatrix meloxicam capsules 5?mg and 10?mg administered once daily for 12 weeks in patients with OA-related pain.

Research design and methods:

This randomized, double-blind study enrolled patients ≥40 years of age with confirmed hip or knee OA (Kellgren–Lawrence grade II–III) who were chronic users of NSAIDs and/or acetaminophen for OA pain and had Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale mean scores ≥40?mm. Eligible patients experienced an OA pain flare (defined as a ≥15?mm increase in the WOMAC pain subscale score) following discontinuation of NSAIDs/acetaminophen. Patients were randomized to receive once-daily SoluMatrix meloxicam 5?mg or 10?mg, or placebo for 12 weeks.

ClinicalTrials.gov identifier: NCT01787188.

Main outcome measures:

The primary outcome measure was the mean change from baseline in WOMAC pain subscale score at week 12.

Results:

Low-dose SoluMatrix meloxicam 5?mg (?36.52 [2.49]; P?=?0.0005) and 10?mg (?34.41 [2.68]; P?=?0.0059) once-daily treatment significantly reduced the mean (standard error) WOMAC pain subscale score from baseline at week 12 compared with placebo (?25.68 [2.64]). Patients treated with SoluMatrix meloxicam 5?mg or 10?mg reported significantly greater improvements in total WOMAC score and in WOMAC stiffness and function subscale scores at 12 weeks compared with placebo. The most common AEs in the combined low-dose SoluMatrix meloxicam group were headache, diarrhea, nausea, osteoarthritis, and urinary tract infection.

Conclusions:

Low-dose SoluMatrix meloxicam may have a potential role as a new therapeutic option for the management of OA-related pain.