Comparative crossover, randomized, open-label bioequivalence study on the bioequivalence of two formulations of thioctic acid in healthy volunteers

An open-label, randomized, crossover single-dose study, using two periods and two sequences with a washout period of seven days was conducted to assess the comparative bioavailability of thioctic (alpha-lipoic) acid (ALA) 600 mg formulation and that of a reference formulation. Blood samples were collected up to +6 h post dosing, the plasma was separated, and thioctic acid concentrations were determined by high-performance liquid chromatographic method with single mass spectrometry detection (HPLC-MS) and a lower limit of quantification of 190.1 ng/ml. Mean values of the individual C(max) were 1338.6 +/- 751.8 ng/ml and 1215.8 +/- 560.5 ng/ml for the test and reference preparations, respectively. Mean +/- standard deviation (SD) total area under the curve up to the last measurable concentration (AUC(t)) was 3510.9 +/- 1088.6 ng x h/ml for the test formulation and 3563.5 +/- 1374.1 ng x h/ml for the reference formulation. Mean +/- SD total area under the curve (AUC(inf)) was 6925.6 +/- 4045.8 ng x h/ml for the test formulation and 7797.1 +/- 5963.1 ng x h/ml for the reference preparation. Terminal elimination half-life was 5.68 +/- 5.05 h for the test and 6.11 +/- 6.15 h for the reference formulations. Time of maximum concentration (t(max)) was 1.24 +/- 1.23 h for the test and 2.05 +/- 1.21 h for the reference formulations. Ninety percent confidence intervals were comprised within the bioequivalence acceptance criteria (80-125%) for all of the parameters analyzed except t(max). The comparison between males and females showed no significant difference for the two drug treatment.     

Lercanidipine, enalapril and their combination in the treatment of elderly hypertensive patients: placebo-controlled, randomized, crossover study with four ABPM

This double-blind, placebo-controlled, four-way balanced design crossover study included hypertensive patients aged 60-85 years with mean office-measured sitting systolic blood pressure (SBP) 160-179 mm Hg and daytime SBP > or =135 mm Hg. After a 2-week run-in period, during which previous medications were discontinued, each patient received the following four treatments in randomized order for 4 weeks each: lercanidipine 10 mg (L), enalapril 20 mg (E), lercanidipine 10 mg plus enalapril 20 mg (L/E) and placebo (P). At the end of each treatment period, office trough blood pressure (BP) was measured and a 24-h Ambulatory Blood Pressure Monitoring (ABPM) was performed. Seventy-five patients (mean age 66 years, office BP 168/92 mm Hg, daytime SBP 151 mm Hg) were randomized and 62 completed the study with four valid post-baseline ABPMs. The administration of P, L, E and L/E was associated with a mean 24-h SBP of 144, 137, 133 and 127 mm Hg, respectively. All active treatments significantly reduced the mean 24-h SBP in comparison with placebo, but L/E was significantly more effective than L and E alone. Similarly, office SBP was significantly more reduced with L/E (-16.9 mm Hg) than with L (-5.0 mm Hg) or E (-5.9 mm Hg). A BP <140/90 mm Hg was recorded in 18% of patients with L, 19% with E and 45% with L/E. Two patients on P and two on L/E were withdrawn from the study due to adverse events. In conclusion, combination therapy with L/E has additive antihypertensive effects on both ambulatory and office BP in elderly patients and is well tolerated.     

HIV protease inhibitor substitution in patients with lipodystrophy: a randomized, controlled, open-label, multicentre study

BACKGROUND: Lipodystrophy, dyslipidaemia and insulin resistance often complicate protease inhibitor-containing antiretroviral therapy. The aims of this study were to determine if these are reversible with continued HIV suppression following protease inhibitor substitution. METHODS: Eighty-one HIV protease inhibitor recipients (78 male; mean antiretroviral therapy, 55 months) with predominant peripheral lipoatrophy, HIV RNA < 400 copies/ml plasma for at least the preceding 6 months, and no prior abacavir, non-nucleoside analogue or adefovir therapy were randomized 3 : 2 to continue nucleoside analogues and substitute protease inhibitor(s) with abacavir, nevirapine, adefovir and hydroxyurea (n = 49) or to continue all therapy (n = 32) with an option to switch at week 24. The primary endpoints were total body fat and HIV RNA at week 24. Other assessments were regimen safety, regional body composition, metabolic parameters, quality of life, and CD4 T-lymphocyte counts to week 48. RESULTS: There was a greater decline in total body fat in the switch group than in the continue group (-1.6 and -0.4 kg, respectively at week 24; P = 0.006). This comprised greater declines in limb and subcutaneous abdominal fat, and in intra-abdominal fat of patients with moderate or severe abdominal fat accumulation. Viral suppression was similar, despite 18 (37%) switch group patients ceasing at least one study drug by week 24 because of adverse events. Total cholesterol and triglycerides declined more in the switch group (both P < 0.002). High density lipoprotein cholesterol increased significantly in both groups at week 48 (P < 0.02). There was no change for any glycaemic parameter. CONCLUSIONS: In predominantly lipoatrophic patients, switching from HIV protease inhibitor therapy lead to improved lipids and less intra-abdominal fat, but also to less peripheral fat, and had minimal effect on insulin resistance. Virological control in these heavily pretreated patients was unaffected, despite frequent switch drug cessations.     

Symptomatology and quality of life in patients with rate-responsive pacemakers: a double-blind, randomized, crossover study

Although the hemodynamic advantages of rate-responsive (RR) pacing are well established, the symptomatic benefits remain controversial and the effects on the quality of life have not been assessed. Sixteen patients with RR pacemakers and a mean age of 56 (range 22-77) years were involved in a double-blind crossover study to assess their exercise capacity (treadmill testing), symptomatology, and quality of life (structured questionnaires). Pacemakers were implanted because of symptomatic heart block or sick sinus syndrome. Ventricular demand pacemakers were randomly programmed into the constant rate (VVI) or RR pacing modes for four-week study periods. All patients exercised longer in the RR mode than in the VVI mode (570 +/- 29 vs. 437 +/- 17 s, p less than 0.001). Statistically significant improvements in "shortness of breath" and "energy during daily activities" as measured by a 10-point scale were reported in the RR pacing mode by the patients and were also observed by their close relatives. Symptoms such as "chest pain" and "palpitations" were not worsened during RR pacing. Nondisease-specific "quality of life" was studied in 11 patients using the Nottingham Health Profile which showed a trend for an improved quality of life in five of the six dimensions of perceived health, although none of the changes were statistically significant. This study suggests that RR pacing should be recommended in selected patients on symptomatic grounds.     

Infliximab and leflunomide combination therapy in rheumatoid arthritis: an open-label study

OBJECTIVE: To study the safety and efficacy of infliximab plus leflunomide combination therapy in adult rheumatoid arthritis (RA). METHODS: Twenty patients with active RA received leflunomide 100 mg for 3 days followed by 20 mg daily for 32 weeks. At week 2 all patients started infliximab 3 mg/kg, and received a further four infusions at weeks 4, 8, 16 and 24. RESULTS: Adverse events led to 11 patients being withdrawn before the end of the study. The commonest adverse event was pruritis associated with an eczematous rash. Other serious reactions included infliximab infusion reactions in four patients and Stevens-Johnson syndrome in one. There was no relationship between the serum concentration of A77 1726, the active metabolite of leflunomide, and adverse events. The mean Disease Activity Score (DAS28) fell from 7.18 at week 0 to 5.18 (P<0.0001, paired t-test) at week 4 and remained between 3.85 and 4.85 up to week 32. In those patients remaining on treatment, more than 80% achieved an ACR20 response from week 8 to week 28, and up to 46% achieved an ACR70 response. CONCLUSION: Infliximab plus leflunomide combination therapy appears to be highly efficacious in the treatment of adult RA. However, widespread use may be limited by adverse events, which were common and in some cases severe.     

Octreotide LAR vs. surgery in newly diagnosed patients with acromegaly: a randomized, open-label, multicentre study

Objective  This prospective randomized study evaluated the efficacy and safety of octreotide LAR vs. surgery in newly diagnosed acromegalic patients.
Methods  Totally 104 male and female patients were enrolled in a 50-week, exploratory, open-label and randomized study. Eligible patients were randomized to receive either octreotide LAR 20 mg every 28 days or to undergo surgery. Efficacy was assessed by changes in mean GH and IGF-I serum concentrations, at weeks 12, 24 and 48. Tumour volume was assessed by contrast-enhanced MRI. In both groups, treatment adjustment was performed for patients uncontrolled at week 12 or 24. Octreotide LAR patients received a dose increased to 30 mg or, if already receiving this dose, investigator and patients could decide to cross-over to surgery. Patients uncontrolled after surgery received octreotide LAR 20 mg, increased to 30 mg if acromegaly was still uncontrolled.
Results  Overall success rates at weeks 24 and 48 were 25% and 28% for the octreotide LAR group and 49% and 39% for the surgery group. Only the difference observed at week 24 was statistically significant ( P =  0·047). Both groups had a significant (> 20%) tumour shrinkage: 73% of patients in the octreotide LAR group and 95% in the surgery group. Major differences between octreotide LAR and surgery group in the occurrence of adverse events were gastrointestinal (71% vs. 27%), hepatobiliary (41% vs. 8%) and respiratory (5% vs. 28%).
Conclusion  This first randomized study in unselected patients indicates that the 48-week treatment outcome of octreotide LAR as first-line treatment of acromegaly does not significantly differ from surgery. As a complete response to surgery in GH-secreting macro-adenomas can be difficult, first-line therapy with octreotide LAR can be considered as a viable alternative for most patients with acromegaly, due to its low complication rate.     

Effect of low-dose metoprolol in combination with sibutramine therapy in normotensive obese patients: a randomized controlled study

OBJECTIVE: Sibutramine is an effective appetite suppresser agent, but treatment is often complicated with side effects, including palpitations and hypertension. In this study, we aimed to assess the effect of low-dose cardio-selective beta blocker combination with sibutramine treatment. METHODS: In total, 57 obese subjects were enrolled in the study and separated into two groups in order to receive sibutramine 10 mg/day plus placebo (group P) or sibutramine 10 mg/day plus metoprolol 25 mg/day (group M). Patients were evaluated in the beginning and at the end of the third month with anthropometric measurements, biochemical analysis, peripheral insulin resistance, and ambulatory 24 h blood pressure monitoring. Side effects were evaluated with a visual analog scale. RESULTS: During the study period, the drop-out rate was significantly higher in group P compared with group M (55 and 21%, respectively, P=0.014). Palpitations and headache were prominent symptoms in group P. Diastolic blood pressure (78.6+/-11.6 and 70.6+/-4.8 mmHg, respectively, P=0.013) and mean heart rate (84.3+/-6.1 and 75.8+/-8.4 beats/min, respectively, P=0.003) were significantly higher in group P compared with group M at the end of the third month. Weight loss was similar between the two groups (100.9+/-11.5 to 91.8+/-12.8 kg for group P, P<0.0001 and 97.9+/-13.2 to 88.9+/-13.8 kg for group M, P<0.0001). We did not find any deleterious effect of metoprolol on metabolic parameters. CONCLUSION: Addition of low-dose metoprolol to sibutramine therapy increased patient compliance to the treatment, and decreased the frequency and severity of side effects including hypertension and palpitations, without decreasing the drug efficacy or causing significant deleterious changes in metabolic parameters.     

Treatment of mastalgia with tamoxifen in male patients with liver cirrhosis: a randomized crossover study

OBJECTIVE: Mastalgia is occasionally found in patients with liver cirrhosis, especially in those receiving spironolactone for treatment of ascites. The pathogenesis is still unclear. Estrogen excess in cirrhotic patients and estrogenic effects of the spironolactone are possible leading causes. Treatment directed against the preponderance of estrogenic stimulation in these patients has never been investigated. This study was designed to investigate the efficacy and safety of tamoxifen, an estrogen antagonist, on mastalgia in patients with liver cirrhosis. METHODS: A total of 16 male cirrhotic patients with mastalgia were randomly assigned to two groups. One group was treated with tamoxifen (20 mg p.o., b.i.d.) for 1 month, followed by placebo for the next month. The other group was treated in the reverse order. All patients received spironolactone for ascites and/or peripheral edema, and the drug was continued during the study period. The size of the breasts and the degree of breast pain and tenderness were recorded in all subjects before and after the treatment periods. Serum levels of estradiol and testosterone were measured using the radioimmunoassay method. RESULTS: Of the 16 patients, 14 experienced a decrease or disappearance of the breast pain and/or tenderness during the tamoxifen treatment period, whereas only two of the 16 patients felt an improvement during the placebo period (p < 0.05). There were significant improvements in the breast pain and tenderness scores and decreases in the breast sizes during the tamoxifen treatment period (before vs after: 1.4+/-0.3 vs 0.4+/-0.2, p = 0.002; 1.9+/-0.2 vs 0.5+/-0.2, p < 0.001; and 6.8+/-0.6 vs 5.5+/-0.6 cm, p = 0.02, respectively), whereas no obvious change was seen during the placebo period. Serum levels of estradiol and testosterone did not change significantly after the tamoxifen or placebo treatments (p > 0.05). No major side effects were noted during the therapeutic periods. CONCLUSIONS: Tamoxifen is effective and safe in the management of mastalgia in male cirrhotic patients taking spironolactone.     

Managing pasireotide-associated hyperglycemia: a randomized,open-label,Phase IV study

Purpose

Pasireotide is an effective treatment for acromegaly and Cushing’s disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs.

Methods

Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤?16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n?=?190) or Cushing’s disease (n?=?59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥?126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA_1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms.

Results

Eighty-one (32.5%) patients were randomized to incretin-based therapy (n?=?38 received sitagliptin, n?=?28 subsequently switched to liraglutide; n?=?12 received insulin as rescue therapy) or insulin (n?=?43). Adjusted mean change in HbA_1c between treatment arms was – 0.28% (95% CI – 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n?=?43)/other OAD (n?=?3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized.

Conclusion

Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed.

ClinicalTrials.gov ID: NCT02060383.

     

Itolizumab in combination with methotrexate modulates active rheumatoid arthritis: safety and efficacy from a phase 2, randomized,open-label,parallel-group,dose-ranging study

Clinical Rheumatology - The objective of this study was to assess the safety and efficacy of itolizumab with methotrexate in active rheumatoid arthritis (RA) patients who had inadequate response to...     

Efficacy of combination therapy with natriuretic and aquaretic drugs in cirrhotic ascites patients: A randomized study

AIM To assess the effects of a combination therapy with natriuretic and aquaretic drugs in cirrhotic ascites patients.METHODS A two-center,randomized,open-label,prospective study was conducted. Japanese patients who met the criteria were randomized to trial group and the combination diuretic group(received 7.5 mg of tolvaptan) or the conventional diuretic group(received 40 mg of furosemide) for 7 d in addition to the natriuretic drug which was used prior to enrolment in this study. The primary endpoint was the change in body weight from the baseline. Vital signs,fluid intake,and laboratory and urinary data were assessed to determine the pharmacological effects after administration of aquaretic and natriuretic drugs.RESULTS A total of 56 patients were randomized to receive either tolvaptan(n = 28) or furosemide(n = 28). In the combination and conventional diuretic groups,the average decrease in body weight from the baseline was 3.21 ± 3.17 kg(P 0.0001) and 1.75 ± 2.36 kg(P = 0.0006),respectively,when measured on the final dosing day. Following 1 wk of treatment,a significantly greater reduction in body weight was observed in the combination diuretic group compared to that in the conventional diuretic group(P = 0.0412).CONCLUSION Compared to a conventional diuretic therapy with only a natriuretic drug,a combination diuretic therapy with natriuretic and aquaretic drugs is more effective for patients with cirrhotic ascites.     

Additional effects of pranlukast in salmeterol/fluticasone combination therapy for the asthmatic distal airway in a randomized crossover study

BackgroundSalmeterol/fluticasone combination (SFC) therapy is used to control inflammation in the distal airway of patients with well-controlled asthma, but the efficacy of this approach is unclear.ObjectivesThe goal of the study was to evaluate the effect of pranlukast, a leukotriene receptor antagonist (LTRA), on distal airway inflammation and pulmonary resistance in patients with asthma that was well-controlled using SFC therapy alone.MethodsThe subjects were 32 patients with well-controlled asthma (age 61.1 ± 17.8 years old, Step 3 in the GINA guidelines, Asthma Control Test score 23.2 ± 1.8 points) based on use of SFC therapy alone for more than 3 months. These subjects were randomly assigned to groups receiving SFC alone or SFC + LTRA (pranlukast 450 mg daily) and then switched to the opposite group after 4 weeks in a crossover manner. Eosinophilic inflammation in induced sputum samples was assessed after each treatment period. Sputum was induced by inhalation of 10% hypertonic saline for 15 min. Impulse oscillometry parameters (R5, R20, X5 and AX) and spirometry were examined during each period. The Asthma-related Quality of Life Questionnaire (AQLQ) was also administered in each period.ResultsThe ECP levels in late-phase sputum were significantly higher than those in early-phase sputum with SFC therapy alone (178.3 ± 166.0 vs. 65.5 ± 68.9 μg/l, p < 0.001), whereas these values did not differ significantly with SFC + LTRA treatment (70.9 ± 95.1 vs. 54.6 ± 65.7, p = 0.554). ECP levels in late-phase sputum with SFC therapy were also significantly higher than those with SFC + LTRA (p = 0.045). The values of R5, R20, R5–R20 (kPa/(L/s)), and AX (kPa/L) all significantly improved during with SFC + LTRA treatment compared with SFC alone (median (25–75 percentile)): 0.350 (0.283–0.440) vs. 0.340 (0.280–0.378), p = 0.036; 0.280 (0.233–0.365) vs. 0.270 (0.240–0.318), p = 0.019; 0.050 (0.030–0.110) vs. 0.500 (0.030–0.073), p = 0.032; and 0.570 (0.308–1.045) vs. 0.410 (0.263–0.820), p = 0.014; respectively. Pulmonary function indexes did not differ significantly between the two treatments, but the symptom and activity limitation domains of the AQLQ were significantly improved by SFC + LTRA treatment.ConclusionThis study suggests that the combination of SFC and LTRA may give better control of residual eosinophilic inflammation in the distal airway compared with SFC therapy alone.     

Comparative efficacy of transvenous cardioversion and pacing in patients with sustained ventricular tachycardia: a prospective, randomized, crossover study

We performed a prospective, randomized crossover study to evaluate the comparative efficacy of transvenous cardioversion and rapid ventricular pacing for termination of induced ventricular tachycardia in patients with spontaneous ventricular tachycardia and organic heart disease. Sixty-two episodes of ventricular tachycardia were induced in 15 patients, mean age 60 +/- 10 years, during electrophysiologic studies. All patients underwent a preselected electrical therapy protocol in a randomized crossover sequence. Transvenous cardioversion was performed by an incremental protocol of three sequential shocks (0.5, 1.1, and 2.7 J). Six asynchronous sequential bursts of rapid ventricular pacing (10 and 15 paced stimuli at 90%, 75%, and 65% of ventricular tachycardia cycle length) were used. Mean cycle length of ventricular tachycardia for the study population was 391 +/- 85 msec. The morphology of the tachycardia was left bundle branch block in 27, right bundle branch block in 32, and indeterminate in three. Characteristics of ventricular tachycardia terminated by the two techniques were comparable. Rate of success for termination of tachycardia with the two methods was also comparable (transvenous cardioversion 83%, rapid ventricular pacing 80%; p greater than .1) and these responses were concordant in 78%. The modes of termination of ventricular tachycardia were similar. The incidence of acceleration of ventricular tachycardia per episode with these preselected protocols was also comparable (transvenous cardioversion 11%, rapid ventricular pacing 6%; p greater than .2). Transient supraventricular tachyarrhythmias were more frequent after transvenous cardioversion (23%) than after rapid ventricular pacing (3%). Significant patient discomfort occurred only after transvenous cardioversion (incidence of 57%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Upgrade to biventricular pacing in patients with conventional pacemakers and heart failure: a double-blind, randomized crossover study.

AIMS: To investigate whether patients with previously implanted conventional pacemakers and severe heart failure benefit from an upgrade to a biventricular system. METHODS AND RESULTS: Study inclusion criteria were New York Heart Association (NYHA) classes III and IV, dominant paced rhythm, and no left bundle branch block in the pre-pacing ECG. Ten patients with pacemakers (four VVIR due to slow atrial fibrillation and six DDDR, of which four were due to high-degree atrioventricular block and two to sinus node disease) were upgraded to a biventricular pacing (BVP) system. The median duration of pacing before the upgrade was 5.7 years. Assessments of 6-min walk test, symptom score, brain natriuretic peptide (pro-BNP), and echocardiography were made pre-operatively. After a run-in period of 1 month in BVP following the upgrade, the patients were randomized to a 2-month period in either BVP or right ventricular pacing (RVP), followed by 2 months in the other mode, in a double-blind crossover fashion. After each period, the pre-operative measurements were repeated. After study completion, patients were asked to select their preferred period. The median 6-min walking distance was significantly longer in BVP (400 m) vs. RVP (315 m), P = 0.02. The symptom score was also significantly better in BVP (P = 0.005). Median pro-BNP was significantly lower in BVP than in RVP, 3,030 vs. 5,064 ng/L (P = 0.005). Six patients demanded an early crossover in RVP but none in BVP (P = 0.015), and all patients except one expressed a preference for BVP. However, echo parameters did not show any significant differences between BVP and RVP. CONCLUSION: Pacemaker patients with heart failure and dominant paced heart rhythm benefit substantially from an upgrade to BVP, in terms of physical performance and symptoms. The upgrade resulted in significantly improved cardiac function as reflected by reduced levels of pro-BNP.     

Octreotide in hepatorenal syndrome: a randomized,double-blind,placebo-controlled,crossover study

The hepatorenal syndrome (HRS) is related to vasoconstriction of the renal cortex induced by systemic hypovolemia that follows splanchnic vasodilatation as the primary event in the cascade of hemodynamic changes associated with portal hypertension. We evaluated the effects of octreotide, a splanchnic vasoconstrictor, on HRS in cirrhotic patients. We compared the effects of octreotide infusion (50 microg/h) to placebo using a randomized, double-blind, cross-over design over 2, 4-day periods. Nineteen patients were included, and 14 patients could complete the 2 phases of the study (group 1: placebo first; n = 8 and group 2: octreotide first; n = 6) The end point of the study was to evaluate improvement in renal function as defined by a 20% decrease in serum creatinine value after a 4-day treatment as compared with baseline. In all the patients, a normal central venous pressure was maintained by daily intravenous administration of 2 units of albumin. The 2 groups were similar with regard to demographic data and liver and kidney function parameters at baseline. Improvement in renal function was observed in 2 patients after the placebo and 1 patient after octreotide infusion in group 1 and in 2 patients after octreotide infusion and 1 patient after placebo in group 2 (P = not significant). In addition, treatment with octreotide infusion did not result in significant changes in creatinine clearance, daily urinary sodium, plasma renin activity, plasma aldosterone and glucagon levels, or renal and mesenteric artery resistance indices as measured by Doppler ultrasonography. In conclusion, the present study demonstrates that, under our experimental conditions, octreotide infusion combined with albumin is not effective for the treatment of HRS in cirrhotic patients.