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PubMed1998

A double-blind, placebo-controlled trial of nefazodone in the treatment of patients hospitalized for major depression.

BACKGROUND: There are few published placebo-controlled clinical trials demonstrating the efficacy of the newer antidepressants in markedly or severely depressed hospitalized patients. This study demonstrates the efficacy of nefazodone compared with placebo in the treatment of patients hospitalized for major depression. METHOD: Nefazodone and placebo treatment were compared in a 6-week trial of 120 patients hospitalized for DSM-III-R diagnosed major depression (without psychosis) at 2 study centers. Efficacy was evaluated using standard psychiatric rating scales, and patients were monitored for safety. RESULTS: Nefazodone treatment resulted in a significant reduction (p < .01) of the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score compared with placebo from the end of the first treatment week through the end of the study (-12.2 nefazodone vs. -7.7 placebo). At the end of the trial, significantly more nefazodone-treated patients (50%) than placebo-treated patients (29%) had responded, as indicated by their Clinical Global Impressions-Improvement score (p = .021) or by a > or = 50% reduction in their HAM-D-17 scores (p = .017). Significantly more patients treated with nefazodone (36%) than placebo-treated patients (14%) had a HAM-D-17 score < or = 10 at the end of treatment (p = .004). Significant treatment differences (p < .01) in favor of nefazodone were also seen in the Montgomery-Asberg Depression Rating Scale; the HAM-D retardation, anxiety, and sleep disturbance factors; and HAM-D item 1 (depressed mood). Patients with dysthymia in addition to major depression also showed significant improvement (p < .05) when treated with nefazodone, with significant differences in response rates seen as early as week 2 and through the end of the trial. The mean nefazodone dose was 491 mg/day at the end of week 2 and 503 mg/day at the end of treatment. Nefazodone was well tolerated, and the number of patients discontinuing owing to adverse events was small, with no significant safety issues noted in either treatment group. Fewer nefazodone-treated than placebo-treated patients discontinued owing to lack of efficacy. CONCLUSION: Nefazodone was superior to placebo in the treatment of marked to severe major depression in patients requiring hospitalization. The clinical benefit of nefazodone was evident as early as the first week of treatment as judged by several measures of efficacy, with significant differences from placebo sustained throughout the trial.

Adult↗
PubMed2003

Treatment of bulimia nervosa with topiramate in a randomized, double-blind, placebo-controlled trial, part 1: improvement in binge and purge measures.

BACKGROUND: This randomized, double-blind, placebo-controlled trial was designed to assess the efficacy and safety of topiramate in bulimia nervosa. METHOD: Patients with DSM-IV bulimia nervosa were randomly assigned in equal proportions to receive topiramate (N = 35) or placebo (N = 34) for 10 weeks (between April 1999 and Dec. 2000). Topiramate treatment was started at 25 mg/day and titrated by 25 to 50 mg/week to a maximum of 400 mg/day. The primary efficacy measure was mean weekly number of binge and/or purge days. Related outcome measures included mean weekly number of binge days and binge frequency, as well as mean weekly number of purge days and purge frequency. RESULTS: Sixty-four outpatients (33 placebo, 31 topiramate) were included in the intent-to-treat analysis. The median topiramate dose was 100 mg/day (range, 25-400 mg/day). Mean +/- SD baseline number of weekly binge and/or purge days was 5.0 +/- 1.6 for topiramate patients and 5.1 +/- 1.5 for placebo patients. The primary efficacy measure, mean weekly number of binge and/or purge days, decreased 44.8% from baseline with topiramate versus 10.7% with placebo (p =.004). The mean weekly number of binge days decreased 48.2% with topiramate versus 17.7% with placebo (p =.015), and mean binge frequency decreased 49.2% with topiramate versus 28.0% with placebo (p =.071). The mean weekly number of purge days decreased 43.4% with topiramate versus 16.6% with placebo (p =.016), and mean purge frequency decreased 49.8% with topiramate versus 21.6% with placebo (p =.016). Three patients (2 placebo, 1 topiramate) discontinued from the trial due to adverse events. CONCLUSION: Topiramate was associated with significant improvements in both binge and purge symptoms in this study population and represents a potential treatment for bulimia nervosa.

Administration, Oral↗
PubMed2005

Sexual functioning assessed in 4 double-blind placebo- and paroxetine-controlled trials of duloxetine for major depressive disorder.

OBJECTIVE: The onset or worsening of sexual dysfunction is a common treatment-emergent side effect of antidepressant medications. Post hoc analyses of pooled data from placebo-controlled studies were utilized to assess sexual functioning in patients receiving duloxetine or paroxetine. METHOD: Acute-phase data were obtained from four 8-week, double-blind, placebo- and paroxetine-controlled trials of similar design in which patients meeting DSM-IV criteria for major depressive disorder were randomly assigned to receive placebo (N = 371), duloxetine (40-120 mg/day; N = 736), or paroxetine (20 mg/day; N = 359). Pooling of data from these studies was anticipated during study design. This represented all available data from duloxetine studies in which the Arizona Sexual Experience Scale (ASEX) was administered both at baseline and endpoint. Long-term data were available from extension phases in 2 of these trials in which acute treatment responders received placebo (N = 129), duloxetine (80-120 mg/day; N = 297), or paroxetine (20 mg/day; N = 140) for an additional 26 weeks. Data were collected between March 2000 and July 2002. RESULTS: The incidence of acute treatment-emergent sexual dysfunction was significantly lower among duloxetine-treated patients compared with those receiving paroxetine (p = .015), although both rates were significantly higher than placebo (p = .007 and p < .001 for duloxetine and paroxetine, respectively). Treatment group differences in the incidence of treatment-emergent dysfunction did not vary significantly by gender. In female patients, acute treatment-emergent sexual dysfunction was significantly lower in the duloxetine treatment group compared with the paroxetine treatment group (p = .032), with both rates being significantly higher than placebo (p = .049 and p < .001 for duloxetine and paroxetine, respectively). In the somewhat smaller group of male patients, acute treatment-emergent dysfunction did not differ significantly between duloxetine and placebo treatment groups, but the incidence was significantly higher in paroxetine-treated male patients compared with male placebo patients (p = .012). The long-term incidence of treatment-emergent dysfunction did not differ significantly between duloxetine-, paroxetine-, and placebo-treated patients. CONCLUSION: In this analysis of pooled data, patients receiving duloxetine (40-120 mg/day) or paroxetine (20 mg/day) had a significantly higher incidence of acute treatment-emergent sexual dysfunction when compared with placebo patients. However, the incidence of acute treatment-emergent dysfunction for duloxetine was significantly lower than that observed for paroxetine.

Adult↗
PubMed1999

Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. Montelukast/Beclomethasone Study Group.

BACKGROUND: Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma. OBJECTIVE: To compare the clinical benefit of montelukast, a once-daily oral leukotriene receptor antagonist; placebo; and inhaled beclomethasone. DESIGN: Randomized, double-blind, double-dummy, placebo-controlled, parallel-group, 12-week study. SETTING: 36 sites worldwide. PATIENTS: 895 patients 15 to 85 years of age with chronic asthma and an FEV1 50% to 85% of predicted. INTERVENTIONS: Montelukast, 10 mg once daily at bedtime; inhaled beclomethasone, 200 microg twice daily, administered with a spacer device; or placebo. MEASUREMENTS: Primary end points were daytime asthma symptom score and FEV1. Secondary end points were peak expiratory flow rates in the morning and evening, as-needed beta-agonist use, nocturnal awakenings, asthma-specific quality of life, and worsening asthma episodes. RESULTS: Over the 12-week treatment period, the average percentage change from baseline in FEV1 was 13.1% with beclomethasone, 7.4% with montelukast, and 0.7% with placebo (P < 0.001 for each active treatment compared with placebo; P < 0.01 for beclomethasone compared with montelukast). The average change from baseline in daytime symptom score was -0.62 for beclomethasone, -0.41 for montelukast, and -0.17 for placebo (P < 0.001 for each active treatment compared with placebo; P < 0.01 for beclomethasone compared with montelukast). Each agent improved peak expiratory flow rates and quality of life, reduced nocturnal awakenings and asthma attacks, increased the number of asthma-control days, and decreased the number of days with asthma exacerbations (P < 0.001 for each active treatment compared with placebo for each end point; P < 0.01 for beclomethasone compared with montelukast for each end point). Although beclomethasone had a greater mean clinical benefit than montelukast, montelukast had a faster onset of action and a greater initial effect. The two agents caused similar decreases in peripheral blood eosinophil counts (P < 0.05 for each agent compared with placebo). Both agents had tolerability profiles similar to that of placebo over the 12-week study. CONCLUSIONS: Although beclomethasone had a larger mean effect than montelukast, both drugs provided clinical benefit to patients with chronic asthma. This finding is consistent with the use of these agents as controller medications for chronic asthma.

Acetates↗
PubMed1978

[Exercise-induced asthma and placebos].

The effectiveness of a placebo in 15 patients with exercise-induced asthma (E.I.A., decrease of FEV1 by more than 10% after a standard run uphill on a treadmill) has been measured. 7 patients repeated the test without placebo protection, to separate the psychological effect of placebo from the emotional influences of the unusual environment of a technically highly developed hospital and adaptation to test procedures. On selection day FEV1 in % of preexercise value 10 min after exercise was 68.2 +/- 7.9% and on control day 67.1 +/- 9.5% (no statistical difference). The second stage comprised 14 patients who took the placebo or Cromolyn (Lomudal) before exercise; on selection day FEV1 in % of preexercise value 10 min after exercise was 70.1 +/- 4.8%; on placebo day it was 76.0 +/- 3.4% and on Cromolyn day 90.7 +/- 3.3%. There was statistically significant (p less than 0.025) protection by placebo. However, the protective effect of Cromolyn was much better than that of placebo (p less than 0.005). Placebo has a significantly greater protective effectiveness in E.I.A. than expected, and one much greater than previously suggested in preexisting asthma. As environmental influences were ruled out, the only explanation for the high degree of protection by placebo is the patients' trust in the placebo.

Adolescent↗
PubMed1991

Systemic alpha-interferon (Wellferon) treatment of genital human papillomavirus (HPV) type 6, 11, 16, and 18 infections: double-blind, placebo-controlled trial.

The efficacy of systemic interferon-alpha (IFN-alpha n1; Wellferon) treatment on genital human papillomavirus (HPV) infections was studied in a double-blind, placebo-controlled trial. A total of 120 women were randomly allocated to receive either interferon (IFN, n = 60) or placebo (n = 60). In both treatment groups, 15 patients with lesions induced by each of the four HPV types (HPV 6, 11, 16, and 18) were included. The dose of IFN was 1.5 x 10(6) IU subcutaneously three times for the first week followed by 3 x 10(6) IU three times weekly for a further 6 weeks. The control patients received matching placebo injections. Ten patients (three IFN-treated and seven placebo-treated) were lost to follow-up. As determined by colposcopy, cytological and histological examinations, and HPV typing (in situ hybridization, ISH), 8 IFN-treated patients (14%) and 11 placebo-treated patients (18%) showed complete response (CR) at the 8th week. The corresponding figures were 22 (37%) and 25 (43%) at the 24th week and 28 (49%) and 25 (49%) at the 52nd week, respectively. The total number of HPV DNA negative patients at Week 8 was 29 (49%) in the IFN group and 24 (40%) in the placebo group (statistically nonsignificant). At Week 24, 37 (63%) of the IFN-treated patients and 39 (67%) of the placebo-treated patients were HPV DNA negative. In 2 placebo-treated cases, cervical lesions progressed to CIN III and were treated by conization after the 24th week. There were 4 recurrences (7%) in the IFN group and no recurrences in the placebo group at the 24th week, corresponding figures at the 52nd week being 6 (11%) and 4 (7%), respectively. When the clinical efficacy was evaluated in relation to the histological grade of lesion and four different HPV types, there were no differences in CR or in the number of HPV DNA negative patients between the two study groups. In conclusion, systemic IFN-alpha therapy did not show any significant therapeutic effect on genital HPV infections (by HPV types 6, 11, 16, and 18) compared to placebo.

Adult↗
PubMed2005

Efficacy of cognitive behavioral therapy and fluoxetine for the treatment of binge eating disorder: a randomized double-blind placebo-controlled comparison.

BACKGROUND: Cognitive behavioral therapy (CBT) and certain medications have been shown to be effective for binge eating disorder (BED), but no controlled studies have compared psychological and pharmacological therapies. We conducted a randomized, placebo-controlled study to test the efficacy of CBT and fluoxetine alone and in combination for BED. METHODS: 108 patients were randomized to one of four 16-week individual treatments: fluoxetine (60 mg/day), placebo, CBT plus fluoxetine (60 mg/day) or CBT plus placebo. Medications were provided in double-blind fashion. RESULTS: Of the 108 patients, 86 (80%) completed treatments. Remission rates (zero binges for 28 days) for completers were: 29% (fluoxetine), 30% (placebo), 55% (CBT+fluoxetine), and 73% (CBT+placebo). Intent-to-treat (ITT) remission rates were: 22% (fluoxetine), 26% (placebo), 50% (CBT+fluoxetine), and 61% (CBT+placebo). Completer and ITT analyses on remission and dimensional measures of binge eating, cognitive features, and psychological distress produced consistent findings. Fluoxetine was not superior to placebo, CBT+fluoxetine and CBT+placebo did not differ, and both CBT conditions were superior to fluoxetine and to placebo. Weight loss was modest, did not differ across treatments, but was associated with binge eating remission. CONCLUSIONS: CBT, but not fluoxetine, demonstrated efficacy for the behavioral and psychological features of BED, but not obesity.

Adult↗
PubMed2004

Efficacy, tolerability, and effect on asthma-related quality of life of formoterol bid via multidose dry powder inhaler and albuterol QID via metered dose inhaler in patients with persistent asthma: a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study.

BACKGROUND: Inhaled beta(2)-agonists are widely used in asthma treatment. The design limitations of pressurized metered dose inhalers (pMDIs) have prompted the development of dry powder inhalers (DPIs) for the delivery of asthma medications. OBJECTIVE: The goal of this study was to evaluate the efficacy, tolerability, and effect on asthma-related quality of life (QOL) of a long-acting beta(2)-adrenoreceptor agonist, formoterol, delivered via multidose DPI, compared with albuterol delivered via pMDI or placebo in adolescents and adults with persistent asthma. METHODS: This multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study was conducted in outpatient clinics at 18 US centers. Adolescents and adults with persistent asthma received formoterol 10 pg BID via multidose DPI, albuterol 180 microg QID via pMDI, or placebo for 12 weeks. The primary efficacy variable was the 12-hour AUC of forced expiratory volume in 1 second (FEV(1)) after 12 weeks treatment. Secondary efficacy variables included asthma-related QOL, asthma symptom scores, rescue medication use, and other pulmonary function measures. RESULTS: A total of 239 patients (147 females, 92 males; age range, 13-85 years) with persistent asthma were enrolled (formoterol, n = 80; albuterol, n = 79; placebo, n = 80). Formoterol delivered via the multidose DPI resulted in clinically relevant and statistically significant increases in 12-hour AUC of FEV(1) after 12 weeks of treatment compared with albuterol pMDI and placebo (P < 0.019 and P < 0.001, respectively). Asthma-related QOL (total score) was significantly improved with formoterol treatment compared with placebo (P < 0.015). Nocturnal asthma symptom scores significantly improved with formoterol compared with albuterol and placebo (P < 0.001 and P < 0.003, respectively) and rescue medication use was significantly less with formoterol compared with albuterol and placebo (P < 0.004 and P < 0.002, respectively). Treatment with formoterol was well tolerated. CONCLUSIONS: In this study of adolescents and adults with persistent asthma, 12 weeks of treatment with formoterol 10 microg BID delivered via a multidose DPI provided significantly greater 24-hour bronchodilation compared with albuterol and placebo and resulted in significant improvements in asthma-related QOL compared with placebo. Formoterol was well tolerated in these patients.

Administration, Inhalation↗
PubMed2005

Triple therapy with glimepiride in patients with type 2 diabetes mellitus inadequately controlled by metformin and a thiazolidinedione: results of a 30-week, randomized, double-blind, placebo-controlled, parallel-group study.

OBJECTIVE: This study evaluated the efficacy and tolerability of glimepiride in patients with type 2 diabetes mellitus that was inadequately controlled with a combination of immediate- or extended-release metformin and a thiazolidinedione. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 2-arm study consisting of a 4-week stabilization and eligibility period and a 26-week treatment period. Patients with a diagnosis of type 2 diabetes for a minimum of 1 year received glimepiride (titrated sequentially from 2 to 4 to 8 mg/d over 6 weeks, followed by 20 weeks of maintenance therapy) or placebo in combination with an established regimen of immediate- or extended release metformin and rosiglitazone or pioglitazone. The primary efficacy outcome was the change in glycosylated hemoglobin (HbA(1c)) from baseline. The safety analysis was based on the incidence of hypo glycemia, adverse events, and laboratory abnormalities. Changes in lipid levels (high-density lipoprotein cholesterol, total cholesterol, low-density lipoprotein cholesterol, very low density lipoprotein cholesterol, and triglycerides) were evaluated, and health-related quality of life was assessed based on scores on the Diabetes Care Profile (DCP) and Health Utilities Index Mark 3 (HU13). RESULTS: Of 170 randomized patients, 159 were included in the efficacy analysis and 168 were included in the safety analysis. Demographic variables were similar at baseline between the glimepiride and placebo groups (mean age, 56.5 and 56.4 years, respectively; percent men/women, 61.0%/39.0% and 62.3%/37.7%; weight, 100.9 and 96.3 kg). HbA(1c) was significantly improved at end point with glimepiride combination therapy compared with placebo (mean [SE], -1.31% [0.08] vs -0.33% [0.08], respectively; P < 0.001). The majority of patients (62.2%) who received glimepiride achieved an HbA(1c) value of < or =7%, compared with 26.0% of patients receiving placebo (P < 0.001 between groups). At end point, the adjusted mean differences between treatments significantly favored the glimepiride combination in terms of fasting plasma glucose (-37.4 [4.0] mg/dL; P < 0.001), fasting insulin (4.06 [1.69] microIU/mL; P < 0.03), and C-peptide (124.5 [35.9] pmol/L; P < 0.001). The adjusted mean changes in body mass index from baseline to end point were 1.26 (0.16) kg/m(2) with glimepiride and 0.17 (0.16) kg/m(2) with placebo (P < 0.001). Similarly, the mean change in weight was greater with glimepiride than with placebo (3.76 [0.54] vs 0.45 [0.52] kg; P < 0.001). There were no significant differences in lipid levels between groups. Clinically significant adverse events, laboratory abnormalities, and rates of severe hypoglycemia were similar between treatment groups. The overall incidence of hypoglycemia, however, was 51.2% in the glimepiride group and 8.3% in the placebo group (P < 0.001). In general, there was no significant difference between treatment groups with respect to scores on the DCP or HUI3 over the study period. CONCLUSIONS: In these patients with type 2 diabetes that was not adequately controlled by dual combination therapy with metformin and a thiazolidinedione, the addition of glimepiride improved glycemic control compared with placebo with an acceptable tolerability profile. Although there were significantly more episodes of hypoglycemia with triple therapy than with dual therapy and placebo, the risk for severe hypoglycemia was low.

Adult↗
PubMed2006

Efficacy and safety of mixed amphetamine salts extended release (Adderall XR) in the management of attention-deficit/hyperactivity disorder in adolescent patients: a 4-week, randomized, double-blind, placebo-controlled, parallel-group study.

BACKGROUND: The ability to recognize and diagnose attention-deficit/hyperactivity disorder (ADHD) has increased in recent years. The persistence of ADHD symptoms puts adolescents with ADHD at risk for long-term adverse psychosocial outcomes. OBJECTIVE: The primary goal of this study was to assess the efficacy and safety of mixed amphetamine salts extended release (MAS XR) in the management of adolescents with ADHD. METHODS: This was a 4-week, randomized, multicenter, double-blind, placebo-controlled, parallel-group, forced-dose-titration study. Adolescents aged 13 to 17 years with ADHD were randomized to 1 of 4 active treatments (MAS XR 10, 20, 30 or 40 mg/d) or to placebo. All doses were given in the morning. This study used a forced-dose-titration design in which patients randomized to the 10-mg/d group received 1 dose of 10 mg/d for 4 weeks. Patients randomized to the 20-mg/d group received 1 dose of 10 mg/d for the first week and 1 dose of 20 mg/d for the remaining weeks; patients randomized to the 30-mg/d group received 1 dose of 10 mg/d for the first week, 1 dose of 20 mg/d for the second week, and 1 dose of 30 mg/d for the remaining 2 weeks; and patients randomized to the 40-mg/d group received 1 dose of 10 mg/d for the first week, 1 dose of 20 mg/d for the second week, 1 dose of 30 mg/d for the third week, and 1 dose of 40 mg/d for the fourth week. The primary efficacy measure was change from baseline to end point in the ADHD Rating Scale-IV (ADHD-RS-IV) score. The secondary efficacy measure was the score on the Clinical Global Impressions-Improvement (CGI-I) scale for ADHD. ADHD-RS-IV total scores were analyzed post hoc in patients with low baseline ADHD-RS-IV severity (ie, patients with baseline ADHD-RS-IV total scores less than the median) and high baseline ADHD-RS-IV severity (ie, patients with baseline ADHD-RS-IV total scores greater than the median). Safety was assessed by recording adverse events, vital signs, and body weight at all study visits and 30 days after drug discontinuation. RESULTS: Of the 287 randomized adolescents, 258 completed the study. The intent-to-treat (ITT) population included 278 patients. The majority of patients were male (65.5%) and white (73.7%) The mean weight (57.8 kg [127.1 lb]) at baseline and the mean height (163.8 cm [64.5 in]) at screening were comparable across all MAS XR treatment groups. Patients in the placebo group had a mean weight of 59.8 kg (131.6 lb) and a mean height of 166.1 cm (65.4 in). Most (56.5%) of the patients had ADHD combined inattentive/hyperactive-impulsive subtype. Two hundred nineteen (78.8%) patients were treatment naive, and 59 (21.2%) had received treatment for ADHD within 30 days before screening. ITT analysis of the ADHD-RS-IV revealed statistically significant (P < 0.001) improvement in mean ADHD-RS-IV total scores in all 4 MAS XR treatment groups, compared with placebo, at all weeks throughout the 4-week study; the mean change from baseline to end point was -17.8 in the MAS XR 10- to 40-mg/d groups and -9.4 in the placebo group. Significant treatment effects were observed in both the ADHD-RS-IV inattentive (P < 0.001) and hyperactive-impulsive (P < 0.001) subscales from baseline. In patients with low baseline ADHD-RS-IV severity, statistically significantly (P < or = 0.01) greater improvements were observed in the MAS XR 20-, 30-, and 40-mg/d groups than in the placebo group; in patients with high baseline ADHD-RS-IV severity, statistically significantly (P < or = 0.02) greater improvements were observed in all active treatment groups compared with placebo. On the CGI-I scale at end point, a higher percentage of adolescents in all MAS XR treatment groups were considered improved (MAS XR 10 mg/d, 51.9% [P < 0.01]; 20 mg/d, 66.0% [P < 0.001]; 30 mg/d, 70.7% [P < 0.001]; 40 mg/d, 63.9% [P < 0.001]) compared with adolescents receiving placebo (26.9%). The most common adverse events in patients receiving MAS XR versus placebo were anorexia/decreased appetite (35.6% vs 1.9%), headache (16.3% vs 22.2%), insomnia (12.0% vs 3.7%), abdominal pain (10.7% vs 1.9%), and weight loss (9.4% vs 0%). Most adverse events were mild or moderate in intensity (97.5%); no serious adverse events were reported. CONCLUSIONS: The adolescents with ADHD treated with 10- to 40-mg/d MAS XR up to 4 weeks had significant improvements in ADHD symptoms compared with those who received placebo. Results of this study suggest that once-daily dosing with MAS XR up to 40 mg was effective and well tolerated for the management of ADHD in these adolescents.

Adolescent↗
PubMed2006

Antipyretic efficacy and tolerability of a single intravenous dose of the acetaminophen prodrug propacetamol in children: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Propacetamol is an acetaminophen prodrug that was available in Europe as an IV formu lation for the treatment of pain and fever for some time. One gram of propacetamol is hydrolyzed in blood to release 0.5 g of acetaminophen and pharmacologically inactive N,N-diethylglycine. OBJECTIVE: This study compared the antipyretic efficacy and tolerability of IV propacetamol and placebo after a single administration in children with acute fever of infectious origin. The study was performed in anticipation of an application for US registration. METHODS: This was a double-blind, placebo-controlled trial in which patients with a body temperature (tympanic probe) of 38.5 degrees C to 41 degrees C were randomized to receive propacetamol 30 mg/kg IV or a placebo of identical appearance, both administered as 15-minute infusions. Temperature was measured at baseline, 0.5 hour after drug administration, and hourly thereafter for 6 hours or until use of rescue medication. The primary efficacy variable was the change in body temperature at each evaluation time compared with baseline. Secondary efficacy variables included the number of children requiring rescue medication and the time to remedication; the number of children with a body temperature <38 degrees C during the evaluation period and the time to reach this temperature; maximal body temperature reduction; and the weighted sum of changes in body temperature over the evaluation period. Tolerability was assessed based on changes in vital signs, monitored for 6 hours after administration of study drug, and adverse events recorded during the 24 hours after administration. RESULTS: Twenty children received propacetamol and 21 received placebo. Twenty patients were white, 17 black, and 4 Hispanic; their age ranged from 3 to 12 years. The actual mean (SD) dose of propacetamol received was 25.5 (0.6) mg/kg (equivalent to acetaminophen 12.8 [0.3] mg/kg). The reduction in body temperature was significantly greater in the propacetamol group compared with the placebo group at each time point over the 6-hour follow-up period (P < 0.001). Rescue medication was administered to 10.0% of patients in the propacetamol group, compared with 52.4% of those in the placebo group (P = 0.004). The weighted mean (SD) sum of the change in body temperature indicated greater antipyretic efficacy for propacetamol compared with placebo (-7.9 [3.8] degrees C x h vs 0.1 [3.6] degrees C x h, respectively; P < 0.001). There was no difference in the number of patients with treatment-emergent adverse events in the propacetamol and placebo groups (8 [40.0%] and 8 [38.1%]). The incidence of IV-site reactions was 10.0% in the propacetamol group and 9.5% in the placebo group. CONCLUSIONS: In these 41 children with acute fever of infectious origin, a propacetamol dose of 25.5 (0.6) mg/kg IV had significantly greater antipyretic efficacy than placebo and was equally well tolerated. Comparisons of this preparation with other IV antipyretic medications are needed.

Acetaminophen↗
PubMed2006

Use of sibutramine in obese mexican adolescents: a 6-month, randomized, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: The prevalence of overweight and obesity in children and adolescents is increasing in both the United States and Mexico. OBJECTIVE: The goal of this article was to assess the efficacy and safety of sibutramine in obese Mexican adolescents. METHODS: This was a 6-month, randomized, double-blind, placebo-controlled, prospective clinical trial of sibutramine QD. Male and female patients aged 14 to 18 years with sex-specific body mass index (BMI) for age and sex >85th percentile were eligible. The primary end points for the trial were the baseline versus end point absolute values for body weight, BMI, and percentage of the initial BMI (%BMI); secondary end points were waist circumference and percentage of the initial waist circumference (%waist). These were measured at days -15, 0, 30, 60, 90, 120, 150, and 180 of the study. Quality of life was assessed at the study start and end using the 36-Item Short-Form Health Survey (SF-36) questionnaire. Blood pressure and heart rate were assessed, and adverse events (AEs) were recorded. Both groups received individually tailored diet and exercise programs. RESULTS: Forty-six patients (age range, 14-18 years) with a BMI >95th percentile for age were included (sibutramine group, n = 23 [14 females, 9 males]; placebo group, n = 23 [12 females, 11 males]). Twenty-one patients in the sibutramine group and 19 patients in the placebo group completed the 6-month trial. Using the intent-to-treat data, weight (mean [SD]) in the sibutramine group changed from 92.5 (14.6) kg to 85.7 (14.4) kg, for a net weight loss of 7.3 kg (95% CI 4.6-9.9), a waist circumference loss of 8.0 cm (95% CI, 4.7-11.3), and a % BMI loss of 9.2% (95% CI, 6.9-11.6). In the placebo group, weight changed from 98.9 (22.7) kg to 94.6 (22.5) kg, a weight loss of 4.3 kg (95% CI, 1.7-6.9), a waist circumference loss of 3.8 cm (95% CI, 0.7-7.0), and a %BMI loss of 5.2% (95% CI, 2.4-7.9) (P < 0.05 for all intragroup comparisons; P > 0.05 for the intergroup comparisons). Mean (SD) scores on the SF-36 scale in the sibutramine group changed from 78.0 (13.3) at baseline to 84.8 (7.4) at study end (P < 0.05); the respective values in the placebo group were 82.8 (10.3) and 87.3 (7.6) (P < 0.05). At base-line, systolic blood pressure (SBP) was 116.7 (5.9) mm Hg in the sibutramine group and 118.3 (7.6) mm Hg in the placebo group; at end point, the respective SBPs were 112.4 (9.6) mm Hg and 112.6 (6.5) mm Hg. At baseline, diastolic blood pressure (DBP) was 78.9 (4.5) mm Hg in the sibutramine group and 79.5 (5.2) mm Hg in the placebo group; at end point, the respective DBPs were 73.5 (6.3) mm Hg and 76.6 (6.2) mm Hg. At baseline, heart rate was 76.3 (6.4) beats/min in the sibutramine group and 81.1 (9.5) beats/min in the placebo group; at end point, the respective findings were 79.8 (8.8) beats/min and 77.6 (8.6) beats/min (P > 0.05 for all preceding intergroup comparisons). One patient in the sibutramine group had increased blood pressure (at month 3) and 3 had increased heart rate (at months 1, 2, and 4); 2 patients receiving placebo had increased blood pressure (month 3) and 2 had increased heart rate (at months 1 and 3). These changes disappeared in 1 week and did not require treatment or trial suspension. Additionally, in the sibutramine group, 3 patients experienced 4 mild AEs: headache, dry mouth, headache with nausea, and headache with weakness and paleness (P > 0.05). In the placebo group, 3 patients experienced 4 mild AEs: 2 cases of headache, as well as 1 case of headache with somnolence and 1 case of headache with dry mouth (P > 0.05). CONCLUSION: Sibutramine 10 mg QD in addition to diet and exercise was effective and generally well tolerated in this population of obese Mexican adolescents.

Adolescent↗
PubMed2006

Rofecoxib 50 mg and valdecoxib 20 or 40 mg in adults and adolescents with postoperative pain after third molar extraction: results of two randomized, double-blind, placebo-controlled, single-dose studies.

OBJECTIVE: These studies assessed the comparative efficacy of rofecoxib and valdecoxib in the treatment of acute postoperative dental pain. METHODS: Two randomized, double-blind, placebo-controlled, single-dose studies were conducted in patients undergoing extraction of > or =2 third molars, with > or =1 mandibular impaction, who experienced moderate or severe pain after extraction. In study 1, patients were randomized in a 4:4:1 ratio to receive rofecoxib 50 mg, valdecoxib 20 mg, or placebo. In study 2, which was an exploratory study, patients were randomized in a 2:2:1 ratio to receive reofecoxib 50 mg, valdecoxib 40 mg, or palcebo. The primary efficacy end point was total pain relief at 12 hours (TOPAR12) for rofecoxib compared with valdecoxib 20 mg (study 1) or valdecoxib 40 mg (study 2). Tolerability was assessed based on clinical adverse experiences (AEs) and vital signs. These studies were performed before both agents were withdrawn from the market. RESULTS: In study 1, 200 patients were randomized to receive rofecoxib 50 mg, 201 to valdecoxib 20 mg, and 49 to placebo. In study 2, 51 patients were randomized to receive rofecoxib 50 mg, 50 to valdecoxib 40 mg, and 24 to placebo. The majority of patients in both studies were female (approximately 54%) and white ( approximately 66%), with a mean age of approximately 22 years and a mean weight of approximately 75 kg. Most (approximately 58%) patients reported experiencing moderate postoperative pain. In study 1, mean TOPAR12 scores were 30.7 for rofecoxib 50 mg, 28.9 for valdecoxib 20 mg, and 5.5 for placebo; in study 2, TOPAR12 scores were 27.0 for rofecoxib 50 mg, 28.6 for valdecoxib 40 mg, and 6.9 for placebo. In both studies, the active treatments were comparable in terms of the primary end point and were statistically superior to placebo (P<0.001). In study 1, rofecoxib was associated with a longer median time to use of rescue medication compared with valdecoxib 20 mg (>24 hours vs 23 hours 58 minutes; P=0.010) and a significantly smaller proportion of patients using rescue medication over 24 hours (35.0% vs 50.2%; P<0.001). In study 2, there were no significant differences in the median time to use of rescue medication or the proportion of patients using rescue medication between active treatments. There were no significant differences in total pain relief at 4 or 8 hours, patients' global assessment, onset of analgesia, or AEs between active treatments in either study. The incidence of clinical AEs in study 1 was similar for rofecoxib 50 mg, valdecoxib 20 mg, and placebo (39.5%, 36.8%, and 49.0%, respectively). In study 2, AEs occurred significantly less frequently with rofecoxib 50 mg compared with placebo (35.3% vs 70.8%, respectively; P<0.01); there was no significant difference between the rate of AEs with valdecoxib 40 mg (50.0%) and placebo. CONCLUSIONS: Rofecoxib 50 mg had comparable analgesic efficacy to valdecoxib 20 and 40 mg in these patients with pain after dental surgery. All active treatments were well tolerated.

Adolescent↗
PubMed2005

Treatment of acute bronchitis in adults with a pelargonium sidoides preparation (EPs 7630): a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Acute bronchitis is a widespread medical problem, and, although predominantly caused by viruses, antibiotics are still prescribed unnecessarily. Therefore, it is of utmost importance to evaluate the use of alternative treatments for acute bronchitis. OBJECTIVE: To evaluate the efficacy and safety of a Pelargonium sidoides preparation (EPs 7630 is a registered trademark of Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany) compared with placebo in patients with acute bronchitis. DESIGN: Randomized, double-blind, placebo-controlled trial using a design with planned interim analyses. SETTING: Six outpatient clinics. PATIENTS: One hundred twenty-four adults with acute bronchitis present </=48 hours, Bronchitis Severity Score (BSS) >/=five points, and informed consent. INTERVENTION: EPs 7630 or placebo (30 drops three times daily) for seven days. MEASUREMENTS: The primary outcome criterion was the change of BSS on day seven. RESULTS: The decrease of BSS from baseline to day seven was 7.2 +/- 3.1 points with EPs 7630 (n = 64) and 4.9 +/- 2.7 points with placebo (n = 60). The 95% confidence interval for the difference of effects between the two treatment groups (EPs 7630 minus placebo) was calculated as (1.21, 3.56) showing a significant improvement of EPs 7630 compared with placebo on day seven (P < .0001). For each of the five individual symptoms, rates of complete recovery were considerably higher in the EPs 7630 group. Within the first four days, onset of treatment effect was recognized in 68.8% of patients in the EPs 7630 group compared with 33.3% of patients in the placebo group (P < .0001). Health-related quality of life improved more in patients treated with EPs 7630 compared with placebo-treated patients. Adverse events occurred in 25 of 124 patients (EPs 7630: 15/64 patients, placebo: 10/60 patients). All adverse events were assessed as nonserious. CONCLUSIONS: EPs 7630 was superior in efficacy compared with placebo in the treatment of adults with acute bronchitis. It may therefore offer an effective alternative for acute bronchitis unless antibiotics are clearly indicated.

Acute Disease↗
PubMed1996

Comparison of acamprosate and placebo in long-term treatment of alcohol dependence.

BACKGROUND: About 50% of alcoholic patients relapse within 3 months of treatment. Previous studies have suggested that acamprosate may help to prevent such relapse. The aim of our study was to assess the efficacy and safety of long-term acamprosate treatment in alcohol dependence. METHODS: In this multicentre, double-blind, placebo-controlled study, we recruited 455 patients, aged 18-65 years, with chronic or episodic alcohol dependence. Patients were randomly allocated treatment with acamprosate (1998 mg daily for bodyweight > 60 kg; 1332 mg daily for < or = kg) or placebo for 360 days. Patients were assessed on the day treatment started and on days 30, 90, 180, 270, and 360 by interview, self-report, questionnaire, and laboratory screening. Patients were classified as abstinent, relapsing, or non-attending. Time to first treatment failure (relapse or non-attendance) was the primary outcome measure. FINDINGS: Seven patients were excluded from the intention-to-treat analysis because they did not attend on the first treatment day and therefore received no medication. The acamprosate (n = 224) and placebo (n = 224) groups were well matched in terms of baseline demographic and alcohol-related variables. 94 acamprosate-treated and 85 placebo-treated patients completed the treatment phase: of those withdrawn, 104 (52 in each group) relapsed, 69 (33 vs 36, respectively) were lost to follow-up, 63 (31 vs 32) refused to continue treatment, 16 (15 vs 11) had concurrent illness, three (two vs one) died, ten (six vs four) had adverse side-effects, one (acamprosate treated) received the wrong medication, and three (placebo treated) were non-compliant. The proportion without treatment failure was higher in the acamprosate than in the placebo group throughout the treatment period (p < 0.001, Mantel-Cox). At the end of treatment, 41 (18.3%) acamprosate-treated and 16 (7.1%) placebo-treated patients had been continuously abstinent (p = 0.007). Mean cumulative abstinence duration was significantly greater in the acamprosate group than in the placebo group (138.8 [SD 137.5] vs 103.8 [119.0] days; p = 0.012). 148 patients (79 acamprosate, 69 placebo) completed 27 months follow-up: 27 (11.9%) acamprosate-treated and 11 (4.9%) placebo-treated patients remained continuously abstinent, and the mean cumulative abstinence duration was 230.8 days (259.1) and 183.0 days (235.2), respectively. Apart from occasional diarrhoea, there was no difference in side-effects between groups. INTERPRETATION: Acamprosate is an effective and well-tolerated pharmacological adjunct to psychosocial and behavioural treatment programmes for treatment of alcohol-dependent patients.

Acamprosate↗
PubMed2003

A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus.

OBJECTIVE: The goal of this study was to compare the effects of 2 doses of pioglitazone hydrochloride (a thiazolidinedione insulin sensitizer) with placebo on glycated hemoglobin (HbA(1c)), insulin sensitivity, and lipid profiles in patients with type 2 diabetes mellitus who had suboptimal glycemic control and mild dyslipidemia. METHODS: Patients with type 2 diabetes mellitus (HbA(1c) >/=6.5% and </=9.8%) who had not previously received insulin or oral antihyperglycemic medications (OAMs) were randomized to treatment with placebo, pioglitazone 30 mg QD, or pioglitazone 45 mg QD in double-blind fashion for 16 weeks at 41 centers in Canada and Spain. RESULTS: A total of 297 patients were randomized (99 in each group). Overall, 286 (96.3%) were white. Mean (SD) age was 58.4 (10.9) years (range, 24-85 years), mean (SD) body mass index was 31.4 (4.8) kg/m(2), mean (SD) duration of type 2 diabetes mellitus was 20.0 (37.4) months, and 30.6% of patients were receiving medication for dyslipidemia. Treatment with pioglitazone 30 or 45 mg QD for 16 weeks reduced mean HbA(1c) by 0.8% and 0.9% from baseline, respectively (both P < 0.001 vs baseline and placebo). A reduction in HbA(1c) of 0.2% was observed in the placebo group (P = 0.025). In patients with medium (>/=7% to <8%) or high (>/=8% to </=9.8%) baseline HbA(1c), both doses of pioglitazone significantly reduced HbA(1c) (both P < 0.001 vs placebo). Pioglitazone 30 and 45 mg significantly reduced fasting serum insulin versus placebo (P = 0.008 and P = 0.006, respectively) and increased insulin sensitivity by Homeostasis Model Assessment versus placebo (P = 0.039 and P = 0.001, respectively). Relative to placebo, pioglitazone 30 and 45 mg significantly increased high-density lipoprotein cholesterol (HDL-C [P = 0.028 and P < 0.001, respectively]) and lowered the atherogenic index of plasma (P = 0.018 and P < 0.001, respectively). Pioglitazone 45 mg also significantly reduced serum triglycerides, apolipoprotein B, and total cholesterol:HDL-C ratio versus placebo (P = 0.007, P = 0.015, and P = 0.005, respectively). Pioglitazone 30 and 45 mg were associated with a significant reduction in serum alanine aminotransferase relative to placebo (P = 0.036 and P = 0.005, respectively). Pioglitazone appeared to be safe and was well tolerated. CONCLUSIONS: In the present study, pioglitazone 30 and 45 mg produced significant improvements in HbA(1c), insulin sensitivity, and lipid profile in OAM-naive patients with type 2 diabetes mellitus with suboptimal glycemic control and mild dyslipidemia.

Adult↗
PubMed2004

Efficacy and tolerability of sumatriptan tablets in a fast-disintegrating, rapid-release formulation for the acute treatment of migraine: results of a multicenter, randomized, placebo-controlled study.

BACKGROUND: Sumatriptan tablets have been developed in a fast-disintegrating, rapid-release formulation designed to facilitate tablet disintegration and drug dispersion and to potentially mitigate the effects of gastric stasis that can accompany migraine. OBJECTIVE: This study was conducted to evaluate the efficacy and tolerability of sumatriptan 50- and 100-mg tablets in a fast-disintegrating, rapid-release formulation compared with those of placebo in patients with migraine. METHODS: This clinical trial had a randomized, double-blind, placebo-controlled, parallel-group design. Exclusion criteria included >6 migraines monthly during either of the 2 months before screening; uncontrolled hypertension; suspected or confirmed cardiovascular or cerebrovascular disease; and ophthalmic, basilar, or hemiplegic migraine. Sumatriptan 50 and 100 mg and placebo were taken on an outpatient basis during the mild-pain phase of a single migraine attack. Patients recorded details of the treated migraine on a diary card and rated pain severity immediately before dosing and 30 minutes, 45 minutes, 1 hour, and 2 hours after dosing using a 4-point scale (from 0 = none to 3 = severe). The primary efficacy end point was the proportion of patients who were pain free 2 hours after dosing. Additional efficacy end points were the proportion of patients who were pain free at 30 minutes, 45 minutes, and 1 hour after dosing; the proportion who were migraine free through 2 hours after dosing; and the proportion with a sustained pain-free response. RESULTS: Patients' mean age ranged from 39.7 to 41.5 years across the 3 groups, and the majority were women (79.7%-85.9%) and white (98.7%-100%). One hundred thirty-seven patients received sumatriptan 50 mg, 142 sumatriptan 100 mg, and 153 placebo. In the intent-to-treat population (n = 432), 51.1% of patients who received sumatriptan 50 mg and 66.2% of patients who received sumatriptan 100 mg were pain free 2 hours after dosing, compared with 19.6% of the placebo group (P < 0.001, each sumatriptan dose vs placebo). In an exploratory analysis, the 2-hour pain-free rate with sumatriptan 100 mg was significantly better than that with sumatriptan 50 mg (P = 0.007). Significantly more patients who received sumatriptan 100 mg were pain free compared with placebo at 30 minutes (P < 0.01), 45 minutes (P < 0.001), and 1 hour after dosing (P < 0.001); similar pain-free results were observed in patients who received sumatriptan 50 mg at 45 minutes (P < 0.05) and 1 hour (P = 0.01). In the per-protocol population (n = 313), pain-free efficacy 2 hours after dosing was 52.7% with sumatriptan 50 mg and 74.8% with sumatriptan 100 mg, compared with 21.0% with placebo (P < 0.001, each sumatriptan dose vs placebo). These rates were greater than those in the overall study population, approximately 12.0% of whom treated moderate or severe pain. The only drug-related adverse events reported in >/=3% of patients in any treatment group were nausea and vomiting (<1%, 5%, and 2% in the sumatriptan 50 and 100 mg and placebo groups, respectively), chest symptoms (2%, 3%, and 0%), and malaise and fatigue (1%, 3%, and <1%). No serious adverse events were reported. CONCLUSIONS: In this study, sumatriptan tablets in a fast-disintegrating, rapid-release oral formulation provided pain-free efficacy in the acute treatment of migraine. Efficacy was maximized with the 100-mg dose compared with the 50-mg dose, and by treating early when pain was mild. In the intent-to-treat population, 51.1% of patients who received sumatriptan 50 mg and 66.2% of those who received sumatriptan 100 mg were pain free 2 hours after dosing. In the per-protocol population, 3 of 4 patients taking the 100-mg tablets for mild pain within 1 hour of its onset were pain free at 2 hours. Sumatriptan tablets were generally well tolerated.

Adult↗
PubMed1998

Randomized, double-blind, placebo-controlled study of the preventive effect of supplemental oral vitamin C on attenuation of development of nitrate tolerance.

OBJECTIVES: This study sought to evaluate the preventive effect of vitamin C, an antioxidant, on the development of nitrate tolerance. BACKGROUND: Decreased intracellular production of cyclic guanosine monophosphate (cGMP) is a mechanism of nitrate tolerance, and increased superoxide levels and reduced activation of guanylate cyclase have been observed in vitro. METHODS: In this double-blind, placebo-controlled study, 24 normal volunteers and 24 patients with ischemic heart disease (IHD) were randomized to receive either vitamin C (2 g three times daily [vitamin C group, n=12]) or placebo (placebo group, n=12). The vasodilator response to nitroglycerin was assessed with forearm plethysmography by measuring the change in FBF before and 5 min after sublingual administration of 0.3 mg of nitroglycerin. Blood samples were simultaneously obtained to measure platelet cGMP levels. FBF was measured, and blood sampling was performed serially at baseline (day 0), 3 days after administration of vitamin C or placebo (day 3) and 3 days after application of a 10-mg/24-h nitroglycerin tape concomitantly with oral vitamin C or placebo (day 6). RESULTS: There were no differences between the vitamin C and placebo groups in percent increases in FBF (%FBF) or platelet cGMP levels (%cGMP) after administration of sublingual nitroglycerin on day O (%FBF: normal volunteers 31+/-8 vs. 32+/-10; patients with IHD 32+/-9 vs. 32+/-8; %cGMP: normal volunteers 37+/-9 vs. 39+/-10; patients with IHD 38+/-10 vs. 39+/-10 [vitamin C group vs. placebo group]) or day 3 (%FBF: normal volunteers 32+/-9 vs. 33+/-9; patients with IHD 31+/-10 vs. 31+/-10; %cGMP: normal volunteers 36+/-8 vs. 37+/-9; patients with IHD 39+/-11 vs. 38+/-10 [vitamin C group vs. placebo group]). The %FBF and %cGMP in the placebo group were significantly lower on day 6 than in the vitamin C group (%FBF: normal volunteers 30+/-8 vs. 19 4, p < 0.01; patients with IHD 29+/-9 vs. 17+/-6, p < 0.01; %cGMP: normal volunteers 36 10 vs. 17+/-6, p < 0.01; patients with IHD 37+/-11 vs. 15+/-5, p < 0.01 [vitamin C group vs. placebo group]). CONCLUSIONS: These results indicate that combination therapy with vitamin C is potentially useful for preventing the development of nitrate tolerance.

Adult↗