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PubMed2026

Neurological effects of encapsulated dexamethasone sodium phosphate in children aged 6-9 years with ataxia telangiectasia (NEAT): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Ataxia telangiectasia is a rare, multisystem disorder with progressive cerebellar neurodegeneration and no approved treatments. The efficacy of corticosteroids, including erythrocyte encapsulated dexamethasone sodium phosphate (eDSP), which have been studied for two decades in this disease, has not yet been proven in randomised trials. We aimed to investigate the safety and efficacy of eDSP in children aged 6-9 years with ataxia telangiectasia. METHODS: NEAT was a multicentre, randomised, double-blind, placebo-controlled phase 3 study, conducted at 20 sites across nine countries (Denmark, Germany, Italy, Norway, Poland, Spain, Switzerland, UK, and USA). Eligible participants were children aged 6 years or older weighing at least 15 kg, with a genetic diagnosis of ataxia telangiectasia and presence of neurological symptoms. Participants were randomly assigned (1:1) to the eDSP or placebo group via an independent interactive web response system and were stratified by age (6-9 years or ≥10 years), sex, and region (USA vs other countries). All participants, investigators, sponsors, and raters were masked to treatment assignments. eDSP was given intravenously every 21-30 days for six doses. All randomly assigned participants were included in the intention-to-treat (ITT) and safety populations; the primary and secondary efficacy analyses were conducted in participants aged 6-9 years in the ITT population. The primary efficacy endpoint was the change in Rescored Modified International Cooperative Ataxia Rating Scale (RmICARS) score between baseline and month 6, and a mixed-model-repeated-measures analysis was used. The trial was registered at ClinicalTrials.gov, NCT06193200, and is completed. FINDINGS: Between June 24, 2024, and Dec 17, 2025, we screened 125 participants for eligibility, of whom 105 (84%) were randomly assigned to the eDSP group (n=51 [49%]) or the placebo group (n=54 [51%]) and received at least one dose of treatment. The mean age was 8·5 years (SD 1·9) in the eDSP group and 8·6 years (2·3) in the placebo group (overall age range 6-17 years). In the eDSP group, 24 (47%) of 51 participants were girls and 27 (53%) were boys and, in the placebo group, 26 (48%) of 54 were girls and 28 (52%) were boys. Of ITT participants aged 6-9 years, 38 (95%) of 40 in the eDSP group and 41 (95%) of 43 in the placebo group completed the study. Compared with the placebo group, no significant differences were identified in change in RmICARS score from baseline to 6 months in participants aged 6-9 years: least squares mean difference -1·30 (95% CI -2·77 to 0·18; p=0·085). Adverse events were reported in 47 (92%) of 51 participants in the eDSP group and in 50 (93%) of 54 participants in the placebo group. The most common treatment-emergent adverse events were vomiting, pyrexia, pruritus, nasopharyngitis, cough, headache, and fatigue. There were no reports of treatment-related serious adverse events or deaths. Safety laboratory parameters did not identify adverse effects on growth, metabolism, bone mineral density, or endocrine function in any of the treatment groups. INTERPRETATION: The primary efficacy endpoint was not achieved, because the effect of eDSP on neurological symptoms did not reach statistical significance. The favourable safety profile of eDSP, previously described in a large study of children with ataxia telangiectasia, was confirmed in this trial. The eDSP programme, comprising two randomised studies and treating the largest cohort of patients with ataxia telangiectasia to date, underscores the need for rigorously designed trials of sufficient duration to detect sustained clinical benefit. FUNDING: Quince Therapeutics.

Humans↗
PubMed2001

Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: a replication analysis of the Food and Drug Administration Database.

The assumption that depressed patients who are assigned to placebo in antidepressant clinical trials are exposed to substantial morbidity and mortality has not been based on research data. Because of worldwide concern about placebo use and the implications of our earlier findings of no increased suicide risk in placebo-treated patients, we conducted a replication study in a new patient sample. We assessed suicide risk and symptom reduction among placebo-treated patients participating in antidepressant clinical trials for two recently approved antidepressants, venlafaxine ER and citalopram, which were unavailable during our previous study. Among 23,201 participant patients, 32 committed suicide and 172 attempted suicide. Rates of suicide and attempted suicide did not differ significantly among the placebo- and drug-treated groups. Based on patient exposure years, annual rates of suicide and attempted suicide were 0.5 and 6.7% with placebo, 0.9% with active comparator (rates for attempted suicide are unavailable), and 0.6 and 6.3% with investigational antidepressants. Symptom reduction was 47.9% with investigational drugs (n = 1172), 47.5% with active comparators (n = 161), and 35.5% with placebo (n = 606). These data may inform discussions about the use of placebo in antidepressant clinical trials.

Adult↗
PubMed2002

Long-term treatment with cetirizine of infants with atopic dermatitis: a multi-country, double-blind, randomized, placebo-controlled trial (the ETAC trial) over 18 months.

H1-receptor antagonists are considered central to the treatment of atopic dermatitis (AD)-associated pruritus and are widely used in the treatment of AD despite a lack of double-blind, randomized clinical trials. In this study we analyzed the effects of the long-term use of cetirizine on the severity, natural history, and treatment of AD. In the prospective, multi-country, double-blind, randomized, placebo-controlled Early Treatment of the Atopic Child (ETAC) study, 817 infants (12-24 months of age) who suffered from AD at study entry and with a history of atopic disease in a parent or sibling were treated for 18 months with either cetirizine (0.25 mg/kg) or placebo twice daily. All concomitant medications for the treatment of AD were allowed but had to be recorded by the investigator in the case report form; the concomitant use of H1-antihistamines was discouraged. The primary end-point for efficacy was the onset of asthma. Secondary parameters of efficacy, however, were the consumption of concomitant medications for AD (topical and systemic treatment) and the severity of symptoms related to AD, which was rated with the AD scale, SCORAD. The severity of AD, as measured by SCORAD, decreased significantly (p < 0.001) over the study period (18 months) in both groups. Other oral H1-antihistamines were significantly more often used in the placebo group than in the cetirizine group (24.9% vs. 18.6%, p = 0.03). The number of infants who developed urticaria during the study period was significantly lower with cetirizine treatment (placebo group: 16.2%; cetirizine group: 5.8%; p < 0.001). For the treatment of AD, mild topical corticosteroids (class I, e.g. hydrocortisone) were used in 41.6% of the patients (placebo group 41.6%, cetirizine group 41.7%) and moderate-to-potent topical corticosteroids (class II, III, IV) in 55.0% (respectively 56.4% and 53.5%). The duration of the use of topical moderate-to-potent corticosteroids differed between the cetirizine group and the placebo group (mean percentage of days: placebo 25.2, median 2.4; cetirizine mean 18.8, median 0.95 p = 0.067, Mann-Whitney test, not statistically significant). In sub-groups of infants with a SCORAD of >or= 25, this cortico-sparing effect was statistically significant (placebo 35.1 vs. 25.8 in the cetirizine group; p = 0.014, Mann-Whitney test). In conclusion, in view of the proven safety of cetirizine, the use of this drug might help to reduce the duration and the amount of moderate-to-strong topical corticosteroids used in the treatment of infants and children with AD. However, further studies designed with the primary end-point of AD are clearly indicated to confirm the benefits of the use of H1-antihistamines in the management of AD.

Administration, Oral↗
PubMed2000

Alpha-dihydroergocryptine in the treatment of de novo parkinsonian patients: results of a multicentre, randomized, double-blind, placebo-controlled study.

INTRODUCTION: A multicentre, randomized, double-blind, placebo-controlled, parallel group study was carried out in 123 patients suffering from never treated (de novo) idiopathic Parkinson's disease (PD). The aim of the study was to confirm the efficiency and safety of alpha-dihydroergocryptine (alpha-DHEC) given as monotherapy in the symptomatic treatment of PD. The total score of the Unified Parkinson's Disease Rating Scale (UPDRS) was identified as the efficacy target variable. PATIENTS AND METHODS: Sixty-two patients (32 males, 30 females, mean age +/- SD 64 +/- 10) were randomized to alpha-dihydroergocryptine and 61 (30 males, 31 females, mean age 63.8 +/- 9.1) to placebo. According to the experimental design, a 18-month double-blind phase vs placebo was followed. Two interim analyses were planned both at the 3rd and 12th month of treatment, in order to avoid continuation on placebo, if clear differences between groups were found (stopping criterium: nominal significance level equal to 0.022 in the analysis of the target variable). Analysis of variance was performed both on the per protocol (PP) and intent-to-treat (ITT) sample. RESULTS: The results on the first interim analysis showed significant differences between treatment groups of the UPDRS total score both in the ITT (115 patients, alpha-DHEC: No. 56; placebo: No. 59; P=0.019) and PP (96 patients, alpha-DHEC: No. 46; placebo: No. 50; P=0.001) sample, why the trial was stopped. At the time of stopping the trial, 73 patients (alpha-DHEC: No. 37; placebo: No. 36) had reached the 6-month observation visit; the analysis carried out on this subset of patients confirmed the efficacy of alpha-dihydroergocryptine in early PD and the correctness of the decision to stop. The incidence of adverse drug reactions (ADR) did not differ between alpha-dihydroergocryptine and placebo recipients, gastrointestinal complaints being the most frequent. CONCLUSION: The results indicate that alpha-dihydroergocryptine is safe and effective in improving symptoms of de novo parkinsonian patients.

Dihydroergotoxine↗
PubMed2002

Efficacy and safety of sibutramine for weight loss in obese patients with hypertension well controlled by beta-adrenergic blocking agents: a placebo-controlled, double-blind, randomised trial.

Sibutramine is a serotonin-noradrenaline reuptake inhibitor that is effective for long-term weight reduction and maintenance in obese patients when used as an adjunct to dietary and behavioural measures. Because the inhibition of noradrenaline reuptake may be expected to increase systolic and diastolic blood pressure (SBP and DBP) and pulse rate (PR), a 12-week multi-centre, placebo-controlled, double-blind study was designed to evaluate the efficacy and tolerability of sibutramine for weight loss in obese patients whose hypertension was well controlled (DBP < or = 95 mm Hg) by beta-adrenergic blocking agents (beta-blockers), with or without concomitant thiazide diuretics. Of the 61 patients randomised to sibutramine 20 mg once daily or placebo, 55 patients (90%) completed the study. After 12 weeks, sibutramine-treated patients lost significantly more weight than placebo-treated patients: mean weight reductions were 4.2 kg (4.5%) in the sibutramine group vs 0.3 kg (0.4%) in the placebo group (P<0.001). Greater weight reduction on sibutramine was accompanied by trends for greater mean reductions in serum triglycerides and very low density lipoprotein cholesterol. Sibutramine was well tolerated, and most adverse events were mild or moderate in severity. No sibutramine patient discontinued treatment because of an adverse event. Mean supine and standing DBP and SBP were not statistically significantly different between the sibutramine group and the placebo group at any post-baseline visit during the 12-week trial. At week 12, mean increases from baseline supine SBP and DBP, respectively, were 1.6 and 1.7 mm Hg for the sibutramine group vs increases of 0.4 and 1.3 mm Hg for the placebo group. At week 12, mean increases from baseline standing SBP and DBP, respectively, were 1.5 and 1.8 mm Hg for the sibutramine group vs an increase of 0.3 and a decrease of 0.8 mm Hg for the placebo group (P > 0.05 for treatment comparison). A statistically significant mean increase of 5.6 bpm (+/-8.25, s.d.) in supine PR from a baseline of 62 bpm was reported in sibutramine-treated patients at week 12, whereas placebo-treated patients had a mean supine PR decrease of 2.2 bpm (+/-6.43) (P < 0.001). In summary, sibutramine was well tolerated and effective in weight reduction. The addition of sibutramine did not result in an increase in BP in obese patients whose hypertension was well controlled by a beta-blocker. However, based on the potential for changes in BP and PR, obese patients being treated with sibutramine should be monitored periodically for changes in BP and PR and managed appropriately.

Adrenergic beta-Antagonists↗
PubMed1997

Cisapride in functional dyspepsia in general practice. A placebo-controlled, randomized, double-blind study.

BACKGROUND: Functional dyspepsia is recognized as a common disorder in clinical practice. The aim of this study was to determine the efficacy and adverse effects of cisapride compared to a placebo in patients from a general practice with functional dyspepsia (FD). Secondly we investigated whether Helicobacter pylori-positive FD patients present with specific symptoms and determined the efficacy of cisapride for FD patients with H. pylori. METHODS: In a placebo-controlled double-blind study, patients were randomized to receive fixed doses of either cisapride (10 mg three times daily) or placebo. Symptoms were evaluated after 2 and 4 weeks of treatment. The selection of FD patients,collection of data, and evaluation of symptoms as well as adverse effects were performed by general practitioners. Dyspeptic patients were referred to the Gastroenterology Department in order to exclude ulcers, oesophagitis, pancreatitis and gallstones. Biopsies of gastric mucosa were taken for histological examination and H. pylori culture. PATIENTS: 121 patients entered this study (61 took cisapride, 60 placebo). There were 113 patients (56 cisapride, 57 placebo) available for analysis of the efficacy and 120 patients (61 cisapride, 59 placebo) for evaluation of adverse effects.In total 102 biopsies were tested for the presence of gastritis by histological examination. There were 30 H. pylori-positive cultures among 111 patients. RESULTS: After 4 weeks a statistically significant reduction in symptoms was found, but it was similar in the two groups. No symptoms specific for H. pylori-positive patients were found. There was not a significant difference in the response to cisapride between H. pylori-positive and H. pylori-negative patients. The difference in overall (63%) response in the cisapride group and the 44% response in the placebo group did not reach statistical significance. CONCLUSIONS: No significant difference was found between placebo and cisapride in the treatment of FD in general practice. H. pylori-positive patients did not present with specific symptoms nor did they exhibit a different response to cisapride.

Adolescent↗
PubMed2003

A randomized, placebo-controlled, double-blind trial of ondansetron in renal itch.

BACKGROUND: Renal itch is a relatively common and distressing problem for patients with chronic renal failure. Ondansetron, a serotonin type 3 receptor antagonist was developed for relief of chemotherapy induced nausea. Recently, anecdotal reports describe relief of renal itch with ondansetron. OBJECTIVES: We performed a double-blind randomized placebo-controlled trial to objectively assess the effectiveness of ondansetron in renal itch. PATIENTS AND METHODS: With approval from the local ethical committee, 24 patients on haemodialysis were enrolled in the trial. On a random basis 14 patients were blindly allocated to the ondansetron-placebo sequence and 10 to the placebo-ondansetron sequence. Baseline values for itch were obtained for 7 days before the treatment period and there was a 7-day washout between the treatment periods. During the treatment patients received either 8 mg of ondansetron three times a day or a placebo tablet three times a day for 2 weeks. Patients were asked to record the severity of their pruritus on a visual analogue scale (VAS) twice a day. At the end of the study patients were asked blindly which treatment they had preferred. RESULTS: Seventeen patients completed the trial. Pruritus decreased by 16% (95% CI: 0.5-32%) during active treatment and by 25% (95% CI: 9-41%) during treatment with placebo. The change in VAS scores during treatment with ondansetron (P = 0.04) and placebo (P = 0.01) were both significant. Eleven patients expressed a preference, seven for placebo and four for ondansetron. CONCLUSIONS: Our results show that ondansetron is no better than placebo in controlling renal itch.

Antipruritics↗
PubMed2003

Addition of fexofenadine to a topical corticosteroid reduces the pruritus associated with atopic dermatitis in a 1-week randomized, multicentre, double-blind, placebo-controlled, parallel-group study.

BACKGROUND: Fexofenadine, a nonsedating, H1-receptor selective antihistamine, exhibits consistent efficacy and safety in the treatment of allergic rhinitis and urticaria. The pruritus associated with atopic dermatitis is considered to be induced, in part, by histamine. Therefore, we thought that fexofenadine may be useful in the relief of pruritus associated with atopic dermatitis. OBJECTIVE: To compare the efficacy of twice-daily fexofenadine hydrochloride (HCl) 60 mg vs. placebo in reducing the pruritus associated with atopic dermatitis. METHODS: In this randomized, multicentre, double-blind, placebo-controlled study, patients (aged >or= 16 years) with atopic dermatitis underwent a 1-week placebo lead-in period, followed by randomization to fexofenadine HCl 60 mg twice daily or placebo for 1 week. All patients also received topical treatment with 0.1% hydrocortisone butyrate twice daily throughout the study. The primary efficacy endpoint was mean change in pruritus score from baseline. Patients reflectively recorded pruritus scores twice daily (day and night) using a five-point scale (0 = none; 4 = very severe). RESULTS: Fexofenadine (n = 201) significantly decreased the severity of pruritus compared with placebo (n = 199) (mean change in score -0.75 (unadjusted 95% confidence interval [-0.88, -0.62]) vs. -0.5 [-0.62, -0.38], respectively; P = 0.0005). This improvement was seen after just 1 day of treatment (P = 0.039) and was maintained throughout the treatment period (P = 0.019). Compared with placebo, fexofenadine significantly improved both diurnal (P = 0.0001) and nocturnal pruritus (P = 0.013). In addition, significantly more patients in the fexofenadine group experienced a reduction in the ratio of pruritus area to body surface area compared with those in the placebo group (P = 0.007). The incidence of adverse events was low and similar across all treatment groups. CONCLUSIONS: Fexofenadine HCl 60 mg twice daily demonstrated a rapid, significant improvement in the pruritus associated with atopic dermatitis, with a safety profile equivalent to that of placebo.

Adolescent↗
PubMed2002

Montelukast for treating seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial performed in the spring.

BACKGROUND: Cysteinyl leukotrienes are important proinflammatory mediators believed to have a role in allergic rhinitis. OBJECTIVE: This multicentre, randomized, double-blind, placebo- and active-controlled trial evaluated the effectiveness and tolerability of montelukast, a cysteinyl leukotriene receptor antagonist, for treating patients with seasonal allergic rhinitis. METHODS: After a 3- to 5-day, single-blind placebo run-in period, 1302 male and female patients (aged 15-81 years) with active allergic rhinitis symptoms were randomly assigned to receive montelukast 10 mg (n = 348), loratadine 10 mg (n = 602), or placebo (n = 352) administered once daily at bedtime for 2 weeks during the spring allergy season. RESULTS: Mean patient characteristics and symptom scores at baseline were similar for the three treatment groups. The primary end-point, daytime nasal symptoms score (mean of nasal congestion, rhinorrhea, nasal pruritus, and sneezing scores; 0-3 scale), improved from baseline during treatment by (least squares mean, 95% confidence interval) - 0.37 (- 0.43, - 0.31), - 0.47 (- 0.52, - 0.43), and - 0.24 (- 0.29, - 0.18) in the montelukast, loratadine, and placebo groups, respectively (P < or = 0.001 comparing each active treatment with placebo). Mean changes from baseline in all other diary-based scores, including night-time and eye symptom scores, were significantly greater for each active treatment than for placebo. The rhinoconjunctivitis quality of life overall score improved significantly with montelukast and with loratadine as compared with placebo. Montelukast and loratadine showed a safety profile comparable to that of placebo. CONCLUSION: Montelukast is well tolerated and provides improvements in daytime and night-time symptoms, as well as quality of life parameters, for patients with seasonal allergic rhinitis.

Acetates↗
PubMed2002

The effects of orlistat on body weight and glycaemic control in overweight patients with type 2 diabetes: a randomized, placebo-controlled trial.

AIM: To assess the long-term effects of orlistat on body weight, glycaemic control and cardiovascular risk factors in overweight patients with type 2 diabetes. METHODS: This was a multicentre, randomized, placebo-controlled study with a 4-week placebo plus diet lead-in period and a 48-week, double-blind treatment period. Overweight or obese adults [body mass index (BMI) >or= 28 kg/m2] with HbA1c of 6.5-11% and clinical type 2 diabetes were randomized to orlistat (120 mg t.i.d. n = 189) or placebo (n = 180) in conjunction with a low-calorie diet. Patients had either received sulphonylurea therapy for at least 2 months before the study or were not receiving any antidiabetic medication (the majority of which were drug-naïve). RESULTS: After 1 year, patients in the orlistat group lost significantly more weight than patients in the placebo group (-5.4% vs. -3.6%; p = 0.006). Moreover, significantly more patients achieved weight loss of >or= 5% with orlistat compared with placebo (51.3% vs. 31.6%; p = 0.0001). Patients treated with orlistat also had significantly greater improvements than placebo-treated patients in HbA1c (-0.9% vs. -0.4%; p < 0.001), fasting glucose (-1.6 vs.-0.7 mmol/l; p = 0.004) and post-prandial glucose (-1.8 vs. -0.5 mmol/l; p = 0.003). In addition, orlistat-treated patients had a significantly greater reduction in LDL cholesterol compared with placebo. Overall, orlistat had a similar safety profile to placebo, with the exception of a higher incidence of generally mild and transient gastrointestinal events known to be associated with the mode of action of orlistat. CONCLUSIONS: Treatment with orlistat plus diet resulted in significant weight loss, improved glycaemic control and cardiovascular risk factor profile in overweight patients with type 2 diabetes.

Adolescent↗
PubMed1997

Double-blind placebo-controlled trial of lithium in episodic cluster headache.

Lithium is widely used in the prophylaxis of episodic cluster headache without formal evidence of efficacy. Placebo-controlled clinical trials are not easy in conditions characterized by frequent severe pain. In this study, it was assumed that lithium would work quickly if at all, and placebo response would be zero. Strict diagnostic criteria excluded uncertain or atypical cases. Patients were male in so-far untreated episodes expected to last for at least 3 weeks more. In a double-blind, placebo-controlled comparison of matched parallel groups, treatment was either slow-release lithium carbonate, 800 mg/day, or placebo. After 7 days, compliance was estimated by tablet count, blood was taken for lithium assay, efficacy was assessed (attacks stopped or substantially improved) and adverse reactions were recorded. The study was stopped after planned sequential analysis of the 27th patient (13 on lithium, 14 on placebo). Estimated compliance was usually but not always good. Plasma lithium levels were mostly in the range 0.5-0.6 mmol/l on lithium, zero on placebo. Cessation of attacks within 1 week occurred in two patients in each group, substantial improvement in 6/14 (43%) on placebo, 8/13 (62%; NS) on lithium. Only minor adverse events were reported. Lithium treatment was therefore associated with a useful subjective improvement rate but the assumptions made at outset had proved wrong. The trial was stopped because superiority over placebo could not be demonstrated. There were lessons for future trials.

Adolescent↗
PubMed2001

Failure of omega-3 polyunsaturated fatty acids in prevention of migraine: a double-blind study versus placebo.

Omega-3 polyunsaturated fatty acids (OPFA) have beneficial effects on inflammatory reactions and production of cytokines. They decrease the release of 5HT by platelets and possess vasorelaxant activity. This led them to be tried in the prophylactic treatment of migraine. After 4 weeks of a single-blind placebo run-in period, patients were randomized and treated in double-blind condition by placebo or OPFA 6 g a day for 16 weeks, followed by a 4-week placebo run-out period. The intention to treat population included 196 patients. Those who received all four treatment periods included 96 patients taking OPFA and 87 taking placebo. The primary efficacy analysis was the number of migraine attacks during the last 4 weeks of treatment. During this period, the mean number of attacks was 1.20 +/- 1.40 in the OPFA group and 1.26 +/- 1.11 in the placebo group (NS). The total number of attacks during the 4-month period of the study was significantly different between groups: 7.05 in the placebo group, 5.95 in the OPFA group (P = 0.036). Mean intensity, mean duration of the attacks and rescue medication use, were not significantly different between the two groups. Except for a significant difference against OPFA for eructations, the tolerance was satisfying. Despite a run-in placebo period of 1 month, a very strong placebo effect was observed in this trial: 45% reduction of the attacks between run-in and 4-month treatment period (55% in the OPFA group, P = 0.058). Finally, this large study did not confirm two previous studies based on a small number of patients.

Adult↗
PubMedDate not supplied

Systemic treatment of venous leg ulcers with high doses of pentoxifylline: efficacy in a randomized, placebo-controlled trial.

Several small studies have indicated that the systemic administration of pentoxifylline may accelerate healing of venous leg ulcers. The goal of this study was to further evaluate these findings in a larger scale placebo controlled trial and to explore the effect of the dose of pentoxifylline on healing. The study used a prospective, randomized, double-blind, parallel group placebo controlled design in a multicenter outpatient setting. Patients with one or more venous ulcer were enrolled, with all patients receiving standardized compression bandaging for treatment for their ulcers. Patients were also randomized to receive either pentoxifylline 400 mg, pentoxifylline 800 mg (two 400 mg tablets), or placebo tablets three times a day for up to 24 weeks. The main outcome measure was time to complete healing of all leg ulcers, using life table analysis. The study was completed as planned in 131 patients. Patients receiving 800 mg three times a day of pentoxifylline healed faster than placebo (p = 0.043, Wilcoxon test). The median time to complete healing was 100, 83, and 71 days for placebo, pentoxifylline 400 mg, and pentoxifylline 800 mg three times a day, respectively. Over half of all patients were ulcer free at week 16 (placebo) and at week 12 in both pentoxifylline groups. Whereas the placebo group had only achieved complete healing in half of the cases by week 16, all of the subjects remaining in the group receiving the high dose of pentoxifylline had healed completely. Treatment with pentoxifylline was well tolerated with similar drop-out rates in all three treatment groups. Complete wound closure occurred at least 4 weeks earlier in the majority of patients treated with pentoxifylline by comparison to placebo. A higher dose of pentoxifylline (800 mg three times a day) was more effective than the lower dose. We conclude that pentoxifylline is effective in accelerating healing of leg ulcers.

Adult↗
PubMed2002

Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled, multicenter outcome study.

OBJECTIVE: To assess the efficacy of tizanidine hydrochloride versus placebo as adjunctive prophylactic therapy for chronic daily headache (chronic migraine, migrainous headache, or tension-type headache). BACKGROUND: Tizanidine is an alpha2-adrenergic agonist that inhibits the release of norepinephrine at both the spinal cord and brain, with antinociceptive effects that are independent of the endogenous opioid system. Previous open-label studies have suggested the drug may be effective for treatment of chronic daily headache. METHODS: Two hundred patients completed a 4-week, single-blind, placebo baseline period, with 134 fulfilling selection criteria and then randomized to tizanidine or placebo. Ninety-two patients completed at least 8 weeks of treatment (tizanidine, n = 45; placebo, n = 47), and 85 patients completed 12 weeks of treatment (tizanidine, n = 44; placebo, n = 41). Most patients (77%) met the diagnostic criteria for migraine of the International Headache Society; 23% had either chronic migrainous headache or chronic tension-type headache. Tizanidine was slowly titrated over 4 weeks to 24 mg or the maximum dose tolerated (mean, 18 mg; SD, 6.4; median, 20.0; range, 2 to 24), divided equally over three dose intervals per day. Overall headache index ([headache days x average intensity x duration in hours]/28 days) was the primary end point. RESULTS: Tizanidine was shown to be superior to placebo in reducing the overall headache index (P =.0025), as well as mean headache days per week (P =.0193), severe headache days per week (P =.0211), average headache intensity (P =.0108), peak headache intensity (P =.0020), and mean headache duration (P =.0127). The mean percentage improvement during the last 4 weeks of treatment with tizanidine versus placebo was 54% versus 19% for the headache index (P =.0144), 55% versus 21% for severe headache days (P =.0331), 35% versus 19% for headache duration (P =.0142), 35% versus 20% for peak headache intensity (P =.0106), 33% versus 20% for average headache intensity (P =.0281), and 30% versus 22% for total headache days (P =.0593). Patients receiving tizanidine also scored higher ratings of overall headache improvement on a visual analog scale (P =.0069). There was no statistically significant difference in outcome for patients with chronic migraine versus those with only migrainous or tension-type headache. Adverse effects reported by more than 10% of the patients included somnolence (47%), dizziness (24%), dry mouth (23%), and asthenia (19%). Dropouts due to adverse events did not differ significantly between tizanidine and placebo. CONCLUSIONS: The results support tizanidine as an effective prophylactic adjunct for chronic daily headache, including migraine, migrainous headache, and tension-type headache. These results also suggest the possible importance of an alpha2-adrenergic mechanism underlying the pathophysiology of this spectrum of headache disorders.

Adolescent↗
PubMed2000

Two randomised and placebo-controlled studies of an oral prostacyclin analogue (Iloprost) in severe leg ischaemia. The Oral Iloprost in severe Leg Ischaemia Study Group.

UNLABELLED: Two separate studies are described using the same prostacyclin analogue in a similar group of patients. OBJECTIVES: to assess the tolerability and efficacy of two dose regimens of oral Iloprost compared with placebo in the treatment of patients with ischaemic ulcers, gangrene or rest pain due to severe arterial disease over a period of 4 weeks (Study A) and one year (Study B). DESIGN: multicentre, placebo controlled, double-blind, randomized prospective studies. SUBJECTS & METHODS: 178 (study A) and 624 (study B) patients with trophic skin lesions (ulcers or gangrene) or ischaemic rest pain due to severe arterial disease. To confirm severe arterial disease patients were required to have a systolic ankle Doppler pressure of 70 mmHg or less or a toe systolic Doppler pressure of 50 mmHg or less in one leg. In both studies patients were randomly allocated to three treatment groups: placebo, low dose Iloprost (50-100 microgram twice a day) or high dose (150-200 microgram twice a day) In Study A the main outcome measures were tolerability of different doses of Iloprost and death, major amputation, healing of trophic lesions and relief of rest pain at the end of the follow up, which was 5 months after the end of the treatment. In Study B the primary end point was time to major amputation and stroke or death up to 12 months. Secondary pre-defined end points included the combined end point of patients alive without amputation, no trophic skin changes, no rest pain and not on regular analgesics. RESULTS: the proportion of patients who completed the 4-week treatment period in Study A at the intended dose was 58%, 43%, 45% respectively in the placebo, low dose and high dose Iloprost groups. In an intention to treat analysis the proportion of patients who survived without major amputation, ulcers or gangrene and had no rest pain was 11% in the placebo group, 19% in the low dose iloprost group and 28% in the high dose Iloprost group. The pooled Iloprost groups showed a statistically significantly better result than the placebo group (p=0.04), as did the high dose Iloprost group compared to the placebo (p=0.014). In Study B there was no treatment benefit in terms of a primary end point of amputation and death. However the secondary combined end point of patients who survived without a major amputation, ulcers or gangrene and had no rest pain, nor a need for regular analgesia was favourable for Iloprost, with 18% of patients in the placebo group reaching this optimal secondary end point, compared to 23% in the low dose Iloprost group and 26% in the higher dose Iloprost group (p<0.05). CONCLUSIONS: oral Iloprost administered for a year showed no clear benefit in patients with advanced severe leg ischaemia (PAOD III and IV). The results obtained with 4 weeks' treatment in Study A and in previous trials of intravenous Iloprost could not be reproduced

Administration, Oral↗
PubMed2006

Hong Kong study using valsartan in IgA nephropathy (HKVIN): a double-blind, randomized, placebo-controlled study.

BACKGROUND: Previous studies showed that angiotensin-receptor blocker (ARB) therapy decreased proteinuria and possibly slowed the rate of renal function decline in patients with chronic proteinuric nephropathies. We performed a double-blind, randomized, placebo-controlled, multicenter study on the ARB valsartan in the treatment of patients with immunoglobulin A (IgA) nephropathy. METHODS: From 6 centers, we recruited 109 patients with IgA nephropathy who had either: (1) proteinuria with protein greater than 1 g/d and serum creatinine level less than 2.8 mg/dL (< 250 micromol/L), or (2) serum creatinine level of 1.4 to 2.8 mg/dL (120 to 250 micromol/L) regardless of degree of proteinuria. Patients were randomly assigned to administration of either valsartan, 80 mg/d (titrated up to 160 mg/d for blood pressure control), or placebo for 104 weeks. Additional antihypertensive therapy was allowed to achieve a target blood pressure of 140/90 mm Hg. The primary end point was doubling of serum creatinine level or dialysis-dependent renal failure. Secondary outcomes included change in proteinuria and decrease in glomerular filtration rate (GFR). RESULTS: There were 54 patients in the treatment group and 55 patients in the placebo group. Baseline clinical characteristics were similar between groups, although the treatment group had a marginally greater baseline GFR (87 +/- 36 versus 78 +/- 38 mL/min/1.73 m2 [1.45 +/- 0.60 versus 1.30 +/- 0.63 mL/s/1.73 m2];P = 0.29) and less proteinuria (protein, 1.8 +/- 1.2 versus 2.3 +/- 1.7 g/d; P = 0.21) than the placebo group. Average blood pressures during the study were 92.7 +/- 10.6 mm Hg in the treatment group and 100.9 +/- 9.1 mm Hg in the placebo group (P < 0.001). During the study period, 4 patients in the placebo group and 1 patient in the treatment group reached the primary end point (log-rank test, P = 0.18). Proteinuria decreased significantly in the treatment group (protein, 1.8 +/- 1.2 to 1.2 +/- 1.2 g/d; P = 0.03), but did not change in the placebo group. With multiple linear regression models, valsartan treatment resulted in a 33.0% decrease in proteinuria (95% confidence interval, 10.9 to 55.1) after adjusting for other confounding factors. There was a significant decrease in mean rate of GFR decrease in the valsartan-treated group (-5.62 +/- 6.79 mL/min/y [-0.09 +/- 0.11 mL/s/y]) compared with the placebo group (-6.98 +/- 6.17 mL/min/y [-0.12 +/- 0.10 mL/s/y]) throughout the study period after adjustment for average blood pressure and proteinuria (P = 0.014). CONCLUSION: Valsartan significantly decreases proteinuria and slows renal deterioration in patients with IgA nephropathy after adjustment for confounding factors, notably blood pressure. The long-term benefit of valsartan needs to be confirmed with additional studies.

Adult↗
PubMed2005

Effects of a mononitrate, a beta1-blocker and a dihydropyridine calcium channel blocker on cardiovascular responsiveness to passive orthostasis: a placebo-controlled double-blind study in normotensive volunteers.

OBJECTIVE: The aim of this study was to compare the influences of antianginal drugs such as mononitrate, beta-blocker and calcium channel blocker on cardiovascular responsiveness to orthostasis. METHODS: The responses to passive orthostasis (tilt provocation at 60 degrees for 3 min) were measured in normotensive healthy volunteers with whole-body impedance cardiography and finger blood-pressure monitoring after a single moderate oral dose of isosorbide-5-mononitrate (CAS 16051-77-7, 10 mg), the beta1-blocker bisoprolol fumarate (CAS 104344-23-2, 5 mg), the dihydropyridine calcium channel blocker nisoldipine (CAS 63675-72-9, 5 mg), and placebo in a randomised, double-blind fashion. RESULTS: In supine position, none of the drugs altered pre-tilt arterial pressure or heart rate (HR) when compared to placebo. Nisoldipine decreased systemic vascular resistance index (SVRI) when compared to either placebo or bisoprolol, and increased the cardiac index (CI) when compared to placebo. During the passive orthostasis, the mononitrate decreased SVRI when compared to placebo or bisoprolol. The mononitrate increased HR and pulse wave velocity (PWV) when compared to the other study groups, and decreased the stroke index when compared to placebo. In the bisoprolol group, the tilt responses of diastolic arterial pressure, HR, CI, left cardiac work index, and PWV decreased significantly compared to those in the placebo group. Nisoldipine did not alter the responses to orthostasis when compared to placebo. When compared to the mononitrate, both nisoldipine and bisoprolol decreased CI response to orthostasis. CONCLUSIONS: The mononitrate adversely affects the cardiovascular responsiveness to orthostasis. The beta-blocker reduces the responses and thus probably oxygen demand during orthostasis. The dihydropyridine calcium blocker seems to influence the responsiveness less than the mononitrate or beta-blocker.

Adrenergic beta-1 Receptor Antagonists↗
PubMed2005

Efficacy and tolerability of a fixed combination of thyme and primrose root in patients with acute bronchitis. A double-blind, randomized, placebo-controlled clinical trial.

In a double-blind, randomized, placebo-controlled, multicenter, prospective study, the clinical efficacy and tolerability of a fixed combination of thyme fluid extract and primose root tincture (Bronchicum Tropfen) was investigated at a dosage of 30 drops (1 ml), taken orally five times daily. 150 outpatients (97 women, 53 men) suffering from acute, not previously treated bronchitis, lasting for less than 48 h, were randomized and treated with either verum (75 patients: 45 women, 30 men) or placebo (75 patients: 52 women, 23 men) over a time period of 7-9 days. 17 patients were excluded from the per-protocol (PP) collective because of either withdrawal from the trial (n = 2) or violations regarding examination time points and/or intake of the study medication (n = 15). The primary outcome criterion for efficacy assessment was the decrease of the Bronchitis Severity Score (BSS) at the end of the study compared to baseline. In the verum group, the BSS decreased from 12.0 +/- 4.4 points at baseline to 1.0 +/- 2.1 at study end compared to a decrease from 11.7 +/- 4.3 points at baseline to 6.5 +/- 4.8 at study end in the placebo group. The inter-group difference of 5.8 points was highly significant (p < or = 10(-3)) in favour of the verum medication [Intention-to-treat (ITT) analysis]. At the end of the study, significantly more patients were symptom free in the verum group (58.7%) than in the placebo group (5.3%) as compared by the ITT analysis (secondary outcome criterion). For both parameters, the PP analysis showed comparable results. The results for the concomitant variables of efficacy support the high superiority of the verum medication compared to placebo. The therapeutic effect was more pronounced the stronger the severity of the acute bronchitis was (as proofed by a stratified evaluation based on severity grade). The tolerability was very good in both groups; neither serious adverse events nor clinically relevant findings in the safety parameters were observed. A total of 7 adverse events occurred, 2 in the verum group and 5 in the placebo group. One of the two adverse events in the verum group was considered to be possibly related to the intake of the study medication. Neither serious nor unknown adverse drug reactions were observed. Two drop-outs occurred during the study related to adverse events, both in the placebo group. In the global safety assessment, the tolerability of both medications was rated as "good" or "very good" by more than 90% of the patients and physicians. In the present study, the fixed combination of thyme fluid extract and primrose root tincture was well tolerated and resulted in a clinically relevant and more pronounced decrease of the bronchitis symptoms (primary outcome criterion) and in shortening the duration of acute bronchitis (secondary outcome criterion) when compared to placebo.

Acute Disease↗