Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials

Objective To establish the effect of statins on muscle symptoms in people who had previously reported muscle symptoms when taking statins. Design Series of randomised, placebo controlled n-of-1 trials. Setting Primary care across 50 sites in the United Kingdom, December 2016 to April 2018. Participants 200 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms. Interventions Participants were randomised to a sequence of six double blinded treatment periods (two months each) of atorvastatin 20 mg daily or placebo. Main outcome measures At the end of each treatment period, participants rated their muscle symptoms on a visual analogue scale (0-10). The primary analysis compared symptom scores in the statin and placebo periods. Results 151 participants provided symptoms scores for at least one statin period and one placebo period and were included in the primary analysis. Overall, no difference in muscle symptom scores was found between the statin and placebo periods (mean difference statin minus placebo −0.11, 95% confidence interval −0.36 to 0.14; P=0.40)). Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long term treatment with statins. Conclusions No overall effect of atorvastatin 20 mg on muscle symptoms compared with placebo was found in participants who had previously reported severe muscle symptoms when taking statins. Most people completing the trial intended to restart treatment with statins. N-of-1 trials can assess drug effects at the group level and guide individual treatment. Trial registration ISRCTN30952488 , EUDRACT 2016-000141-31, NCT02781064 .

The time has come to limit the placebo period in rheumatoid arthritis trials to 3 months: a systematic comparison of 3- and 6-month response rates in trials of biological agents

Background:Most registration trials in rheumatoid arthritis (RA) include a placebo arm in the setting of an incomplete response to disease-modifying antirheumatic treatment (DMARD-IR). A minimum duration of 6 months is required despite serious methodological and ethical shortcomings.Objective:To study whether a 3-month placebo period is sufficient to prove efficacy.Methods:Meta-analysis of placebo- or active control trials of biological agents in DMARD-IR RA, comparing the contrast in ACR response between experimental and control groups at 3 and 6 months.Results:Twenty trials yielded 15 placebo and 18 active control contrasts (>10 000 patients). At 3 months active treatment showed a highly significant contrast with placebo for ACR20 and ACR50 in every instance. As all groups improved further the mean contrast at 6 months was unchanged. For ACR70 the contrast was clearly greater at 6 months owing to further improvement only in the experimental groups. In active control trials contrasts were smaller, and for ACR50 and ACR70 these decreased somewhat owing to “catch-up” responses in the control groups.Conclusion:The placebo phase of registration trials for RA can be limited to 3 months. An accompanying viewpoint proposes that patients receiving placebo should then be switched to standard of care, allowing a more valid and comprehensive assessment, including safety.

Efficacy of moxomdme m chronic migraine

This study is the first blind placebo-controlled trial of moxonidine for chronic migraine. The subjects with migraine without aura (n= 30), mean frequency attacks of 5,6 per 4 weeks, were randomy assigned to a three month trial of moxonidine (0,2-0,4 mg/ day) or an identical placebo. Patients kept daily headache records. Twenty-one of 30 included patients completed the study. Five patients stopped medication because of drowsiness and dry mouth with moxonidine. and four other non-related reasons (one on M, two on placebo). The mean frequency attacks was signifcantly decreased, from 5,2 per 4 weeks during placebo period to 3,1 attacs during M (Wile. P=0.0017), as well as compared with the baseline period (Wile. P=0.0007). Forty nine percent were responders (i.e. showed a reduction of the midraine days to 50 percent or less of the migraine attaks during M treatment compared with baseline period), whereas 9 percent deteriorated. During the placebo period, 9 percent were responders, whereas 38 percent deteriorated. These findings suggest that moxonidine may be an effective drug in chronic migraine.

Naltrexone Does Not Relieve Uremic Pruritus

Improvement of uremic pruritus was reported under short-term administration of the μ-receptor antagonists naltrexone and naloxone. The aim of the present study was to confirm the efficacy and safety of the oral μ-receptor antagonist naltrexone during a 4-wk treatment period in patients on hemodialysis and peritoneal dialysis. A placebo-controlled, double-blind crossover study of uremic patients with persistent, treatment-resistant pruritus was performed. Of 422 patients screened between December 1997 and June 1998, 93 suffered from pruritus and 23 were eligible for the study. Patients were started either with a 4-wk naltrexone sequence (50 mg/d) or matched placebo. This was followed by a 7-d washout, and patients continued with a 4-wk sequence of the alternate medication. Pruritus intensity was scored daily by a visual analogue scale (VAS) and weekly by a detailed score assessing scratching activity, distribution of pruritus, and frequency of pruritus-related sleep disturbance. Sixteen of 23 patients completed the study. During the naltrexone period, pruritus decreased by 29.2% (95% confidence interval [CI], 18.7 to 39.6) on the VAS and by 17.6% (95% CI, 4.2 to 31.1) on the detailed score. In comparison, pruritus decreased by 16.9% (95% CI, 6.8 to 26.9) on the VAS and by 22.3% (95% CI, 9.3 to 35.2) on the detailed score during the placebo period. The difference between the naltrexone and the placebo treatment period was not statistically significant. Nine of 23 patients complained of gastrointestinal disturbances during the naltrexone period compared with only one of 23 patients during the placebo period (P < 0.05). These results show that treatment of uremic pruritus with naltrexone is ineffective. In addition, a high incidence of adverse effects was observed during treatment with naltrexone.

Effect of short-term dietary administration of eugenol in humans

1 In order to study the antigenotoxic potential of eugenol in humans, ten healthy non-smoking males ingested a daily amount of 150 mg eugenol or the placebo for seven consecutive days. After a washout period of one week, groups ingesting eugenol or the placebo were crossed and received the other treatment for seven consecutive days. 2 On days 8 and 22 blood samples were taken for the assessment of standard clinical biochemical parameters. To study the possible antigenotoxic effect of eugenol, on day 8 and 22 blood samples were collected and exposed in vitro to the established genotoxic agents mitomycin C and vinblastine. After exposure the percentage of cells with chromosome aberrations and micronuclei was deter mined in cultured white blood cells. On days 8 and 22 paracetamol (500 mg p.o.) was administered as test substance to measure phase-II biotransformation capa city. Glutathione-S-transferase (GST) activities were determined in erythrocytes and blood plasma. 3 No significant differences in the clinical biochemical parameters were detected between the eugenol-period and the placebo-period, indicating that daily administration of 150 mg eugenol for 7 days has no toxic affects. 4 No significant differences on the cytogenetic para meters were found after ingestion of eugenol. Thus, there are no indications for an antigenotoxic potential of eugenol in humans, consuming daily 150 mg eugenol for 7 days. 5 A significant reduction in α-class GSTs in plasma (P<0.05), but not in the other measured biotransformation parameters, was found in volunteers during the eugenol- period as compared to the placebo-period. This may either reflect GST-inhibition by eugenol or protection against background damage of liver cells by eugenol.

Alprazolam Effects in Children with Anxiety Disorders*

Children with overanxious and/or avoidant disorder (DSM-III) were treated with alprazolam (Xanax, Upjohn) to determine its safety, clinical and cognitive effects. Ten male and two female patients (age range 8.8 to 16.5 years; mean 11.5)participated in an open clinical trial consisting of a baseline placebo period (1 week), alprazolam therapy (4 weeks), a drug-tapering period (1 week), and a post-drug placebo period (1 week). There was a drug-free follow-up approximately 4 weeks after termination of the study. Dosages were individually adjusted and the daily maximum ranged from 0.50 mg to 1.5 mg. Evaluations included clinical assessments, parent, teacher and self ratings, and cognitive tests. Clinical global improvement with alprazolam therapy was marked in 1 patient, moderate in 6, minimal in 4, and none in 1. Clinician ratings indicated significant improvements of anxiety, depression, and psychomotor excitation. Parent questionnaires indicated significant improvements of anxiety and hyperactivity while teacher questionnaires showed significant improvement of an anxious-passive factor. Significant improvements in the paired associate learning tasks, maze task and the block design tasks were maintained after drug withdrawal suggesting a practice effect. Adverse effects were infrequent, mild and transient. There were no clinically significant changes of laboratory values, blood pressure, pulse or respiration during the 4 weeks of alprazolam administration. Body weight increased significantly (mean increase was 0.87 kg). Double-blind trials with alprazolam are recommended in child psychiatry disorders.