Complementary and alternative medicine for management of premature ejaculation: a systematic review and meta-analysis

Introduction: Premature ejaculation (PE) is defined as ejaculation within one minute (lifelong PE) or three minutes (acquired PE); inability to delay ejaculation; and negative personal consequences. Management includes behavioral and pharmacological approaches. Aim: To systematically review effectiveness, safety, and robustness of evidence for complementary and alternative medicine (CAM) in managing PE. Methods: Nine databases including MEDLINE were searched to September 2015. Randomized controlled trials (RCTs) evaluating CAM for PE were included. Outcome measures: Studies were included if they reported intra-vaginal ejaculatory latency time (IELT) and/or another validated premature ejaculation measure. Adverse effects were summarized. Results: Ten RCTs were included. Two assessed acupuncture, five Chinese herbal medicine, one Ayurvedic herbal medicine, and two topical “severance secret” (SS) cream. Risk of bias was unclear in all studies due to unclear allocation concealment or blinding, and only five studies reported stopwatch-measured IELT. Acupuncture slightly increased IELT over placebo in one study (mean difference [MD]=0.55 min, p=0.001). In another study, Ayurvedic herbal medicine slightly increased IELT over placebo (MD=0.80 min, p=0.001). Topical SS cream improved IELT over placebo in two studies (MD=8.60 min, p<0.001), though inclusion criteria were broad (IELT <3 min). Three studies comparing Chinese herbal medicine against selective serotonin reuptake inhibitors (SSRIs) favored SSRIs (MD=1.01 min, p=0.02). However, combination treatment with Chinese medicine plus SSRIs improved IELT over SSRIs alone (two studies, MD=1.92 min, p<0.00001) and over Chinese medicine alone (two studies, MD=2.52 min, p<0.00001). Adverse effects were not consistently assessed, but where reported were generally mild. Conclusions: There is preliminary evidence for effectiveness of acupuncture, Chinese herbal medicine, Ayurvedic herbal medicine and topical SS cream in improving IELT and other outcomes. However, results are based on clinically heterogeneous studies of unclear quality. There is little data on adverse effects or potential for drug interactions. Further well-conducted RCTs would be valuable

Blinded Outcome Assessment Was Infrequently Used and Poorly Reported in Open Trials

Objective Unblinded outcome assessment can lead to biased estimates of treatment effect in randomised trials. We reviewed published trials to assess how often blinded assessment is used, and whether its use varies according to the type of outcome or assessor. Design and setting A review of parallel group, individually randomised phase III trials published in four general medical journals (BMJ, Journal of the American Medical Association, The Lancet, and New England Journal of Medicine) in 2010. Main outcome measures Whether assessment of the primary outcome was blinded, and whether this differed according to outcome or assessor type. Results We identified 258 eligible trials. Of these, 106 (41%) were reported as double-blind, and 152 (59%) as partially or fully open-label (that is, they included some groups who were unblinded, such as patients, those delivering the intervention, or those in charge of medical care). Of the 152 open trials, 125 required outcome assessment. Of these 125 trials, only 26% stated that outcome assessment was blinded; 51% gave no information on whether assessment was blinded or not. Furthermore, 18% of trials did not state who performed the assessment. The choice of outcome type (e.g. instrument measured, rated, or naturally occurring event) did not appear to influence whether blinded assessment was performed (range 24-32% for the most common outcome types). However, the choice of outcome assessor did influence blinding; independent assessors were blinded much more frequently (71%) than participant (5%) or physician (24%) assessors. Despite this, open trials did not use independent assessors any more frequently than double-blind trials (17% vs. 18% respectively). Conclusions Blinding of outcome assessors is infrequently used and poorly reported. Increased use of independent assessors could increase the frequency of blinded assessment

Reducing bias in open-label trials where blinded outcome assessment is not feasible: strategies from two randomised trials

Background Blinded outcome assessment is recommended in open-label trials to reduce bias, however it is not always feasible. It is therefore important to find other means of reducing bias in these scenarios. Methods We describe two randomised trials where blinded outcome assessment was not possible, and discuss the strategies used to reduce the possibility of bias. Results TRIGGER was an open-label cluster randomised trial whose primary outcome was further bleeding. Because of the cluster randomisation, all researchers in a hospital were aware of treatment allocation and so could not perform a blinded assessment. A blinded adjudication committee was also not feasible as it was impossible to compile relevant information to send to the committee in a blinded manner. Therefore, the definition of further bleeding was modified to exclude subjective aspects (such as whether symptoms like vomiting blood were severe enough to indicate the outcome had been met), leaving only objective aspects (the presence versus absence of active bleeding in the upper gastrointestinal tract confirmed by an internal examination). TAPPS was an open-label trial whose primary outcome was whether the patient was referred for a pleural drainage procedure. Allowing a blinded assessor to decide whether to refer the patient for a procedure was not feasible as many clinicians may be reluctant to enrol patients into the trial if they cannot be involved in their care during follow-up. Assessment by an adjudication committee was not possible, as the outcome either occurred or did not. Therefore, the decision pathway for procedure referral was modified. If a chest x-ray indicated that more than a third of the pleural space filled with fluid, the patient could be referred for a procedure; otherwise, the unblinded clinician was required to reach a consensus on referral with a blinded assessor. This process allowed the unblinded clinician to be involved in the patient’s care, while reducing the potential for bias. Conclusions When blinded outcome assessment is not possible, it may be useful to modify the outcome definition or method of assessment to reduce the risk of bias

Investigating the effect of independent blinded digital image assessment on the STOP GAP trial

Background Blinding is the process of keeping treatment assignment hidden and is used to minimise the possibility of bias. Trials at high risk of bias have been shown to report larger treatment effects than low risk studies. In dermatology, one popular method of blinding is to have independent outcome assessors who are unaware of treatment allocation assessing the end point using digital photographs. However, this can be complex, expensive and time-consuming. The objective of this study was to compare the effect of blinded and unblinded outcome assessment on the results of the STOP GAP trial. Methods The STOP GAP trial compared prednisolone to ciclosporin in treating pyoderma gangrenosum. Participants’ lesions were measured at baseline and 6 weeks to calculate the primary outcome, speed of healing. Independent blinded assessors obtained measurements from digital photographs using specialist software. In addition, unblinded treating clinicians estimated lesion area by measuring length and width. The primary outcome was determined using blinded measurements where available, otherwise unblinded measurements were used (method referred to as trial measurements). In this study, agreement between the trial and unblinded measurements was determined using the intraclass correlation coefficient (ICC). The STOP GAP primary analysis was repeated using unblinded measurements only. We introduced differential and non-differential error in unblinded measurements and investigated the effect on the STOP GAP primary analysis. Results 86 (80%) of the 108 patients were assessed using digital images. Agreement between trial and unblinded measurements was excellent (ICC=0.92 at baseline; 0.83 at 6 weeks). There was no evidence that the results of the trial primary analysis differed according to how the primary outcome was assessed (p-value for homogeneity = 1.00). Conclusions Blinded digital image assessment in STOP GAP did not meaningfully alter trial conclusions compared with unblinded assessment. However, as the process brought added accuracy and credibility to the trial it was considered worthwhile. These findings question the usefulness of digital image assessment in a trial with an objective outcome and where bias is not expected to be excessive. Further research should investigate if there are alternative, less complex ways of incorporating blinding in clinical trials

Influence of trial sample size on treatment effect estimates: meta-epidemiological study

Objective To assess the influence of trial sample size on treatment effect estimates within meta-analyses. Design Meta-epidemiological study. Data sources 93 meta-analyses (735 randomised controlled trials) assessing therapeutic interventions with binary outcomes, published in the 10 leading journals of each medical subject category of the Journal Citation Reports or in the Cochrane Database of Systematic Reviews. Data extraction Sample size, outcome data, and risk of bias extracted from each trial. Data synthesis Trials within each meta-analysis were sorted by their sample size: using quarters within each meta-analysis (from quarter 1 with 25% of the smallest trials, to quarter 4 with 25% of the largest trials), and using size groups across meta-analyses (ranging from <50 to ≥1000 patients). Treatment effects were compared within each meta-analysis between quarters or between size groups by average ratios of odds ratios (where a ratio of odds ratios less than 1 indicates larger effects in smaller trials). Results Treatment effect estimates were significantly larger in smaller trials, regardless of sample size. Compared with quarter 4 (which included the largest trials), treatment effects were, on average, 32% larger in trials in quarter 1 (which included the smallest trials; ratio of odds ratios 0.68, 95% confidence interval 0.57 to 0.82), 17% larger in trials in quarter 2 (0.83, 0.75 to 0.91), and 12% larger in trials in quarter 3 (0.88, 0.82 to 0.95). Similar results were obtained when comparing treatment effect estimates between different size groups. Compared with trials of 1000 patients or more, treatment effects were, on average, 48% larger in trials with fewer than 50 patients (0.52, 0.41 to 0.66) and 10% larger in trials with 500-999 patients (0.90, 0.82 to 1.00). Conclusions Treatment effect estimates differed within meta-analyses solely based on trial sample size, with stronger effect estimates seen in small to moderately sized trials than in the largest trials

Risk of Herpes Zoster in Individuals on Biologics, DMARDS and/or Corticosteroids for Autoimmune Diseases:A Systematic Review and Meta-Analysis

Background: Studies examining the risk of herpes zoster (HZ) associated with immunosuppressants, such as biologics, non-biological disease modifying agents (nbDMARDs) or corticosteroids, have generated conflicting results. Methods: We conducted a systematic literature search from Jan 1946 to Feb 2016. Search terms related to HZ, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematous or inflammatory bowel disease, biologics, nbDMARDS and corticosteroids were used. We included randomized controlled trials (RCTs) and observational studies reporting associations between immunosuppressants and HZ outcomes in adults. For RCTs, we used the Mantel-Haenszel fixed-effects model to estimate pooled odds ratios (OR) and 95% confidence intervals (CI) for HZ risk. For observational studies, adjusted ORs were pooled separately using random-effects inverse variance models. Findings: Data were pooled from 40 eligible RCTs (20,136 patients) and 19 observational studies (810,939 patients). Biologics were associated with a greater risk of HZ than control (RCTs: OR 1.71, 95% CI 1.11-2.64; Observational studies: OR OR 1.58, 95% CI 1.39-1.81). In RCTs, the OR of non-TNF blockers was 2.19 (95% CI 1.20-4.02), but that of TNF blockers was not significantly different from control. Increased risks of HZ with nbDMARDs (OR 1.21, 95% CI 1.15-1.28) and corticosteroids (OR 1.73, 95% CI 1.57-1.89) were observed in observational studies, but few RCTs examined these comparisons. Conclusions: Immunocompromized patients receiving biologics were associated with an increased risk of HZ. The risk is also increased with corticosteroids and nbDMARDs. These findings raise the issue of prophylaxis with zoster vaccine in patients initiating immunosuppressive therapy for autoimmune diseases

Quality of Reporting of Bioequivalence Trials Comparing Generic to Brand Name Drugs: A Methodological Systematic Review

BACKGROUND: Generic drugs are used by millions of patients for economic reasons, so their evaluation must be highly transparent. OBJECTIVE: To assess the quality of reporting of bioequivalence trials comparing generic to brand-name drugs. METHODOLOGY/PRINCIPAL FINDINGS: PubMed was searched for reports of bioequivalence trials comparing generic to brand-name drugs between January 2005 and December 2008. Articles were included if the aim of the study was to assess the bioequivalency of generic and brand-name drugs. We excluded case studies, pharmaco-economic evaluations, and validation dosage assays of drugs. We evaluated whether important information about funding, methodology, location of trials, and participants were reported. We also assessed whether the criteria required by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) to conclude bioequivalence were reported and that the conclusions were in agreement with the results. We identified 134 potentially relevant articles but eliminated 55 because the brand-name or generic drug status of the reference drug was unknown. Thus, we evaluated 79 articles. The funding source and location of the trial were reported in 41% and 56% of articles, respectively. The type of statistical analysis was reported in 94% of articles, but the methods to generate the randomization sequence and to conceal allocation were reported in only 15% and 5%, respectively. In total, 65 articles of single-dose trials (89%) concluded bioequivalence. Of these, 20 (31%) did not report the 3 criteria within the limits required by the FDA and 11 (17%) did not report the 2 criteria within the limits required by the EMA. CONCLUSIONS/SIGNIFICANCE: Important information to judge the validity and relevance of results are frequently missing in published reports of trials assessing generic drugs. The quality of reporting of such trials is in need of improvement

Mechanical versus manual chest compressions in the treatment of in-hospital cardiac arrest patients in a non-shockable rhythm : a randomised controlled feasibility trial (COMPRESS-RCT)

Background Mechanical chest compression devices consistently deliver high-quality chest compressions. Small very low-quality studies suggest mechanical devices may be effective as an alternative to manual chest compressions in the treatment of adult in-hospital cardiac arrest patients. The aim of this feasibility trial is to assess the feasibility of conducting an effectiveness trial in this patient population. Methods COMPRESS-RCT is a multi-centre parallel group feasibility randomised controlled trial, designed to assess the feasibility of undertaking an effectiveness to compare the effect of mechanical chest compressions with manual chest compressions on 30-day survival following in-hospital cardiac arrest. Over approximately two years, 330 adult patients who sustain an in-hospital cardiac arrest and are in a non-shockable rhythm will be randomised in a 3:1 ratio to receive ongoing treatment with a mechanical chest compression device (LUCAS 2/3, Jolife AB/Stryker, Lund, Sweden) or continued manual chest compressions. It is intended that recruitment will occur on a 24/7 basis by the clinical cardiac arrest team. The primary study outcome is the proportion of eligible participants randomised in the study during site operational recruitment hours. Participants will be enrolled using a model of deferred consent, with consent for follow-up sought from patients or their consultee in those that survive the cardiac arrest event. The trial will have an embedded qualitative study, in which we will conduct semi-structured interviews with hospital staff to explore facilitators and barriers to study recruitment. Discussion The findings of COMPRESS-RCT will provide important information about the deliverability of an effectiveness trial to evaluate the effect on 30-day mortality of routine use of mechanical chest compression devices in adult in-hospital cardiac arrest patients

Timing and Completeness of Trial Results Posted at ClinicalTrials.gov and Published in Journals

Background: The US Food and Drug Administration Amendments Act requires results from clinical trials of Food and Drug Administration–approved drugs to be posted at ClinicalTrials.gov within 1 y after trial completion. We compared the timing and completeness of results of drug trials posted at ClinicalTrials.gov and published in journals. Methods and Findings: We searched ClinicalTrials.gov on March 27, 2012, for randomized controlled trials of drugs with posted results. For a random sample of these trials, we searched PubMed for corresponding publications. Data were extracted independently from ClinicalTrials.gov and from the published articles for trials with results both posted and published. We assessed the time to first public posting or publishing of results and compared the completeness of results posted at ClinicalTrials.gov versus published in journal articles. Completeness was defined as the reporting of all key elements, according to three experts, for the flow of participants, efficacy results, adverse events, and serious adverse events (e.g., for adverse events, reporting of the number of adverse events per arm, without restriction to statistically significant differences between arms for all randomized patients or for those who received at least one treatment dose). From the 600 trials with results posted at ClinicalTrials.gov, we randomly sampled 50% (n = 297) had no corresponding published article. For trials with both posted and published results (n = 202), the median time between primary completion date and first results publicly posted was 19 mo (first quartile = 14, third quartile = 30 mo), and the median time between primary completion date and journal publication was 21 mo (first quartile = 14, third quartile = 28 mo). Reporting was significantly more complete at ClinicalTrials.gov than in the published article for the flow of participants (64% versus 48% of trials, p<0.001), efficacy results (79% versus 69%, p = 0.02), adverse events (73% versus 45%, p<0.001), and serious adverse events (99% versus 63%, p<0.001). The main study limitation was that we considered only the publication describing the results for the primary outcomes. Conclusions: Our results highlight the need to search ClinicalTrials.gov for both unpublished and published trials. Trial results, especially serious adverse events, are more completely reported at ClinicalTrials.gov than in the published article

Topical NSAIDs for chronic musculoskeletal pain in adults

Background: Use of topical nonsteroidal anti-inflammatory drugs (NSAIDs) to treat chronic musculoskeletal conditions has become widely accepted because they can provide pain relief without associated systemic adverse events. This review is an update of 'Topical NSAIDs for chronic musculoskeletal pain in adults', originally published in Issue 9, 2012. Objectives: To review the evidence from randomised, double-blind, controlled trials on the efficacy and safety of topically applied NSAIDs for chronic musculoskeletal pain in adults. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and our own in-house database; the date of the last search was February 2016. We also searched the references lists of included studies and reviews, and sought unpublished studies by asking personal contacts and searching online clinical trial registers and manufacturers' web sites. Selection criteria: We included randomised, double-blind, active or inert carrier (placebo) controlled trials in which treatments were administered to adults with chronic musculoskeletal pain of moderate or severe intensity. Studies had to meet stringent quality criteria and there had to be at least 10 participants in each treatment arm, with application of treatment at least once daily. Data collection and analysis: Two review authors independently assessed studies for inclusion and extracted data. We used numbers of participants achieving each outcome to calculate risk ratio and numbers needed to treat (NNT) or harm (NNH) compared to carrier or other active treatment. We were particularly interested to compare different formulations (gel, cream, plaster) of individual NSAIDs. The primary outcome was 'clinical success', defined as at least a 50% reduction in pain, or an equivalent measure such as a 'very good' or 'excellent' global assessment of treatment, or 'none' or 'slight' pain on rest or movement, measured on a categorical scale. Main results: We identified five new studies for this update, which now has information from 10,631 participants in 39 studies, a 38% increase in participants from the earlier review; 33 studies compared a topical NSAID with carrier. All studies examined topical NSAIDs for treatment of osteoarthritis, and for pooled analyses studies were generally of moderate or high methodological quality, although we considered some at risk of bias from short duration and small size. In studies lasting 6 to 12 weeks, topical diclofenac and topical ketoprofen were significantly more effective than carrier for reducing pain; about 60% of participants had much reduced pain. With topical diclofenac, the NNT for clinical success in six trials (2343 participants) was 9.8 (95% confidence interval (CI) 7.1 to 16) (moderate quality evidence). With topical ketoprofen, the NNT for clinical success in four trials (2573 participants) was 6.9 (5.4 to 9.3) (moderate quality evidence). There was too little information for analysis of other individual topical NSAIDs compared with carrier. Few trials compared a topical NSAID to an oral NSAID, but overall they showed similar efficacy (low quality evidence). These efficacy results were almost completely derived from people with knee osteoarthritis. There was an increase in local adverse events (mostly mild skin reactions) with topical diclofenac compared with carrier or oral NSAIDs, but no increase with topical ketoprofen (moderate quality evidence). Reporting of systemic adverse events (such as gastrointestinal upsets) was poor, but where reported there was no difference between topical NSAID and carrier (very low quality evidence). Serious adverse events were infrequent and not different between topical NSAID and carrier (very low quality evidence). Clinical success with carrier occurred commonly - in around half the participants in studies lasting 6 to 12 weeks. Both direct and indirect comparison of clinical success with oral placebo indicates that response rates with carrier (topical placebo) are about twice those seen with oral placebo. A substantial amount of data from completed, unpublished studies was unavailable (up to 6000 participants). To the best of our knowledge, much of this probably relates to formulations that have never been marketed. Authors' conclusions: Topical diclofenac and topical ketoprofen can provide good levels of pain relief beyond carrier in osteoarthritis for a minority of people, but there is no evidence for other chronic painful conditions. There is emerging evidence that at least some of the substantial placebo effects seen in longer duration studies derive from effects imparted by the NSAID carrier itself, and that NSAIDs add to that