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The Cochrane Database of Systematic... Mar 2021Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in the lungs, promoting improved clearance of secretions. This is an update of a previously published review.
OBJECTIVES
To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other medications that improve airway clearance, and to identify any adverse events associated with its use.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences. Date of the most recent search of the Group's Cystic Fibrosis Register: 12 October 2020. Clinicaltrials.gov and the International Clinical Trials Registry Platform were also searched to identify unpublished or ongoing trials. Date of most recent search: 08 February 2021.
SELECTION CRITERIA
All randomised and quasi-randomised controlled trials comparing dornase alfa to placebo, standard therapy or other medications that improve airway clearance.
DATA COLLECTION AND ANALYSIS
Authors independently assessed trials against the inclusion criteria; two authors carried out analysis of methodological quality and data extraction. GRADE was used to assess the level of evidence.
MAIN RESULTS
The searches identified 74 trials, of which 19 (2565 participants) met our inclusion criteria. 15 trials compared dornase alfa to placebo or no dornase alfa (2447 participants); two compared daily dornase to hypertonic saline (32 participants); one compared daily dornase alfa to hypertonic saline and alternate day dornase alfa (48 participants); one compared dornase alfa to mannitol and the combination of both drugs (38 participants). Trial duration varied from six days to three years. Dornase alfa compared to placebo or no treatment Dornase alfa probably improved forced expiratory volume at one second (FEV) at one month (four trials, 248 participants), three months (one trial, 320 participants; moderate-quality evidence), six months (one trial, 647 participants; high-quality evidence) and two years (one trial, 410 participants). Limited low-quality evidence showed treatment may make little or no difference in quality of life. Dornase alfa probably reduced the number of pulmonary exacerbations in trials of up to two years (moderate-quality evidence). One trial that examined the cost of care, including the cost of dornase alfa, found that the cost savings from dornase alfa offset 18% to 38% of the medication costs. Dornase alfa: daily versus alternate day One cross-over trial (43 children) found little or no difference between treatment regimens for lung function, quality of life or pulmonary exacerbations (low-quality evidence). Dornase alfa compared to other medications that improve airway clearance Results for these comparisons were mixed. One trial (43 children) showed dornase alfa may lead to a greater improvement in FEV compared to hypertonic saline (low-quality evidence), and one trial (23 participants) reported little or no differences in lung function between dornase alfa and mannitol or dornase alfa and dornase alfa plus mannitol (low-quality evidence). One trial (23 participants) found dornase alfa may improve quality of life compared to dornase alfa plus mannitol (low-quality evidence); other comparisons found little or no difference in this outcome (low-quality evidence). No trials in any comparison reported any difference between groups in the number of pulmonary exacerbations (low-quality evidence). When all comparisons are assessed, dornase alfa did not cause significantly more adverse effects than other treatments, except voice alteration and rash.
AUTHORS' CONCLUSIONS
There is evidence to show that, compared with placebo, therapy with dornase alfa may improve lung function in people with cystic fibrosis in trials lasting from one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer, probably due to treatment. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials. There is not enough evidence to firmly conclude if dornase alfa is superior to other hyperosmolar agents in improving lung function.
Topics: Adolescent; Adult; Child; Child, Preschool; Cystic Fibrosis; Deoxyribonuclease I; Disease Progression; Expectorants; Forced Expiratory Volume; Humans; Infant; Mannitol; Placebos; Randomized Controlled Trials as Topic; Recombinant Proteins; Saline Solution, Hypertonic; Vital Capacity
PubMed: 33735508
DOI: 10.1002/14651858.CD001127.pub5 -
The Cochrane Database of Systematic... Apr 2021Lennox-Gastaut syndrome (LGS) is an age-specific epilepsy syndrome characterised by multiple seizure types, including drop seizures. LGS has a characteristic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Lennox-Gastaut syndrome (LGS) is an age-specific epilepsy syndrome characterised by multiple seizure types, including drop seizures. LGS has a characteristic electroencephalogram, an onset before age eight years and an association with drug resistance. This is an updated version of the Cochrane Review published in 2013.
OBJECTIVES
To assess the efficacy and tolerability of anti-seizure medications (ASMs) for LGS.
SEARCH METHODS
We searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 28 February 2020) on 2 March 2020. CRS Web includes randomised controlled trials (RCTs) or quasi-RCTs from the Cochrane Central Register of Controlled Trials (CENTRAL); the Specialised Registers of Cochrane Review Groups, including Cochrane Epilepsy; PubMed; Embase; ClinicalTrials.gov; and the World Health Organization's International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We contacted pharmaceutical companies and colleagues in the field to seek any unpublished or ongoing studies.
SELECTION CRITERIA
We considered RCTs, including cross-over trials, of ASMs for LGS in children and adults. We included studies of ASMs used as either monotherapy or as an add-on (adjunctive) therapy. We excluded studies comparing different doses of the same ASM.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methodological procedures, including independent, dual assessment for risk of bias and application of the GRADE approach to rate the evidence certainty for outcomes.
MAIN RESULTS
We found no trials of ASM monotherapy. The review included 11 trials (1277 participants; approximately 11 weeks to 112 weeks follow-up after randomisation) using add-on ASMs for LGS in children, adolescents and adults. Two studies compared add-on cannabidiol (two doses) with add-on placebo in children and adolescents only. Neither study reported overall seizure cessation or reduction. We found high-certainty evidence that 72 more people per 1000 (confidence interval (CI) 4 more to 351 more) had adverse events (AE) leading to study discontinuation with add-on cannabidiol, compared to add-on placebo (two studies; 396 participants; risk ratio (RR) 4.90, 95% CI 1.21 to 19.87). One study compared add-on cinromide with add-on placebo in children and adolescents only. We found very low-certainty evidence that 35 more people per 1000 (CI 123 fewer to 434 more) had 50% or greater average reduction of overall seizures with add-on cinromide compared to add-on placebo (one study; 56 participants; RR 1.15, 95% CI 0.47 to 2.86). This study did not report participants with AE leading to study discontinuation. One study compared add-on clobazam (three doses) with add-on placebo. This study did not report overall seizure cessation or reduction. We found high-certainty evidence that 106 more people per 1000 (CI 0 more to 538 more) had AE leading to study discontinuation with add-on clobazam compared to add-on placebo (one study; 238 participants; RR 4.12, 95% CI 1.01 to 16.87). One study compared add-on felbamate with add-on placebo. No cases of seizure cessation occurred in either regimen during the treatment phase (one study; 73 participants; low-certainty evidence). There was low-certainty evidence that 53 more people per 1000 (CI 19 fewer to 716 more) with add-on felbamate were seizure-free during an EEG recording at the end of the treatment phase, compared to add-on placebo (RR 2.92, 95% CI 0.32 to 26.77). The study did not report overall seizure reduction. We found low-certainty evidence that one fewer person per 1000 (CI 26 fewer to 388 more) with add-on felbamate had AE leading to study discontinuation compared to add-on placebo (one study, 73 participants; RR 0.97, 95% CI 0.06 to 14.97). Two studies compared add-on lamotrigine with add-on placebo. Neither study reported overall seizure cessation. We found high-certainty evidence that 176 more people per 1000 (CI 30 more to 434 more) had ≥ 50% average seizure reduction with add-on lamotrigine compared to add-on placebo (one study; 167 participants; RR 2.12, 95% CI 1.19 to 3.76). We found low-certainty evidence that 40 fewer people per 1000 (CI 68 fewer to 64 more) had AE leading to study-discontinuation with add-on lamotrigine compared to add-on placebo (one study; 169 participants; RR 0.49, 95% CI 0.13 to 1.82). Two studies compared add-on rufinamide with add-on placebo. Neither study reported seizure cessation. We found high-certainty evidence that 202 more people per 1000 (CI 34 to 567 more) had ≥ 50% average seizure reduction (one study; 138 participants; RR 2.84, 95% CI 1.31 to 6.18). We found low-certainty evidence that 105 more people per 1000 (CI 17 fewer to 967 more) had AE leading to study discontinuation with add-on rufinamide compared to add-on placebo (one study; 59 participants; RR 4.14, 95% CI 0.49 to 34.86). One study compared add-on rufinamide with another add-on ASM. This study did not report overall seizure cessation or reduction. We found low-certainty evidence that three fewer people per 1000 (CI 75 fewer to 715 more) had AE leading to study discontinuation with add-on rufinamide compared to another add-on ASM (one study; 37 participants; RR 0.96, 95% CI 0.10 to 9.57). One study compared add-on topiramate with add-on placebo. This study did not report overall seizure cessation. We found low-certainty evidence for ≥ 75% average seizure reduction with add-on topiramate (one study; 98 participants; Peto odds ratio (Peto OR) 8.22, 99% CI 0.60 to 112.62) and little or no difference to AE leading to study discontinuation compared to add-on placebo; no participants experienced AE leading to study discontinuation (one study; 98 participants; low-certainty evidence).
AUTHORS' CONCLUSIONS
RCTs of monotherapy and head-to-head comparison of add-on ASMs are currently lacking. However, we found high-certainty evidence for overall seizure reduction with add-on lamotrigine and rufinamide, with low-certainty evidence for AE leading to study discontinuation compared with add-on placebo or another add-on ASM. The evidence for other add-on ASMs for overall seizure cessation or reduction was low to very low with high- to low-certainty evidence for AE leading to study discontinuation. Future research should consider outcome reporting of overall seizure reduction (applying automated seizure detection devices), impact on development, cognition and behaviour; future research should also investigate age-specific efficacy of ASMs and target underlying aetiologies.
Topics: Adolescent; Adult; Age of Onset; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Cinnamates; Clobazam; Electroencephalography; Felbamate; Humans; Lamotrigine; Lennox Gastaut Syndrome; Middle Aged; Placebos; Randomized Controlled Trials as Topic; Topiramate; Triazoles; Wakefulness; Young Adult
PubMed: 33825230
DOI: 10.1002/14651858.CD003277.pub4 -
International Journal of Clinical... Jan 2021Reflecting the extended scope of the valid EMA regulation, this analysis intends to contribute to the knowledge about risk for participants in first-in-human (FiH)... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Reflecting the extended scope of the valid EMA regulation, this analysis intends to contribute to the knowledge about risk for participants in first-in-human (FiH) multiple-dose studies.
MATERIALS AND METHODS
All FiH multiple-dose studies in healthy subjects performed by the Bayer Department of Clinical Pharmacology, Cardiovascular, between 2006 and 2019 were analyzed. Study reports were reviewed for study designs, demographics, treatment-emergent adverse events (TEAEs), and safety laboratory results above the 1.5-fold of the upper limit of normal (aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), amylase, lipase, glutamate dehydrogenase (GLDH), gamma glutamyl transpeptidase (GGT), total bilirubin, and creatinine in serum), and data were analyzed.
RESULTS
12 out of 16 studies were included. Indications for development were cardiovascular (7), pulmonary (3), kidney (1), and hematological (1) diseases. 496 healthy male subjects (mean age 33.8 years, mean BMI of 24.7 kg/m) received treatment (370 active, 126 placebo). 293 subjects had at least 1 TEAE (59.1%): 231 (62.4%) after active treatment and 126 (49.2%) after placebo. Subjects with a maximum TEAE intensity of moderate did not differ between active and placebo. The only severe TEAE was unrelated to the study, the only serious TEAE on active treatment was not considered drug-related. Subjects had a significantly higher relative risk on active treatment versus placebo to experience an overall TEAE. No relevant differences between active and placebo for the analyzed laboratory increases were seen.
CONCLUSION
Subjects were not exposed to an undue risk in the analyzed studies. Adverse events and laboratory value increases occur frequently under placebo treatment. The results can help in the risk stratification for and interpretation of other phase I studies.
Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Double-Blind Method; Healthy Volunteers; Humans; Kidney Diseases; Liver Diseases; Male; Pharmaceutical Preparations; Placebos
PubMed: 32990215
DOI: 10.5414/CP203760 -
Pain Jul 2024Previous research has indicated that an open-label placebo can reduce pain in both healthy participants and patients with chronic pain. Because nondeceptive placebos... (Randomized Controlled Trial)
Randomized Controlled Trial
Previous research has indicated that an open-label placebo can reduce pain in both healthy participants and patients with chronic pain. Because nondeceptive placebos seem to be an effective and more ethical alternative to deceptive placebos, optimizing this kind of treatment is essential. Observational learning was previously shown to induce the deceptive placebo effect; therefore, this study aimed to verify its effectiveness in fortifying the open-label placebo effect. Healthy volunteers (N = 117) were randomly assigned to 4 groups: open-label placebo with observational learning (OLP + OBL), open-label placebo (OLP), deceptive placebo with observational learning (OBL), or control group. Participants underwent baseline and testing measurements, during which they self-reported pain induced by heat stimulation. Between assessments, placebo cream was openly administered in the OLP and OLP + OBL groups. The OLP + OBL group next watched a model experiencing hypoalgesia after cream application. In the OBL group, participants received placebo cream with no information about its effect, and then they watched the model. The placebo effect was successfully evoked in all experimental groups (OLP + OBL, OLP, and OBL), which confirms the effectiveness of both open-label and deceptive placebo interventions for pain reduction. However, the hypoalgesic effect was of similar magnitude in the OLP and OLP + OBL groups, which indicates that observation did not contribute to the effect. The results showed that reinforcing the open-label placebo by observational learning may be redundant, but more research is needed to confirm these findings.
Topics: Humans; Male; Female; Placebo Effect; Adult; Young Adult; Pain Measurement; Pain Threshold; Learning; Adolescent; Pain; Placebos
PubMed: 38227574
DOI: 10.1097/j.pain.0000000000003161 -
The Cochrane Database of Systematic... May 2021Otomycosis is a fungal infection of the outer ear, which may be treated with topical antifungal medications. There are many types, with compounds belonging to the azole... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Otomycosis is a fungal infection of the outer ear, which may be treated with topical antifungal medications. There are many types, with compounds belonging to the azole group ('azoles') being among the most widely used.
OBJECTIVES
To evaluate the benefits and harms of topical azole treatments for otomycosis.
SEARCH METHODS
The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The search date was 11 November 2020.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) in adults and children with otomycosis comparing any topical azole antifungal with: placebo, no treatment, another type of topical azole or the same type of azole but applied in different forms. A minimum follow-up of two weeks was required.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Our primary outcomes were: 1) clinical resolution as measured by the proportion of participants with complete resolution at between two and four weeks after treatment (however defined by the authors of the studies) and 2) significant adverse events. Secondary outcomes were 3) mycological resolution and 4) other less serious adverse effects. We used GRADE to assess the certainty of evidence for each outcome.
MAIN RESULTS
We included four studies with 559 participants from Spain, Mexico and India. Three studies included children and adults; one included only adults. The duration of symptoms was not always explicitly stated. Mycological resolution results were only reported in one study. The studies assessed two comparisons: one type of topical azole versus another and the same azole but administered in different forms (cream versus solution). A. Topical azoles versus placebo None of the studies assessed this comparison. B. Topical azoles versus no treatment None of the studies assessed this comparison. C. One type of topical azole versus another type of topical azole i) Clotrimazole versus other types of azoles (eberconazole, fluconazole, miconazole) Three studies examined clotrimazole versus other types of azoles. The evidence is very uncertain about the difference between clotrimazole and other types of azole in achieving complete clinical resolution at four weeks (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.59 to 1.07; 3 studies; 439 participants; very low-certainty evidence). The anticipated absolute effects are 668 per 1000 for clotrimazole versus 835 per 1000 for other azoles. One study planned a safety analysis and reported no significant adverse events in either group. The evidence is therefore very uncertain about any differences between clotrimazole and other types of azole (no events in either group; 1 study; 174 participants; very low-certainty evidence). Clotrimazole may result in little or no difference in mycological resolution at two weeks follow-up (RR 1.01, 95% CI 0.96 to 1.06; 1 study; 174 participants; low-certainty evidence) or in other (less serious) adverse events at two weeks follow-up (36 per 1000, compared to 45 per 1000, RR 0.79, 95% CI 0.18 to 3.41; 1 study; 174 participants; very low-certainty evidence). ii) Bifonazole cream versus bifonazole solution One study compared bifonazole 1% cream with solution. Bifonazole cream may have little or no effect on clinical resolution at two weeks follow-up when compared to solution, but the evidence is very uncertain (RR 1.07, 95% CI 0.73 to 1.57; 1 study; 40 ears; very low-certainty evidence). Bifonazole cream may achieve less mycological resolution compared to solution at two weeks after the end of therapy, but the evidence for this is also very uncertain (RR 0.53, 95% CI 0.29 to 0.96; 1 study; 40 ears; very low-certainty evidence). Five out of 35 patients sustained severe itching and burning from the bifonazole solution but none with the bifonazole cream (very low-certainty evidence).
AUTHORS' CONCLUSIONS
We found no studies that evaluated topical azoles compared to placebo or no treatment. The evidence is very uncertain about the effect of clotrimazole on clinical resolution of otomycosis, on significant adverse events or other (non-serious) adverse events when compared with other topical azoles (eberconazole, fluconazole, miconazole). There may be little or no difference between clotrimazole and other azoles in terms of mycological resolution. It may be difficult to generalise these results because the range of ethnic backgrounds of the participants in the studies is limited.
Topics: Administration, Topical; Adult; Antifungal Agents; Bias; Child; Clotrimazole; Cycloheptanes; Fluconazole; Humans; Imidazoles; Miconazole; Otomycosis; Placebos; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 34033120
DOI: 10.1002/14651858.CD009289.pub2 -
JAMA Jul 2021In 2019, the US Food and Drug Administration (FDA) received a citizen petition indicating that ranitidine contained the probable human carcinogen N-nitrosodimethylamine... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
In 2019, the US Food and Drug Administration (FDA) received a citizen petition indicating that ranitidine contained the probable human carcinogen N-nitrosodimethylamine (NDMA). In addition, the petitioner proposed that ranitidine could convert to NDMA in humans; however, this was primarily based on a small clinical study that detected an increase in urinary excretion of NDMA after oral ranitidine consumption.
OBJECTIVE
To evaluate the 24-hour urinary excretion of NDMA after oral administration of ranitidine compared with placebo.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, double-blind, placebo-controlled, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) conducted in 18 healthy participants. The study began in June 2020, and the end of participant follow-up was July 1, 2020.
INTERVENTIONS
Participants were randomized to 1 of 4 treatment sequences and over 4 periods received ranitidine (300 mg) and placebo (randomized order) with a noncured-meats diet and then a cured-meats diet. The cured-meats diet was designed to have higher nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA.
MAIN OUTCOME AND MEASURE
Twenty-four-hour urinary excretion of NDMA.
RESULTS
Among 18 randomized participants (median age, 33.0 [interquartile range {IQR}, 28.3 to 42.8] years; 9 women [50%]; 7 White [39%], 11 African American [61%]; and 3 Hispanic or Latino ethnicity [17%]), 17 (94%) completed the trial. The median 24-hour NDMA urinary excretion values for ranitidine and placebo were 0.6 ng (IQR, 0 to 29.7) and 10.5 ng (IQR, 0 to 17.8), respectively, with a noncured-meats diet and 11.9 ng (IQR, 5.6 to 48.6) and 23.4 ng (IQR, 8.6 to 36.7), respectively, with a cured-meats diet. There was no statistically significant difference between ranitidine and placebo in 24-hour urinary excretion of NDMA with a noncured-meats diet (median of the paired differences, 0 [IQR, -6.9 to 0] ng; P = .54) or a cured-meats diet (median of the paired differences, -1.1 [IQR, -9.1 to 11.5] ng; P = .71). No drug-related serious adverse events were reported.
CONCLUSIONS AND RELEVANCE
In this trial that included 18 healthy participants, oral ranitidine (300 mg), compared with placebo, did not significantly increase 24-hour urinary excretion of NDMA when participants consumed noncured-meats or cured-meats diets. The findings do not support that ranitidine is converted to NDMA in a general, healthy population.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04397445.
Topics: Administration, Oral; Adult; Cross-Over Studies; Dimethylnitrosamine; Double-Blind Method; Female; Histamine H2 Antagonists; Humans; Male; Placebos; Ranitidine
PubMed: 34180947
DOI: 10.1001/jama.2021.9199 -
IET Nanobiotechnology May 2021Nanotheranostics has attracted much attention due to its widespread application in molecular imaging and cancer therapy. Molecular imaging using nanoparticles has... (Review)
Review
Nanotheranostics has attracted much attention due to its widespread application in molecular imaging and cancer therapy. Molecular imaging using nanoparticles has attracted special attention in the diagnosis of cancer at early stages. With the progress made in nanotheranostics, studying drug release, accumulation in the target tissue, biodistribution, and treatment effectiveness are other important factors. However, according to the studies conducted in this regard, each nanoparticle has some advantages and limitations that should be examined and then used in clinical applications. The main goal of this review is to explore the recent advancements in nanotheranostics for cancer therapy and diagnosis. Then, it is attempted to present recent studies on nanotheranostics used as a contrast agent in various imaging modalities and a platform for cancer therapy.
Topics: Humans; Nanoparticles; Neoplasms; Theranostic Nanomedicine; Tissue Distribution
PubMed: 34694670
DOI: 10.1049/nbt2.12021 -
Medecine Sciences : M/S 2019A placebo drug is defined as a treatment without any specific pharmacological efficacy, that works when the patient thinks to receive an active treatment, through a... (Review)
Review
A placebo drug is defined as a treatment without any specific pharmacological efficacy, that works when the patient thinks to receive an active treatment, through a psychological and physiological mechanism. This study aimed to evaluate the use of placebo in French hospitals, in Polyvalent Medicine units. A questionnaire comprising 15 items was sent to 372 units. The analysis of 153 responses was conducted from dynamic crosstabs in Excel and using the R software available online. The survey confirmed that the use of placebos in hospital is frequent, with nearly 2/3 of professionals answering the questionnaire declared to use it. The oral capsule is the most commonly used form. Placebo is mainly administered at night, in case of pain, insomnia or anxiety, to so-called "difficult" patients. Placebo is not always given after medical prescription. In most cases, patients are not informed that they receive a placebo. The majority of professionals believed in the placebo effect but considered to be insufficiently informed and trained in the use of placebo in current practice. Although the placebo effect is now demonstrated, ethical and legal considerations recommend placebo treatment only on medical prescription, with the prior information of the patient. The placebo could be used as complementary therapy to conventional treatment in the cases of this therapeutic effectiveness has been demonstrated. Professionals should be trained in the use of placebo in order to avoid nocebo effect and potentiate beneficial effects of placebo.
Topics: Adult; Disclosure; Female; France; General Practice; Hospital Units; Hospitals; Humans; Male; Morals; Physician-Patient Relations; Placebo Effect; Placebos
PubMed: 31532380
DOI: 10.1051/medsci/2019127 -
The New England Journal of Medicine Jul 2020The World Health Organization (WHO) recommends oral amoxicillin for patients who have pneumonia with tachypnea, yet trial data indicate that not using amoxicillin to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The World Health Organization (WHO) recommends oral amoxicillin for patients who have pneumonia with tachypnea, yet trial data indicate that not using amoxicillin to treat this condition may be noninferior to using amoxicillin.
METHODS
We conducted a double-blind, randomized, placebo-controlled noninferiority trial involving children at primary health care centers in low-income communities in Karachi, Pakistan. Children who were 2 to 59 months of age and who met WHO criteria for nonsevere pneumonia with tachypnea were randomly assigned to a 3-day course of a suspension of amoxicillin (the active control) of 50 mg per milliliter or matched volume of placebo (the test regimen), according to WHO weight bands (500 mg every 12 hours for a weight of 4 to <10 kg, 1000 mg every 12 hours for a weight of 10 to <14 kg, or 1500 mg every 12 hours for a weight of 14 to <20 kg). The primary outcome was treatment failure during the 3-day course of amoxicillin or placebo. The prespecified noninferiority margin was 1.75 percentage points.
RESULTS
From November 9, 2014, through November 30, 2017, a total of 4002 children underwent randomization (1999 in the placebo group and 2003 in the amoxicillin group). In the per-protocol analysis, the incidence of treatment failure was 4.9% among placebo recipients (95 of 1927 children) and 2.6% among amoxicillin recipients (51 of 1929 children) (between-group difference, 2.3 percentage points; 95% confidence interval [CI], 0.9 to 3.7). Results were similar in the intention-to-treat analysis. The presence of fever and wheeze predicted treatment failure. The number needed to treat to prevent one treatment failure was 44 (95% CI, 31 to 80). One patient (<0.1%) in each group died. Relapse occurred in 40 children (2.2%) in the placebo group and in 58 children (3.1%) in the amoxicillin group.
CONCLUSIONS
Among children younger than 5 years of age with nonsevere pneumonia, the frequency of treatment failure was higher in the placebo group than in the amoxicillin group, a difference that did not meet the noninferiority margin for placebo. (Funded by the Joint Global Health Trials Scheme [of the Department for International Development, Medical Research Council, and Wellcome] and others; RETAPP ClinicalTrials.gov number, NCT02372461.).
Topics: Administration, Oral; Amoxicillin; Anti-Bacterial Agents; Child, Preschool; Double-Blind Method; Duration of Therapy; Female; Humans; Infant; Male; Pakistan; Placebos; Pneumonia; Recurrence; Tachypnea; Treatment Failure
PubMed: 32609980
DOI: 10.1056/NEJMoa1911998 -
The British Journal of Surgery Aug 2020Placebo-controlled trials play an important role in the evaluation of healthcare interventions. However, they can be challenging to design and deliver for invasive...
BACKGROUND
Placebo-controlled trials play an important role in the evaluation of healthcare interventions. However, they can be challenging to design and deliver for invasive interventions, including surgery. In-depth understanding of the component parts of the treatment intervention is needed to ascertain what should, and should not, be delivered as part of the placebo. Assessment of risk to patients and strategies to ensure that the placebo effectively mimics the treatment are also required. To date, no guidance exists for the design of invasive placebo interventions. This study aimed to develop a framework to optimize the design and delivery of invasive placebo interventions in RCTs.
METHODS
A preliminary framework was developed using published literature to: expand the scope of an existing typology, which facilitates the deconstruction of invasive interventions; and identify placebo optimization strategies. The framework was refined after consultation with key stakeholders in surgical trials, consensus methodology and medical ethics.
RESULTS
The resulting DITTO framework consists of five stages: deconstruct treatment intervention into constituent components and co-interventions; identify critical surgical element(s); take out the critical element(s); think risk, feasibility and role of placebo in the trial when considering remaining components; and optimize placebo to ensure effective blinding of patients and trial personnel.
CONCLUSION
DITTO considers invasive placebo composition systematically, accounting for risk, feasibility and placebo optimization. Use of the framework can support the design of high-quality RCTs, which are needed to underpin delivery of healthcare interventions.
Topics: Humans; Placebos; Randomized Controlled Trials as Topic; Risk Assessment
PubMed: 32187680
DOI: 10.1002/bjs.11509