-
JAMA Oct 2021Smoking cessation medications are routinely used in health care. Research suggests that combining varenicline with the nicotine patch, extending the duration of... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Smoking cessation medications are routinely used in health care. Research suggests that combining varenicline with the nicotine patch, extending the duration of varenicline treatment, or both, may increase cessation effectiveness.
OBJECTIVE
To compare combinations of varenicline plus the nicotine or placebo patch vs combinations used for either 12 weeks (standard duration) or 24 weeks (extended duration).
DESIGN, SETTINGS, AND PARTICIPANTS
Double-blind, 2 × 2 factorial randomized clinical trial conducted from November 11, 2017, to July 9, 2020, at 1 research clinic in Madison, Wisconsin, and at 1 clinic in Milwaukee, Wisconsin. Of the 5836 adults asked to participate in the study, 1251 who smoked 5 cigarettes/d or more were randomized.
INTERVENTIONS
All participants received cessation counseling and were randomized to 1 of 4 medication groups: varenicline monotherapy for 12 weeks (n = 315), varenicline plus nicotine patch for 12 weeks (n = 314), varenicline monotherapy for 24 weeks (n = 311), or varenicline plus nicotine patch for 24 weeks (n = 311).
MAIN OUTCOMES AND MEASURES
The primary outcome was carbon monoxide-confirmed self-reported 7-day point prevalence abstinence at 52 weeks.
RESULTS
Among 1251 patients who were randomized (mean [SD] age, 49.1 [11.9] years; 675 [54.0%] women), 751 (60.0%) completed treatment and 881 (70.4%) provided final follow-up. For the primary outcome, there was no significant interaction between the 2 treatment factors of medication type and medication duration (odds ratio [OR], 1.03 [95% CI, 0.91 to 1.17]; P = .66). For patients randomized to 24-week vs 12-week treatment duration, the primary outcome occurred in 24.8% (154/622) vs 24.3% (153/629), respectively (risk difference, -0.4% [95% CI, -5.2% to 4.3%]; OR, 1.01 [95% CI, 0.89 to 1.15]). For patients randomized to varenicline combination therapy vs varenicline monotherapy, the primary outcome occurred in 24.3% (152/625) vs 24.8% (155/626), respectively (risk difference, 0.4% [95% CI, -4.3% to 5.2%]; OR, 0.99 [95% CI, 0.87 to 1.12]). Nausea occurrence ranged from 24.0% to 30.9% and insomnia occurrence ranged from 24.4% to 30.5% across the 4 groups.
CONCLUSIONS AND RELEVANCE
Among adults smoking 5 cigarettes/d or more, there were no significant differences in 7-day point prevalence abstinence at 52 weeks among those treated with combined varenicline plus nicotine patch therapy vs varenicline monotherapy, or among those treated for 24 weeks vs 12 weeks. These findings do not support the use of combined therapy or of extended treatment duration.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03176784.
Topics: Carbon Monoxide; Combined Modality Therapy; Confidence Intervals; Double-Blind Method; Female; Humans; Male; Middle Aged; Nausea; Nicotinic Agonists; Odds Ratio; Placebos; Self Report; Sleep Initiation and Maintenance Disorders; Smoking Cessation; Temperance; Time Factors; Tobacco Use Cessation Devices; Varenicline; Wisconsin
PubMed: 34665204
DOI: 10.1001/jama.2021.15333 -
International Review of Neurobiology 2020A critical issue facing the therapeutic area of neurological diseases is the large number of failed randomized clinical trials, especially when moving from promising... (Review)
Review
A critical issue facing the therapeutic area of neurological diseases is the large number of failed randomized clinical trials, especially when moving from promising Phase 2 trials to failed Phase 3 trials. A common cited reason for these failures is a high placebo response rate that thereby reduces the observed treatment effect. Explanations for this higher than anticipated placebo response include small sample sizes, inadequate study designs and/or analytic methods, baseline characteristics of the trial sample, possible investigator bias and a participant's own expectations and conditional learning. Several innovative study designs and new methodological approaches to statistical analyses have been proposed to handle placebo effects anticipated or observed in double blind, randomized clinical trials (RCT's). This chapter examines current study designs being used to reduce the observed placebo response and statistical analysis methods being employed for addressing this problem in neuroscience clinical trials.
Topics: Data Interpretation, Statistical; Humans; Nervous System Diseases; Placebo Effect; Placebos; Randomized Controlled Trials as Topic; Research Design
PubMed: 32563284
DOI: 10.1016/bs.irn.2020.04.004 -
Small Methods Feb 2022Nanotheranostic materials (NTMs) shed light on the mechanisms responsible for complex diseases such as cancer because they enable making a diagnosis, monitoring the... (Review)
Review
Nanotheranostic materials (NTMs) shed light on the mechanisms responsible for complex diseases such as cancer because they enable making a diagnosis, monitoring the disease progression, and applying a targeted therapy simultaneously. However, several issues such as the reproducibility and mass production of NTMs hamper their application for clinical practice. To address these issues and facilitate the clinical application of NTMs, microfluidic systems have been increasingly used. This perspective provides a glimpse into the current state-of-art of NTM research, emphasizing the methods currently employed at each development stage of NTMs and the related open problems. This work reviews microfluidic technologies used to develop NTMs, ranging from the fabrication and testing of a single NTM up to their manufacturing on a large scale. Ultimately, a step-by-step vision on the future development of NTMs for clinical practice enabled by microfluidics techniques is provided.
Topics: Animals; Humans; Lab-On-A-Chip Devices; Theranostic Nanomedicine
PubMed: 34957704
DOI: 10.1002/smtd.202101217 -
Clinical Gastroenterology and... Jun 2024Coconut water (CW) is anti-inflammatory, can manipulate the gut microbiome, and is a rich source of potassium. Gut microbiome modulation improves outcomes in ulcerative... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Coconut water (CW) is anti-inflammatory, can manipulate the gut microbiome, and is a rich source of potassium. Gut microbiome modulation improves outcomes in ulcerative colitis (UC), and potassium possesses in vitro anti-inflammatory property. We evaluated the effect of CW as an adjunct therapy for patients with mild-moderate UC.
METHODS
This single-center, double-blind, placebo-controlled trial randomized patients with mild to moderate (Simple Clinical Colitis Activity Index [SCCAI]: 3-9) endoscopically active UC (Ulcerative Colitis Endoscopic Index of Severity [UCEIS] >1) in 1:1 ratio to CW + standard medical therapy (SMT) vs placebo + SMT. Four hundred mL of CW was administered for 8 weeks. Primary outcome measure was clinical remission (SCCAI ≤2), and secondary outcome measures were clinical response (SCCAI decline ≥3) and adverse events at 8 weeks. Microbiome was analyzed at baseline and 8 weeks.
RESULTS
Of 121 patients screened, 95 were included for modified intention to treat analysis (CW, n = 49; placebo, n = 46) (mean age, 37.2 ± 11.2 years; males, 54.1%; disease duration, 48 months [interquartile range (IQR), 24-90 months]; pancolitis, 26.1%; SCCAI, 5 [IQR, 4-6]; UCEIS, 4 [IQR, 3-5]). Clinical response (57.1% vs 28.3%; odds ratio [OR], 3.4; 95% confidence interval [CI], 1.4-7.9; P = .01), remission (53.1% vs 28.3%; OR, 2.9; 95% CI, 1.2-6.7; P = .02), and proportion of patients with fecal calprotectin (FCP) <150 μg/g (30.6% vs 6.5%; OR, 6.3; 95% CI, 1.7-23.6; P = .003) were significantly higher in CW. The relative abundance of bacterial taxa that had a significant or trend towards negative correlation with SCCAI, UCEIS, or FCP increased at 8 weeks in CW, and this effect was independent of disease activity and dietary fiber. Adverse events were comparable, and no patient developed hyperkalemia.
CONCLUSIONS
CW was more effective than placebo for induction of clinical remission in patients with mild to moderate UC. The trial was prospectively registered on Clinical Trials Registry of India (ctri.nic.in, Number: CTRI/2019/03/01827).
Topics: Humans; Colitis, Ulcerative; Male; Female; Double-Blind Method; Adult; Middle Aged; Treatment Outcome; Cocos; Placebos; Young Adult; Gastrointestinal Microbiome; Aged; Remission Induction; Anti-Inflammatory Agents; Severity of Illness Index
PubMed: 38278200
DOI: 10.1016/j.cgh.2024.01.013 -
International Review of Neurobiology 2020The placebo effect is a widely recognized phenomenon in clinical research, with a negative perception that it could hide the "true" drug effect. In clinical care its... (Review)
Review
The placebo effect is a widely recognized phenomenon in clinical research, with a negative perception that it could hide the "true" drug effect. In clinical care its positive potential to increase known drug effects has been neglected for too long. The placebo and nocebo responses have been described in many neurologic disorders such as Parkinson's, Huntington's and Alzheimer's diseases, restless leg syndrome, tics, essential tremor, dystonia, functional movement disorders, neuropathic pain, headaches, migraine, amyotrophic lateral sclerosis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis and epilepsy. Knowledge regarding placebo mechanisms and their consequences on clinical outcome have greatly improved over the last two decades. This evolution has led to reconsiderations of the importance of placebo response in the clinic and has given several clues on how to improve it in daily practice. In this chapter, we first illustrate "why," e.g. the reasons (relevance to clinical practice, help in differential diagnosis/treatment of psychogenic movements, clinical impact, proven neurobiological grounds, health economic potential), and "how," e.g. the means (increase patients' knowledge, increase learning, improve patient-doctor relationship, increase Hawthorne effect, increase positive/decrease negative expectations (the Rosenthal effect), personalize placebo response), the placebo should be maximized (and nocebo avoided) in neurological clinical practice. Future studies regarding more specific neurobiological mechanisms will allow a finer tuning of placebo response in clinical practice. The use of placebo in clinical practice raises ethical issues, and a recent expert consensus regarding placebo use in the clinic is a first step to future guidelines necessary to this field.
Topics: Humans; Nervous System Diseases; Personality; Placebo Effect; Placebos
PubMed: 32563294
DOI: 10.1016/bs.irn.2020.04.003 -
Gastroenterology Feb 2021Pruritus may seriously impair quality of life in patients with cholestatic diseases such as primary or secondary sclerosing cholangitis (PSC, SSC) and primary biliary... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
Pruritus may seriously impair quality of life in patients with cholestatic diseases such as primary or secondary sclerosing cholangitis (PSC, SSC) and primary biliary cholangitis (PBC). Pharmacologic strategies show limited efficacy and can provoke serious side effects. We hypothesized that bezafibrate, a broad peroxisome proliferator-activated receptor (PPAR) agonist, relieves cholestasis-associated itch by alleviating hepatobiliary injury. The aim of this investigator-initiated FITCH trial (Fibrates for cholestatic ITCH) was to assess effects of bezafibrate on pruritus in patients with PSC, PBC, and SSC.
METHODS
Patients with moderate to severe pruritus (≥5 of 10 on visual analog scale [VAS]) due to PSC, PBC, or SSC were recruited for this double-blind, randomized, placebo-controlled trial between 2016 and 2019. Patients received once-daily bezafibrate (400 mg) or placebo for 21 days. The primary end point was ≥50% reduction of pruritus (VAS; intention-to-treat).
RESULTS
Of 74 randomized patients, 70 completed the trial (95%; 44 PSC, 24 PBC, 2 SSC). For the primary end point, bezafibrate led in 45% (41% PSC, 55% PBC) and placebo in 11% to ≥50% reduction of severe or moderate pruritus (P = .003). For secondary end points, bezafibrate reduced morning (P = .01 vs placebo) and evening (P = .007) intensity of pruritus (VAS) and improved the validated 5D-Itch questionnaire (P = .002 vs placebo). Bezafibrate also reduced serum alkaline phosphatase (-35%, P = .03 vs placebo) correlating with improved pruritus (VAS, P = .01) suggesting reduced biliary damage. Serum bile acids and autotaxin activity remained unchanged. Serum creatinine levels tended to mildly increase (3% bezafibrate, 5% placebo, P = .14).
CONCLUSIONS
Bezafibrate is superior to placebo in improving moderate to severe pruritus in patients with PSC and PBC.
TRIAL REGISTRATION
Netherlands Trial Register, ID: NTR5436 (August 3, 2015), ClinicalTrials.gov ID: NCT02701166 (March 2, 2016).
Topics: Adult; Bezafibrate; Cholangitis, Sclerosing; Double-Blind Method; Female; Humans; Liver Cirrhosis, Biliary; Male; Middle Aged; Placebos; Pruritus; Quality of Life; Severity of Illness Index; Treatment Outcome; Visual Analog Scale
PubMed: 33031833
DOI: 10.1053/j.gastro.2020.10.001 -
PLoS Medicine Sep 2020Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their...
BACKGROUND
Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their delivery have been shown to affect study outcomes, placebo and sham controls are rarely reported and often not matched to those of the active comparator. This can influence how beneficial or harmful the active intervention appears to be. Without adequate descriptions of placebo or sham controls, it is difficult to interpret results about the benefits and harms of active interventions within placebo-controlled trials. To overcome this problem, we developed a checklist and guide for reporting placebo or sham interventions.
METHODS AND FINDINGS
We developed an initial list of items for the checklist by surveying experts in placebo research (n = 14). Because of the diverse contexts in which placebo or sham treatments are used in clinical research, we consulted experts in trials of drugs, surgery, physiotherapy, acupuncture, and psychological interventions. We then used a multistage online Delphi process with 53 participants to determine which items were deemed to be essential. We next convened a group of experts and stakeholders (n = 16). Our main output was a modification of the existing Template for Intervention Description and Replication (TIDieR) checklist; this allows the key features of both active interventions and placebo or sham controls to be concisely summarised by researchers. The main differences between TIDieR-Placebo and the original TIDieR are the explicit requirement to describe the setting (i.e., features of the physical environment that go beyond geographic location), the need to report whether blinding was successful (when this was measured), and the need to present the description of placebo components alongside those of the active comparator.
CONCLUSIONS
We encourage TIDieR-Placebo to be used alongside TIDieR to assist the reporting of placebo or sham components and the trials in which they are used.
Topics: Checklist; Humans; Placebos; Research Design; Research Personnel; Research Report; Surveys and Questionnaires
PubMed: 32956344
DOI: 10.1371/journal.pmed.1003294 -
Archivum Immunologiae Et Therapiae... Mar 2021
Topics: Humans; Antiviral Agents; Controlled Clinical Trials as Topic; COVID-19; COVID-19 Drug Treatment; Evidence-Based Medicine; Placebos; United States; United States Food and Drug Administration
PubMed: 33782781
DOI: 10.1007/s00005-021-00612-x -
British Journal of Anaesthesia Aug 2019Over the past decade, the mechanisms underlying placebo effects have begun to be identified. At the same time, the placebo response appears to have increased in... (Review)
Review
Over the past decade, the mechanisms underlying placebo effects have begun to be identified. At the same time, the placebo response appears to have increased in pharmacological trials and marked placebo effects are found in neurostimulation and surgical trials, thereby posing the question whether non-pharmacological interventions should be placebo-controlled to a greater extent. In this narrative review we discuss how the knowledge of placebo mechanisms may help to improve placebo control in pharmacological and non-pharmacological trials. We review the psychological, neurobiological, and genetic mechanisms underlying placebo analgesia and outline the current problems and potential solutions to the challenges with placebo control in trials on pharmacological, neurostimulation, and surgical interventions. We particularly focus on how patients' perception of the therapeutic intervention, and their expectations towards treatment efficacy may help develop more precise placebo controls and blinding procedures and account for the contribution of placebo factors to the efficacy of active treatments. Finally, we discuss how systematic investigations into placebo mechanisms across various pain conditions and types of treatment are needed in order to 'personalise' the placebo control to the specific pathophysiology and interventions, which may ultimately lead to identification of more effective treatment for pain patients. In conclusion this review shows that it is important to understand how patients' perception and expectations influence the efficacy of active and placebo treatments in order to improve the test of new treatments. Importantly, this applies not only to assessment of drug efficacy but also to non-pharmacological trials on surgeries and stimulation procedures.
Topics: Analgesia; Humans; Pain; Placebo Effect; Placebos; Treatment Outcome
PubMed: 30915982
DOI: 10.1016/j.bja.2019.01.040 -
American Journal of Therapeutics
Topics: Humans; Aromatherapy; Fruit; Plant Oils; Post-Acute COVID-19 Syndrome; Randomized Controlled Trials as Topic; Placebos; Fermented Foods
PubMed: 36608066
DOI: 10.1097/MJT.0000000000001574