General lack of use of placebo in prophylactic, randomised, controlled trials in adult migraine. A systematic review

Background The Clinical Trials Subcommittee of the International Headache Society (IHS) recommends that a placebo arm is included in comparative randomised clinical trials (RCTs) of multiple prophylactic drugs due to the highly variable placebo response in migraine prophylaxis studies. The use of placebo control in such trials has not been systematically assessed. Methods We performed a systematic review of all comparative RCTs of prophylactic drug treatment of migraine published in English from 2002 to 2014. PubMed was searched using the Cochrane Highly Sensitive Search Strategy for identifying reports of RCTs. Results A placebo arm was used in <10% (three of 31) of prophylactic RCTs in migraine. In only 7.1% (two of 28) of the comparative RCTs without placebo was one drug superior to another drug. Thus in 26 RCTs, including one study requiring more than 75,000 patient days, no difference was identified across treatment arms and conclusions regarding drug superiority could not be drawn. Conclusions The majority of comparative, prophylactic migraine RCTs do not include a placebo arm. Failure to include a placebo arm may result in failure to demonstrate efficacy of potentially effective migraine-prophylactic agents. In order to benefit current and future patients, the current strong tendency to omit placebo-controls in these RCTs should be replaced by adherence to the guidelines of the IHS.

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Title: The Effectiveness of Participant Blinding of Non-Penetrating Sham/Placebo Acupuncture in Clinical Trials: A Systematic Review with Meta-Analysis

10.21203/rs.3.rs-156277/v1 ◽

2021 ◽

Author(s):

Yee Hung Gan ◽

Nway Aye Saint ◽

Yen Suan Sin

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Control Method ◽

Data Extraction ◽

Meta Analysis ◽

Sham Acupuncture ◽

Placebo Control ◽

Skin Contact ◽

Randomised Controlled ◽

Healthy Participants

Abstract Background: Acupuncture clinical trial is important to evaluate the efficacy of acupuncture. However, it is challenging to achieve effective blinding due to the nature of acupuncture. A standardised placebo control method of acupuncture has yet to be established. The study focuses on the non-penetrating sham acupuncture because it eliminates the placebo effect and generates lesser physiological responses. The study aims to evaluate and compare the participant blinding effectiveness of non-penetrating sham acupuncture devices, and analyse the factors which may influence the participant blinding.Methods: The study followed the PRISMA guidelines. An electronic search was conducted on PubMed, Ovid and CNKI up until 1st of October 2020 to include English and Chinese randomised controlled trials which evaluated the awareness on the type of acupuncture (real or sham) in any population who received acupuncture. Data screening, data extraction and quality assessment were done independently by two researchers and discrepancies were sorted out via discussion with a co-researcher. Data analysis was performed using RevMan 5.4.1.Results: 34 full-text articles had been included in the systematic review and meta-analysis. The quality of the studies ranged from moderate to good. Generally, non-penetrating sham acupuncture devices were effective in blinding participants in clinical trials. The foam device demonstrated a better blinding effect, followed by Streitberger, Park and Takakura devices. Sham needles with no skin contact could not blind the participants successfully. Naive, experienced, healthy and diseased participants all could be blinded using non-penetrating sham acupuncture devices but naive and healthy participants could be blinded comparatively easily. Acupoints from different regions could achieve blinding, however, the acupoints on the back could blind the participants more easily compared to the other areas.Conclusion: Non-penetrating sham acupuncture devices are valid placebo control for acupuncture clinical trials. The foam device has a better blinding effect, followed by Streitberger, Park and Takakura devices. Recruiting naive healthy participants and choosing acupoints from the back can achieve better blinding effects in the participants.

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Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies

The Lancet Psychiatry ◽

10.1016/s2215-0366(16)30307-8 ◽

2016 ◽

Vol 3 (11) ◽

pp. 1059-1066 ◽

Cited By ~ 86

Author(s):

Toshi A Furukawa ◽

Andrea Cipriani ◽

Lauren Z Atkinson ◽

Stefan Leucht ◽

Yusuke Ogawa ◽

...

Keyword(s):

Systematic Review ◽

Placebo Response ◽

Response Rates ◽

Double Blind ◽

Randomised Controlled

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Use of a placebo in clinical trials

European Psychiatry ◽

10.1016/s0924-9338(98)80031-x ◽

1998 ◽

Vol 13 (5) ◽

pp. 254-263 ◽

Cited By ~ 2

Author(s):

G Emilien ◽

JM Maloteaux ◽

A Seghers ◽

G Charles

Keyword(s):

Clinical Trials ◽

Placebo Response ◽

Drug Efficacy ◽

Placebo Treatment ◽

High Response Rate ◽

Experimental Methodology ◽

Necessary Condition ◽

Control Group ◽

Placebo Control ◽

Experimental Drug

SummaryThe use of a placebo control group in the evaluation of a new product is today considered by most as a necessary condition of experimental drug research. Placebo response is an essential consideration in all clinical trials. If not properly controlled, incorrect and dangerous conclusion may be inferred for a product efficacy and safety profile. However, the inclusion of a placebo group in clinical trials in neuropsychiatric research raises several ethical and scientific questions. Whereas in certain indications, such as suicidal patients and severe and psychotic depression, the use of a placebo is generally not accepted, it is difficult to assess drug efficacy. This article discusses the concept of placebo in clinical trials, the occurrence of adverse events after placebo treatment and the high response rate of placebo in neuropsychiatric clinical research. The experimental methodology to adequately control all the factors involved is also analysed and discussed.

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Placebo comparator group selection and use in surgical trials: the ASPIRE project including expert workshop

Health Technology Assessment ◽

10.3310/hta25530 ◽

2021 ◽

Vol 25 (53) ◽

pp. 1-52

Author(s):

David J Beard ◽

Marion K Campbell ◽

Jane M Blazeby ◽

Andrew J Carr ◽

Charles Weijer ◽

...

Keyword(s):

Randomised Controlled Trials ◽

Medical Research Council ◽

Placebo Control ◽

Controlled Trials ◽

Surgical Trials ◽

Surgical Interventions ◽

Placebo Controls ◽

Randomised Controlled ◽

The Uk ◽

Future Work

Background The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. Objectives To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials. Design To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout. Setting A workshop to discuss and summarise the existing knowledge and to develop the new guidelines. Results To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect. Conclusions The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial. Limitations Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS. Future work Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space. Funding Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council–National Institute for Health Research Methodology Research programme.

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Integration of subclassification strategies in randomised controlled clinical trials evaluating manual therapy treatment and exercise therapy for non-specific chronic low back pain: a systematic review

British Journal of Sports Medicine ◽

10.1136/bjsm.2009.063289 ◽

2009 ◽

Vol 44 (14) ◽

pp. 1054-1062 ◽

Cited By ~ 54

Author(s):

K. V. Fersum ◽

W. Dankaerts ◽

P. B. O'Sullivan ◽

J. Maes ◽

J. S. Skouen ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Low Back Pain ◽

Back Pain ◽

Manual Therapy ◽

Chronic Low Back Pain ◽

Low Back ◽

Controlled Clinical Trials ◽

Randomised Controlled ◽

Therapy Treatment

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Interventions for oropharyngeal dysphagia in acute and critical care: a protocol for a systematic review and meta-analysis

Systematic Reviews ◽

10.1186/s13643-019-1196-0 ◽

2019 ◽

Vol 8 (1) ◽

Cited By ~ 4

Author(s):

Sallyanne Duncan ◽

Jennifer Mc Gaughey ◽

Richard Fallis ◽

Daniel F. McAuley ◽

Margaret Walshe ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Critical Care ◽

Acute Care ◽

Randomised Controlled Trials ◽

Meta Analysis ◽

Oropharyngeal Dysphagia ◽

Length Of Hospital Stay ◽

Controlled Trials ◽

Randomised Controlled

Abstract Background Oropharyngeal dysphagia or swallowing difficulties are common in acute care and critical care, affecting 47% of hospitalised frail elderly, 50% of acute stroke patients and approximately 62% of critically ill patients who have been intubated and mechanically ventilated for prolonged periods. Complications of dysphagia include aspiration leading to chest infection and pneumonia, malnutrition, increased length of hospital stay and re-admission to hospital. To date, most dysphagia interventions in acute care have been tested with acute stroke populations. While intervention studies in critical care have been emerging since 2015, they are limited and so there is much to learn about the type, the delivery and the intensity of treatments in this setting to inform future clinical trials. The aim of this systematic review is to summarise the evidence regarding the relationship between dysphagia interventions and clinically important patient outcomes in acute and critical care settings. Methods We will search MEDLINE, EMBASE, CENTRAL, Web of Science, CINAHL and clinical trial registries from inception to the present. We will include studies conducted with adults in acute care settings such as acute hospital wards or units or intensive care units and critical care settings. Studies will be restricted to randomised controlled trials and quasi-randomised controlled trials comparing a new dysphagia intervention with usual care or another intervention. The main outcomes that will be collected include length of time taken to return to oral intake, change in incidence of aspiration and pneumonia, nutritional status, length of hospital stay and quality of life. Key intervention components such as delivery, intensity, acceptability, fidelity and adverse events associated with such interventions will be collected to inform future clinical trials. Two independent reviewers will assess articles for eligibility, data extraction and quality appraisal. A meta-analysis will be conducted as appropriate. Discussion No systematic review has attempted to summarise the evidence for oropharyngeal dysphagia interventions in acute and critical care. Results of the proposed systematic review will inform practice and the design of future clinical trials. Systematic review registration PROSPERO CRD 42018116849 (http://www.crd.york.ac.uk/PROSPERO/)

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Placebo Response in Clinical Randomized Trials of Analgesics in Migraine

Cephalalgia ◽

10.1046/j.1468-2982.2003.00528.x ◽

2003 ◽

Vol 23 (7) ◽

pp. 487-490 ◽

Cited By ~ 49

Author(s):

L Bendtsen ◽

P Mattsson ◽

J-A Zwart ◽

RB Lipton

Keyword(s):

Clinical Trials ◽

Randomized Clinical Trials ◽

Response Rate ◽

International Headache Society ◽

Placebo Response ◽

Patient Characteristics ◽

Placebo Treatment ◽

Primary Efficacy ◽

Efficacy Parameter ◽

Efficacy Measure

The objective was to assess the placebo response in randomized clinical trials of analgesics in the treatment of migraine attacks. We included placebo-controlled studies that used the criteria of the International Headache Society for the diagnosis of migraine and headache response as the primary efficacy parameter. In the 11 studies that qualified for inclusion, headache response occurred after placebo treatment in 7-50% of the migraineurs with an average placebo response rate of 30% (95% confidence interval (CI) 23-36). Two hours after treatment with placebo an average of 9% (95% CI 7-12, range 7-17%) of the patients were found to be pain free. In conclusion, the average headache response rate to placebo was 30% in randomized clinical trials of analgesics in migraine with a tremendous variation among studies. Placebo response rates vary with the choice of primary efficacy measure as well as patient characteristics and study design.

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Evidence Based Migraine Prophylactic Drug Therapy

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100000160 ◽

1999 ◽

Vol 26 (3) ◽

pp. 27-32 ◽

Cited By ~ 19

Author(s):

W.J. Becker

Keyword(s):

Clinical Trials ◽

Drug Therapy ◽

Scientific Evidence ◽

Tension Type Headache ◽

Beneficial Effects ◽

Symptomatic Medication ◽

Prophylactic Drugs ◽

Prophylactic Drug ◽

Patient Will ◽

Type Headache

Prophylactic drug therapy is a major component of overall migraine management. However, because we do not know how currently used prophylactic drugs exert their beneficial effects in migraine, their use is based primarily on clinical trials. In general, prophylactic drugs are indicated when patients have three or more attacks a month and symptomatic medication use alone is not satisfactory. The choice of drug must be individualized, and is influenced by contraindications, potential side effects, the need to treat associated symptoms like tension-type headache and insomnia, and drug cost. Whether an individual patient will respond to a given drug cannot be predicted, but there are varying degrees of scientific evidence supporting the use of each prophylactic drug in migraine. This evidence is best for metoprolol, divalproex, amitriptyline, atenolol, flunarizine and naproxen. Based on placebo-controlled crossover studies, it would appear that at least some prophylactic drugs exert the greater part of their prophylactic effects very quickly, and that these also disappear very quickly once the drug is stopped. This may not apply to all prophylactic drugs and more research is needed. More well designed clinical trials are needed to guide our use of migraine prophylactic drugs. Although clinical experience is useful, placebo responses and variations in the migraine tendency over time can make interpretation of this experience difficult. Major advances will likely only occur once the pathogenesis of migraine and the mode of action of the prophylactic drugs is better understood.

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Ethical, Scientific, and Regulatory Perspectives Regarding the Use of Placebos in Cancer Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2007.13.5335 ◽

2008 ◽

Vol 26 (8) ◽

pp. 1371-1378 ◽

Cited By ~ 31

Author(s):

Christopher K. Daugherty ◽

Mark J. Ratain ◽

Ezekiel J. Emanuel ◽

Ann T. Farrell ◽

Richard L. Schilsky

Keyword(s):

Clinical Trials ◽

Placebo Response ◽

Drug Approval ◽

Active Treatment Group ◽

Cancer Clinical Trials ◽

Full Disclosure ◽

Placebo Controls ◽

Regulatory Standards ◽

New Treatment ◽

Oncology Drug Development

PurposeTo examine the ethical, scientific, and regulatory issues in the design and conduct of placebo-controlled cancer clinical trials.MethodsSeveral content experts contributed to this article.ResultsSpecific criteria can be applied to determine the appropriate use of placebos in oncology drug development. Placebo controls may be justified to prove efficacy of a new treatment in diseases with high placebo response rates; in conditions that wax and wane in severity, have spontaneous remissions, or have an uncertain and unpredictable course; when existing therapies are minimally effective or have serious adverse effects; or in the absence of effective therapy. Use of placebos may also be justified to assure blinding of physicians and patients regarding treatment assignment so as to minimize bias in assessment of study end points. If a trial meets these methodologic criteria, it must then fulfill additional criteria to be considered ethical. These criteria include full disclosure to patients and an assurance that participants randomly assigned to placebo are not substantially more likely than those in active treatment group(s) to die; suffer irreversible morbidity, disability, or other substantial harms; suffer reversible but serious harm; or suffer severe discomfort.ConclusionWe conclude that placebo-controlled oncology trials are scientifically feasible, ethically justifiable, and may be necessary or desirable to meet regulatory standards for drug approval. Using cross-over or randomized withdrawal trial designs, requiring inclusion of state-of-the-art palliative care, and developing valid and acceptable surrogates for survival are critical strategies to address some of the ethical dilemmas associated with placebo-controlled trials.

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