Background: The placebo effect and the placebo response is a misunderstood phenomenon and their potential is wildly underestimated. Most people, including health care professionals, consider the placebo effect to be a “make believe” effect which only affects gullible people. It is argued that the nurse is in an unusually advantageous position to observe and facilitate the placebo effect and make use of the benefits for the patients. Observation of said response is made by many authors but there is little to no research on the placebo effect from a nursing standpoint. Some of the research results can however be translated to the nurse profession and used in clinical settings. Aim: The purpose is to describe areas where the placebo effect may affect nursing of the patient. Method: A literature review format was chosen to comprise existing knowledge on the placebo effect, which can be applied for nursing. Results: Themes that arose from examination of chosen literature included: Emotional state, Expectation and Conditioning, Conscious and Social learning and Patient-caregiver relationship. Many of the observed interventions could be applied using the nursing philosophy of Hildegard Peplau. Conclusion: The placebo effect can be used by the nurse to improve the result of the patient´s treatment. If placebo becomes a focus in nursing research the results could be more applicable to benefit patients than if researched by other professional groups.

This thesis presents the results of three studies examining the management of migraine in children. First we conducted a systematic review of all clinical trials conducted in children and adolescents of the acute migraine therapy. A meta-analysis of the 26 randomized controlled trials is presented. A single trial with a focus on Emergency Department (ED) management was identified. As such, we then examined current ED practice in two retrospective practice variation studies. The first compared four regional hospital EDs where practice patterns were significantly different between mixed population EDs (both adult and pediatric patients) and the tertiary pediatric ED. The second examined practice variation among ten tertiary pediatric EDs in Canada where significant differences were again observed. Factors that influenced the choice of medications included increasing patient age and the physicians diagnosis of migraine. Important areas of future investigation include: (1) the effectiveness of intravenous fluids alone; and (2) the use of combined medications. / Clinical Epidemiology

No description available.

Fragile X Syndrome (FXS) is a disorder caused by a congenital mutation of the FMR1 gene on the X chromosome. FXS is associated with moderate to severe intellectual disability and is one known cause of autism spectrum disorders. There are no approved medications to treat FXS symptoms. In 2013, Seaside Therapeutics completed two Phase 3 studies of an investigational medication, STX209, for treatment of social withdrawal in FXS. Efficacy results for these studies were not positive. Clinical trials of psychoactive drugs often fail to show a statistical difference from placebo controls and a robust response to placebo is often cited as a reason for the failure. Retrospective studies of baseline variables in clinical trials have identified characteristics that were associated with an increased likelihood of responding to placebo. Such information is valuable for the design of future clinical trials and no such studies have been conducted in FXS. This study was a post-hoc analysis of data from Seaside Therapeutics' Phase 3 clinical trials in FXS. Baseline variables for subjects receiving placebo were pooled for analysis. To determine if a subject responded to placebo, the parent-rated ABC-SA and the ABC-IR were used. Clinician-rated assessments, including the CGI-S and CGI-I, were examined as well. Two-sample t-testing, one-way ANOVA testing, and correlation coefficients were calculated to compare the responses of subjects with different baseline characteristics. General linear regression modeling was used to determine if there were multiple baseline variables that could predict placebo response. Logistic regression modeling was used to determine if the baseline variables could predict whether a subject had a higher chance of being a treatment responder. A total of 287 subjects were randomized and completed the Phase 3 studies. Analyses for this study were conducted in a subgroup containing 106 subjects who received placebo. 76% improved during the study on the ABC-SA, indicating that there was a strong placebo effect on the study. None of the dichotomous baseline variables were associated with statistically significant differences in ABC-SA, ABC-IR, CGI-S, or CGI-I scores. Placebo-treated subjects in the 209FX302 study who were taking antipsychotics improved less on the CGI-S than those not on those medications. A similar pattern was observed on the ABC-IR and ABC-SA. Other categorical baseline variables were tested and there was no difference in the mean changes. The CGI-S score at baseline appeared to predict a statistically significant difference in the ABC-IR as more severe subjects were more likely to show a larger change in the ABC-IR. Similar, although not statistically significant results were seen with ABC-SA, CGI-I, and CGI-S changes, in that more severe subjects had greater responses to placebo. ABC-IR score changes were correlated independently with each of the ABC-C subscales but also with parental distress, CGI-S, and VAS-Anxiety. Only one variable, the ABC-IR at baseline, was significantly correlated with the ABC-SA score change, the rest of the variables were not significant. A multiple linear regression model predicting placebo response for the ABC-SA included only the baseline ABC-SA score. When the studies were modeled separately, the 209FX302 model contained additional variables including gender, antipsychotic use, and ABC-stereotypy scores. For the ABC-IR change model, the highest correlation coefficient was found in the 209FX301 study with ABC-IR, gender, Vineland-communication, maternal FMR1 status, and ABC-SL included in the model. 70% of the placebo treated subjects improved on the ABC-SA by at least 25%. Placebo responders were less frequently observed in clinician-rated assessments such as the CGI-I and CGI-S. In logistic regression models, for the ABC-IR response, a higher score on the hyperactivity subscale of the ABC-C was predictive of a lower placebo response. The CGI-S model was statistically significant and included the subject's age, race and ABC-IS score. The ABC-SA response could be modeled only in the 209FX302 study with gender and ADHD medication use remaining in the model. Also in the 209FX302 study, subjects were far less likely to be a responder on the ABC-IR or a total responder, if they were taking antipsychotic medications. Results of this study indicate that the ABC-SA is not recommended in future trials in the FXS patient population. Future trials should also allow ADHD and antipsychotic medication use as they were associated with a lower placebo response in some analyses. In addition, due to their inclusion in regression models, future studies should consider baseline variables such as parental stress and Vineland scores, and when designing study eligibility criteria or stratification variables.

In clinical trials, placebo response is considered a beneficial effect arising from multiple factors, including the patient’s expectations for the treatment. Due to the presence of placebo response, the classical parallel design often fails to declare an efficacious treatment. The Sequential Parallel Comparison Design (SPCD), a two-stage design where the first stage is a classical parallel trial, followed by another parallel trial among placebo patients from the first stage, was proposed to mitigate the placebo response. In SPCD, in lieu of treatment effect, a weighted average of the mean treatment difference in Stage I among all randomized patients and the mean treatment difference in Stage II among placebo non-responders was proposed as the efficacy measure. However, by mixing two possibly different populations, this weighted average lacks interpretability, the choice of weight remains controversial, and the classification of patients into placebo responders and non-responders via hard criterion-based rule warrants careful consideration. In this work, we first elaborate and study the shortcomings surrounding this efficacy measure, which motivates us to propose causal estimands for clinically meaningful principal strata under the principal stratification framework. To make the estimands identifiable, we invoke a set of assumptions and introduce two sensitivity parameters. Meanwhile, in the absence of a clinically proven criterion for classifying responders and non-responders, we additionally suggest estimating the response status and sensitivity parameters via the Expectation-Maximization (EM) algorithm by treating the principal strata as full latent characteristics. Next, we further refine and alternatively propose a more consistent and sophisticated EM procedure for classification, point estimation, and hypothesis testing. Finally, we evaluate our methods with extensive simulation studies and apply them to an actual SPCD study of antidepressant therapy to assess the benefit of low-dose aripiprazole adjunctive to antidepressant therapy treatment, the ADAPT-A trial. In conclusion, we believe this is an important step toward a more rigorous and transparent approach to evaluating the treatment benefit in the presence of placebo response. / 2025-09-18T00:00:00Z

Thesis (MNutr)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: It is estimated that 1.3 billion people worldwide are either overweight or obese, making this a global epidemic. An effective weight-loss method involves the lifestyle changes of increased physical activity and lowered energy intake. These changes are difficult to carry out and to maintain. As a result, there is a soaring demand for weight-loss aids, including dietary supplements, which exploit consumers’ eagerness to find an effortless weight-loss solution. These supplements are easily accessible, require no prescription and are heavily marketed to suggest that weight loss is achievable without exercise and dieting. One such dietary supplement, Bioslim, is tested in this study. The aim of this study was to investigate whether Bioslim results in greater weight loss than a placebo, and whether the marketing of the Bioslim brand has an influence on the placebo response. Overweight adults residing in Cape Town (n = 87) were recruited by advertising in community newspapers and setting up stands at shopping centres. The subjects were randomised into one of four groups: Bioslim in Bioslim packaging (n = 26), Bioslim in unbranded packaging (n = 22), placebo in Bioslim packaging (n = 17) and placebo in unbranded packaging (n = 22). At baseline, the subjects were given one of the four products and anthropometric measurements (weight, height and skinfold thickness) were taken. After four weeks, these measurements were repeated. The subjects also had to complete a questionnaire regarding their experiences. The body mass index (BMI) for the total population was 31.90 kg/m2 (SD = 3.91) at baseline and 31.89 kg/m2 (SD = 3.92) at follow-up. None of the measured anthropometric variables had changed significantly after four weeks. When the total study group sample was analysed, based on the allocated drug treatment groups (active or placebo), neither group showed significant weight loss from baseline to follow-up. Twenty-three subjects from the Bioslim group and 21 from the unbranded group reported exercising during the trial. The total group’s exercise time correlated significantly with fat-mass reduction (r = -0.31, p = 0.004). Furthermore, when data was analysed separately for the active and placebo groups, the active group showed a significant correlation (r = -0.45, p = 0.0012), while the placebo group showed an insignificant correlation (r = -0.05, p = 0.77). The same was not reflected in weight loss (r = -0.007, p = 0.95). It is concluded that Bioslim is an ineffective weight-loss supplement: subjects receiving active pills evidenced no significant beneficial changes in weight, waist circumference or body composition. More than half of the subjects attempted dieting and exercising, but these efforts were insufficient to impact on weight loss. The marketing and packaging of Bioslim did not enhance the placebo effect. One subject from the active group withdrew from the study, complaining of severe headaches and heart palpitations. There was no difference in adverse events reported by the remaining active and placebo group subjects. In conclusion, this study emphasises the need for better regulation of the efficacy and safety of dietary supplements. / AFRIKAANSE OPSOMMING: Daar word geskat dat 1.3 biljoen mense wêreldwyd oorgewig of vetsugtig is, wat dit ‘n globale problem maak. ‘n Effektiewe gewigsverlies metode inkorporeer leefstyl veranderinge soos verhoogde fisiese aktiwiteit en ‘n laer energie inname. Hierdie veranderinge is moeilik om uit te voer en vol te hou. Die gevolg is ‘n stygende aanvraag vir gewigsverliesprodukte en supplemente, wat verbruikers se gretigheid om ‘n maklike gewigsverlies oplossing te kry, uitbuit. Hierdie supplemente is maklik verkrygbaar sonder ‘n voorskrif en word aggressief bemark met bewering dat gewigsverlies moontlik is sonder oefening en dieetaanpassing. Een van die beskikbare produkte, Bioslim, is getoets in die studie. Die doel van die studie was om te ondersoek of die gewigsverlies produk, Bioslim, lei tot ‘n groter gewigsverlies as ‘n plasebo produk en of die bemarking van die Bioslim handelsmerk ‘n invloed op die plasebo-effek het. Oorgewig volwassenes woonagtig in Kaapstad (n = 87) is gewerf deur advertering in gemeenskapskoerante en deur stalletjies by inkopiesentrums. Die proefpersone is ewekansig in vier groepe ingedeel: Bioslim in Bioslim verpakking (n = 26); Bioslim in verpakking sonder ‘n handelsmerk (n = 22); ‘n plasebo produk in Bioslim verpakking (n = 17) en ‘n plasebo produk in verpakking sonder ‘n handelsmerk (n = 17). Met aanvang van die studie is een van die vier produkte aan die proefpersone gegee en antropometriese metings (gewig, lengte en velvoudikte) is gemeet. Metings is na vier weke herhaal. Die proefpersone moes ook ‘n vraelys oor hul ervarings voltooi. Die liggaamsmassa indeks (LMI) van die totale populasie was 31,90 kg/m2 (SD = 3.91) by basislyn en 31.89 kg/m2 (SD = 3.92) met opvolg. Geen van die antropometriese veranderlikes het betekenisvol verander na vier weke nie. Met ontleding van die totale studie polulasie, gebasseer op die toegekende behandeling (aktiewe of plasebo bestanddele), is gevind dat geen groep ‘n betekenisvolle gewigsverlies getoon het van basislyn tot opvolg nie. Drie-en-twintig proefpersone uit die Bioslim groep en 21 uit die geen-handelsmerk-groep het gerapporteer dat hul geoefen het gedurende die studie. Die totale groep se oefenings tydsduur het betekenisvol gekorreleer met ‘n verlaging in vetmassa (r = -0.31, p = 0.004). Met verdere analiese van die data in die aktiewe en plasebo groepe, is gevind dat die aktiewe groep ‘n betekenisvolle korrelasie getoon het (r = -0.45, p = 0.0012), maar die plasebo groep nie (r = -0.05, p = 0.77). Hierdie bevinding is nie gevind in die gewigsverlies nie (r = -0.007, p = 0.95). Die gevolgtrekking word gemaak dat Bioslim ‘n oneffektiewe gewigsverlies supplement is, aangesien proefpersone wat die aktiewe pille geneem het, geen betekenisvolle voordelige veranderinge in hul gewig, middelomtrek of liggaamsamestelling getoon het nie. Alhoewel ‘n betekenisvolle korrelasie gevind is tussen oefeningsduur en verlies aan vetmassa in meer as die helfte van die proefpersone, was die omvang daarvan onvoldoende om ‘n impak op hul gewigsverlies te hê. Die bemarking en Bioslim handelsmerk het nie die placebo-effek versterk nie. Een persoon uit die aktiewe groep het van die studie onttrek as gevolg van erge hoofpyn en hartkloppings. Daar was geen verskil in die nadelige effekte gerapporteer deur die oorblywende proefpersone in die aktiewe en plasebo groepe nie. Ten slotte beklemtoon die studie die behoefte aan beter regulering van die effektiwiteit en veiligheid van dieetsupplemente.

The placebo response can affect inference in analysis of data from clinical trials. It can bias the estimate of the treatment effect, jeopardize the effort of all involved in a clinical trial and ultimately deprive patients of potentially efficacious treatment. The Sequential Parallel Comparison Design (SPCD) is one of the novel approaches addressing placebo response in clinical trials. The analysis of SPCD clinical trial data typically involves classification of subjects as ‘placebo responders’ or ‘placebo non-responders’. This classification is done using a specific criterion and placebo response is treated as a measurable characteristic. However, the use of criterion may lead to subject misclassification due to measurement error or incorrect criterion selection. Subsequently, misclassification can directly affect SPCD treatment effect estimate. We propose to view placebo response as an unknown random characteristic that can be estimated based on information collected during the trial. Two strategies are presented here. First strategy is to model placebo response using criterion classification as a starting point or the observed data, and to include the placebo response estimate into the treatment effect estimation. Second strategy is to jointly model latent placebo response and the observed data, and estimate treatment effect from the joint model. We evaluate both strategies on a wide range of simulated data scenarios in terms of type I error control, mean squared error and power. We then evaluate the strategies in presence of missing data and propose a method for missing data imputation under the non-informative missingness assumption. The data from a recent SPCD clinical trial is used to compare results of the proposed methods with reported results of the trial. / 2018-01-01T00:00:00Z

Placebo response, an apparent improvement in the clinical condition of patients randomly assigned to the placebo treatment, is a major issue in clinical trials on psychiatric and pain disorders. Properly addressing the placebo response is critical to an accurate assessment of the efficacy of a therapeutic agent. The Sequential Parallel Comparison Design (SPCD) is one approach for addressing the placebo response. A SPCD trial runs in two stages, re-randomizing placebo patients in the second stage. Analysis pools the data from both stages. In this thesis, we propose a Bayesian approach for analyzing SPCD data. Our primary proposed model overcomes some of the limitations of existing methods and offers greater flexibility in performing the analysis. We find that our model is either on par or, under certain conditions, better, in preserving the type I error and minimizing mean square error than existing methods. We further develop our model in two ways. First, through prior specification we provide three approaches to model the relationship between the treatment effects from the two stages, as opposed to arbitrarily specifying the relationship as was done in previous studies. Under proper specification these approaches have greater statistical power than the initial analysis and give accurate estimates of this relationship. Second, we revise the model to treat the placebo response as a continuous rather than a binary characteristic. The binary classification, which groups patients into “placebo-responders” or “placebo non-responders”, can lead to misclassification, which can adversely impact the estimate of the treatment effect. As an alternative, we propose to view the placebo response in each patient as an unknown continuous characteristic. This characteristic is estimated and then used to measure the contribution (or the weight) of each patient to the treatment effect. Building upon this idea, we propose two different models which weight the contribution of placebo patients to the estimated second stage treatment effect. We show that this method is more robust against the potential misclassification of responders than previous methods. We demonstrate our methodology using data from the ADAPT-A SPCD trial.

Background: Interest in alternatives to hormone therapy (HT) for menopausal symptoms increased following its association with serious health risks. In terms of phytotherapeutic interventions, while traditional use supports a range of herbs for treating menopausal symptoms, evidence from rigorous scientific trials is limited, and has largely focused on the phytoestrogenic plants. Because of some safety concerns over long-term use of isoflavones, the present study focused on two non-estrogenic herbs, Hypericum perforatum and Vitex agnus-castus, also employed in this context in the Anglo-American and European traditions. Both herbs have shown effectiveness for the alleviation of symptoms of premenstrual syndrome (PMS), which is reported to be more severe during the perimenopause, and may account for many of the so-called 'menopausal symptoms' at this time. Research on menopausal vasomotor symptoms is prone to substantial placebo responses. There has been much interest in increasing our understanding of the placebo response with a view to controlling it in clinical research and harnessing it in clinical practice. Methods & Results: A double-blind, randomised controlled trial (RCT), with a 16-week treatment phase, was conducted on 100 late-perimenopause and early postmenopause women. The herbal combination (Hypericum and Vitex) was not found to be superior to placebo for any of the endpoints - daily weighted flushing scores, overall menopausal symptoms (on the Greene Climacteric Scale) and depression (on the Hamilton Depression Inventory). However, significant improvements across the treatment phase were observed in both arms for all of these outcome measures. No significant change was found for either group on the Utian quality of life scale. The effects of the herbal combination were also examined on PMS-like symptoms in the small sub-population of late-perimenopausal women, and found to be superior to placebo for total PMS-like symptoms and the sub-clusters, PMS-D (depression) and PMS-C (cravings). The active treatment group also showed significant improvements on PMS-A (anxiety) and PMS-H (hydration), although these effects were not superior to placebo. Predictors of the placebo response were investigated and found to include study-entry anxiety for the outcome measures of flushing, depression and overall menopausal symptoms, and improvement during non-treatment run-in for depression and overall symptoms. Because no difference had been found between 'active' and placebo groups in the menopause RCT, it was hypothesised that the same predictors would predict the response to the study treatment. However, low anxiety was significantly associated with improvement in this group. None of the other variables that predicted the placebo response was relevant to the study treatment response. This finding is discussed with reference to the possibility that 'drug' effects and placebo effects are not necessarily additive, and that the same magnitude of effect in both arms might not necessarily imply activity via the same pathways. Conclusions: This research contributes to the growing body of scientific knowledge about evidence-based complementary therapies that informs the community, health-care providers and regulatory authorities. The findings may facilitate identification of potential placebo responders in future research. The need for more research in the area of mechanisms of placebo versus active responses is supported.

No description available.