Placebo Arms Of Clinical Trials Research Articles

APOE-ε4 allele[s]-associated adverse events reported from placebo arm in clinical trials for Alzheimer's disease: implications for anti-amyloid beta therapy

APOE-ε4 allele[s] is a risk factor for Alzheimer's disease (AD) and Amyloid-Related Imaging Abnormalities (ARIA) in anti-amyloid beta therapy, and is also associated with cerebrovascular risk factors such as hyperlipidemia or atherosclerosis. During AD clinical trials, APOE-ε4 carriers may experience neuropsychiatric adverse events (AEs) related to these risks, complicating the differentiation of ARIA from cerebrovascular events based on symptoms. This study aimed to examine the hypothetical impact of considering the APOE-ε4 allele's risk for non-ARIA AEs during AD clinical trials. We used data from the Critical Path for Alzheimer's Disease (CPAD) from the placebo arm of randomized controlled trials (RCT) for AD treatment. We determined whether AEs were reported more frequently in APOE-ε4 carriers, quantifying with reporting odds ratio (ROR) using a mixed effect model. We also evaluated the association between ROR levels and the prior probability that an AE is symptomatic ARIA. We analyzed 6,313 patients with AD or mild cognitive impairment in 28 trials. Of the prespecified 35 neuropsychiatric or related AEs, several had a significantly high ROR: “delusion” (ROR = 4.133), “confusional state” (ROR = 1.419), “muscle spasms” (ROR = 9.849), “irritability” (ROR = 12.62), “sleep disorder” (ROR = 2.944), or “convulsion” (ROR = 13.00). However, none remained significant after adjusting for Mini-Mental State Examination scores. There is no strong evidence to suggest that specific neuropsychiatric AEs occur more frequently without drug treatment association among APOE-ε4 carriers. The influence of APOE-ε4 allele[s] on the clinicians' assessment of the likelihood of ARIA during safety monitoring in anti-amyloid beta monoclonal antibody treatment might be unchanged, thus maintaining the current level of awareness of clinicians of AEs.

Meta-regression to explain the placebo effects in clinical trials of anti-CGRP monoclonal antibodies for migraine prevention

Background: Commonly used methods of comparison (e.g. network meta-analyses) require common comparator(s) across trials, such as placebo in placebo-controlled trials. Recent literature indicates that route of administration differences across placebo arms of clinical trials in pain disorders may contribute to differences in placebo effect.Methods: We conducted a meta-regression on placebo data from pivotal clinical trials of anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies for migraine prevention to quantify the impact of route of administration, migraine type (episodic/chronic), and number of prior treatment failures on placebo reduction in monthly migraine days (MMDs) across weeks 1–12 of treatment. A systematic literature review of Embase, MEDLINE, the Cochrane Library, and grey literature conducted in June 2021 identified 14 relevant, randomized placebo-controlled trials for analysis.Results: After testing models with different covariates, a meta-regression was fitted to the extracted placebo data with the covariates of route of administration, migraine type, and proportion of patients with ≥2 prior preventive treatment failures. An intravenous route of administration for the placebo arm was a predictor for higher MMD reduction. Predictors of lower MMD reduction were migraine type (episodic migraine) and a higher proportion of patients having ≥2 failed preventive treatments.Conclusions: The efficacy of intravenous anti-CGRP monoclonal antibodies are likely underestimated, and differences in the route of administration of placebo may necessitate use of alternative methods that do not assume the presence of a common comparator when comparing anti-CGRP monoclonal antibodies in migraine prevention. Further research into the contextual effects of the placebo effect is warranted.

Adverse Events in Patients Receiving Placebo in Phase III Trials of Biologics for Psoriasis: A Systematic Review and Meta-Analysis

Background Patients and practitioners often consider the risk of side effects when starting a treatment for psoriasis and often consult reported adverse events (AE) in studies. However, most of these AEs are unrelated to treatment and patients consider what is the risk of an event should you not start a treatment. This is what would be observed in the placebo-arm of clinical trials. Objective To investigate the proportion of patients experiencing AEs during treatment with placebo in clinical trials. Methods We conducted a systematic literature search using PubMed, Embase and Web of Science databases for phase 3 randomized clinical trials that registered adverse events of using placebo vs biological agents for psoriasis. The search term was “ Psoriasis AND (Phase III OR Phase 3)”. Results Of 7142 screened articles, 54 were included in the metanalysis. The pooled proportion of placebo-treated patients experiencing any AEs was .52 (95% Cl: .51 to .53) after 12 weeks and .53 (95% Cl: .50 to .55) after 16 weeks. The pooled proportion of patients with any serious AEs was .02 (95% Cl: .01 to .02) and .03 (95% Cl: .02 to .03) after 12 and 16 weeks, respectively. The most common AEs in placebo-treated patients were infections, nasopharyngitis, and headache. Conclusion About half of the patients with moderate-to-severe psoriasis not starting an active treatment would experience disease events that would be categorized as AEs during a 12-16 weeks period.

Cardiorenal Nexus: A Review With Focus on Combined Chronic Heart and Kidney Failure, and Insights From Recent Clinical Trials.

The cardiorenal nexus encompasses a bidirectional relationship between the heart and the kidneys. Chronic abnormalities in cardiac function can lead to progressive kidney disease, and chronic kidney disease can lead to progressively decreasing cardiac function and increasing risk of cardiovascular disease, including heart failure. About 15% of US adults have chronic kidney disease, 2% have heart failure, and 9% have cardiovascular disease. Prevalence rates of chronic kidney disease, cardiovascular disease, and associated morbidities such as type 2 diabetes are expected to increase with an aging population. Observational studies provide evidence for the cardiorenal nexus. Follow‐up data from placebo arms of clinical trials in chronic kidney disease or cardiovascular disease show higher rates of renal and cardiovascular outcome events in patient subgroups with type 2 diabetes than in those without type 2 diabetes. The cardiorenal syndromes develop along an interlinked pathophysiological trajectory that requires a holistic, collaborative approach involving a multidisciplinary team. There is now a compendium of treatment options. Greater understanding of the underlying pathophysiology of the cardiorenal nexus will support optimization of the management of these interlinked disease states.

Disability Progression and Improvement Among Active and Nonactive Secondary Progressive Multiple Sclerosis Patients in Placebo Arms of Clinical Trials (P1-1.Virtual)

Disability Progression and Improvement Among Active and Nonactive Secondary Progressive Multiple Sclerosis Patients in Placebo Arms of Clinical Trials (P1-1.Virtual)

Application of predictive models in boosting power of Alzheimer's disease clinical trials: A post hoc analysis of phase 3 solanezumab trials.

BackgroundThe ideal participants for Alzheimer's disease (AD) clinical trials would show cognitive decline in the absence of treatment (i.e., placebo arm) and would also respond to the therapeutic intervention.ObjectiveTo investigate if predictive models can be an effective tool for identifying and excluding people unlikely to show cognitive decline as an enrichment strategy in AD trials.MethodWe used data from the placebo arms of two phase 3, double‐blind trials, EXPEDITION and EXPEDITION2. Patients had 18 months of follow‐up. Based on the longitudinal data from the placebo arm, we classified participants into two groups: one showed cognitive decline (any negative slope) and the other showed no cognitive decline (slope is zero or positive) on the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS‐cog). We used baseline data for EXPEDITION to train regression‐based classifiers and machine learning classifiers to estimate probability of cognitive decline. Models were applied to EXPEDITION2 data to assess predicted performance in an independent sample. Features used in predictive models included baseline demographics, apolipoprotein E ε4 genotype, neuropsychological scores, functional scores, and volumetric magnetic resonance imaging.ResultIn EXPEDITION, 46.3% of placebo‐treated patients showed no cognitive decline and the proportion was similar in EXPEDITION2 (45.6%). Models had high sensitivity and modest specificity in both the training (EXPEDITION) and replication samples (EXPEDITION2) for detecting the stable group. Positive predictive value of models was higher than the base prevalence of cognitive decline, and negative predictive value of models were higher than the base rate of participants who had stable cognition.ConclusionExcluding persons with AD unlikely to decline from the active and placebo arms of clinical trials using predictive models may boost the power of AD trials through selective inclusion of participants expected to decline.

Expert consensus on the monitoring of transthyretin amyloid cardiomyopathy.

Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a life‐threatening condition with a heterogeneous clinical presentation. The recent availability of treatment for ATTR‐CM has stimulated increased awareness of the disease and patient identification. Stratification of patients with ATTR‐CM is critical for optimal management and treatment; however, monitoring disease progression is challenging and currently lacks best‐practice guidance. In this report, experts with experience in treating amyloidosis and ATTR‐CM developed consensus recommendations for monitoring the course of patients with ATTR‐CM and proposed meaningful thresholds and frequency for specific parameters. A set of 11 measurable features across three separate domains were evaluated: (i) clinical and functional endpoints, (ii) biomarkers and laboratory markers, and (iii) imaging and electrocardiographic parameters. Experts recommended that one marker from each of the three domains provides the minimum requirements for assessing disease progression. Assessment of cardiac disease status should be part of a multiparametric evaluation in which progression, stability or improvement of other involved systems in transthyretin amyloidosis should also be considered. Additional data from placebo arms of clinical trials and future studies assessing ATTR‐CM will help to elucidate, refine and define these and other measurements.

The natural history of idiopathic pulmonary fibrosis in a large European population: the role of age, sex and comorbidities.

Placebo arms of clinical trials provide an opportunity to investigate the natural history of idiopathic pulmonary fibrosis (IPF) but these patients are not representative of the real life IPF population. Objective of this article is to evaluate patients' characteristics of incident IPF cases and their impact on mortality and hospitalizations risk. We conducted a retrospective cohort study using data from administrative databases from 2000 to 2010. Based on different algorithms reported in literature, incident IPF cases were identified. We applied Cox proportional hazards models to assess relationship between patients' characteristics, mortality and hospitalization. According to three case definitions, we identified 2338, 460 and 1704 incident IPF cases. Mean age at diagnosis was about 72years, the proportion of male varied between 59 and 62% and patients with at least one chronic disease were between 70 and 74%. Age, male sex and comorbidities were associated to worse outcomes. Congestive heart failure (CHF), diabetes and cancer were conditions associated to mortality, while those associated to hospitalization were CHF and chronic obstructive pulmonary disease. Our data source provided one of the largest samples of unselected patients with a long follow-up period. Using different algorithms proposed and validated in literature, we observed that mortality and hospitalization rate are high in patients with IPF and age, sex and comorbidities significantly affect clinical outcomes. Females show a significant survival advantage over males, even after adjusting for age and comorbidities. Patients with pre-existing diseases, especially those with pulmonary and cardiovascular diseases are at higher risk.

Risk of falls in patients with low bone mineral density : Analysis of placebo arms from clinical trials.

Falls are amajor risk factor for osteoporotic fractures. Therefore, the aim of this study was to analyze the risk of falls in patients with low bone mineral density (BMD) and osteoporosis. The risk of falls in patients with low BMD and/or osteoporosis was analyzed using data from placebo arms of clinical trials, indexed on clinicaltrials.gov. The risk was estimated using asingle arm meta-analysis method and by applying abinary random effects model. In addition, meta-regression analyses were performed to identify associations between risk of falls and age, body mass index (BMI) and BMD. Atotal of 8762 patients from placebo arms of clinical trials were included into the analysis. Risk of falls was 5.2% (0.052, 95% confidence interval [95% CI] 0.022-0.082; n = 8714; I2 = 97.3%, p ≤ 0.001) in patients with low BMD and/or osteoporosis and 5.9% (0.059, 95% CI 0.036-0.083; n = 7819; I2 = 87.8%, p ≤ 0.001) in patients with osteoporosis. Asignificant association with risk of falls was identified for age in patients with low BMD and/or osteoporosis. BMD at total hip (TH; coefficient -0.077, 95% CI: -0.113--0.040, p ≤ 0.001; n = 7715) and femoral neck (FN; coefficient -0.044, 95% CI -0.065--0.023, p ≤ 0.001; n = 7662) were significantly associated with risk of falls in patients with osteoporosis. This analysis identified the risk of falls in patients with low BMD and osteoporosis and an association of falls with age and BMD. Therefore, patients with osteoporosis need to receive mandatory fall risk mitigation measures, and the BMD at total hip or femoral neck could function as an indicator for the risk of falling.

P120 Prevalence of endoscopic improvement and endoscopic remission according to patient reported outcomes in ulcerative colitis

Abstract Background We aimed to quantify the prevalence of endoscopic improvement (EI) and remission (ER) amongst ulcerative colitis patients with various permutations of patient reported outcomes (PRO) following treatment with biologic agents or tofacitinib. Methods Individual participant data from active intervention and placebo arms of clinical trials of infliximab, golimumab, vedolizumab, and tofacitinib were pooled to estimate the prevalence of EI (Mayo endoscopic sub-score [MES] 0 or 1) and ER (MES 0) scores with various permutations of the rectal bleeding sub-score (RBS) and stool frequency sub-score (SFS) of the Mayo score, following induction (6–8 weeks) and maintenance (30–54 weeks) therapy. Subgroup analyses were performed by year of publication and centrally read endoscopy scoring. Results Data from 2586 trial participants were analysed. Using locally scored endoscopy, the prevalence of EI and ER was highest among participants with a RBS 0 + SFS 0 post induction (EI: 81%, [95% CI 78–84]; ER: 29% [26–33]) and during maintenance (EI: 91% [87–93]; ER: 57% [52–62]). Prevalence estimates were lower for more recently performed trials (p < 0.01). In comparison to locally scored endoscopy, when using central endoscopy scoring the prevalence of EI and ER were lower post-induction (EI 57% [50–64], p < 0.001; ER 15% [11–21], p = 0.09) and during maintenance (EI 74% [67–81], p = 0.001; ER 31% [24–38], p = 0.001) for participants achieving a RBS 0 + SFS 0. Conclusion Approximately eight out of 10 patients with normalisation of rectal bleeding and stool frequency have improvement in endoscopic disease activity, whereas approximately only half of these patients have endoscopic remission.

What are the chances for personalised treatment with antidepressants? Detection of patient-by-treatment interaction with a variance ratio meta-analysis

ObjectivesTo investigate if the treatment effect of antidepressants in patients with depression substantially varies in each patient (patient-by-treatment interaction or treatment heterogeneity), a necessary but largely unexplored prerequisite of personalised...

Prevalence of endoscopic improvement and remission according to patient‐reported outcomes in ulcerative colitis

Treatment targets for ulcerative colitis are evolving towards achievement of endoscopic improvement and remission in addition to symptom resolution. It remains to be accurately quantified what proportion of patients with symptom resolution have residual endoscopic activity that might warrant treatment modification. To quantify the prevalence of endoscopic improvement and remission amongst ulcerative colitis patients with various permutations of patient-reported outcomes. Individual participant data from active intervention and placebo arms of clinical trials of infliximab, golimumab, vedolizumab and tofacitinib were pooled to estimate the prevalence of endoscopic improvement (Mayo endoscopic sub-score [MES] 0 or 1) and remission (MES 0) scores with various permutations of the rectal bleeding sub-score (RBS) and stool frequency sub-score (SFS) of the Mayo score, following induction (6-8weeks) and maintenance (30-54weeks) therapy. Subgroup analyses were performed by year of publication and centrally read endoscopy scoring. Data from 2586 trial participants were analysed. Using locally scored endoscopy, the prevalence of endoscopic improvement and remission was highest among participants with a RBS 0+SFS 0 post-induction (MES 0/1:81%, [95% CI 78-84]; MES 0:29% [26-33]) and during maintenance (MES 0/1:91% [87-93]; MES 0:57% [52-62]). Prevalence estimates were lower for more recently performed trials (P<.01). In comparison to locally scored endoscopy, when using central endoscopy scoring, the prevalence of endoscopic improvement and remission was lower post-induction (MES 0/1 57% [50-64], P<.001; MES 0 15% [11-21], P=.09) and during maintenance (MES 0/1 74% [67-81], P=.001; MES 0 31% [24-38], P=.001) for participants achieving a RBS 0+SFS 0. Approximately 8 of 10 patients with normalisation of rectal bleeding and stool frequency have improvement in endoscopic disease activity, whereas approximately only half of these patients have endoscopic remission.

An update on the diagnosis and treatment of diabetic somatic and autonomic neuropathy.

Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes. It poses a significant challenge for clinicians as it is often diagnosed late when patients present with advanced consequences such as foot ulceration. Autonomic neuropathy (AN) is also a frequent and under-diagnosed complication unless it is overtly symptomatic. Both somatic and autonomic neuropathy are associated with increased mortality. Multiple clinical trials have failed because of limited efficacy in advanced disease, inadequate trial duration, lack of effective surrogate end-points and a lack of deterioration in the placebo arm in clinical trials of DPN. Multifactorial risk factor reduction, targeting glycaemia, blood pressure and lipids can reduce the progression of DPN and AN. Treatment of painful DPN reduces painful symptoms by about 50% at best, but there is limited efficacy with any single agent. This reflects the complex aetiology of painful DPN and argues for improved clinical phenotyping with the use of targeted therapy, taking into account co-morbid conditions such as anxiety, depression and sleep disturbance.

Incidence and characteristics of the nocebo response from meta‐analyses of the placebo arms of clinical trials of olanzapine for bipolar disorder

In the clinical setting, the nocebo phenomenon is where clinical worsening or adverse events occur as a response to a treatment, in a situation in which conditioning from previous treatment exposure and/or expectations of sickness or symptoms lead to sickness and symptoms in a conditioned or expectant individual. The nocebo response may thus be a confounder in clinical treatment and clinical research. There is a need to know how to predict if an individual is likely to be a nocebo responder, and how significant and commonplace the nocebo effect might be. An analysis was conducted on nine placebo-controlled, randomized clinical trials of olanzapine for the treatment of bipolar disorder using data from placebo-treated study participants only. Data were analysed to identify participant or study characteristics associated with a nocebo event, defined as any treatment-emergent adverse event (TEAE) or an increase in score from baseline to endpoint for primary measures of clinical symptoms. A total of 1185 participants were randomized to placebo, of whom 806 (68%) reported a TEAE. Hamilton Depression Rating Scale (HDRS) data were only available for 649 placebo-treated participants, of whom 321 (49.5%) demonstrated worsening. Nocebo events were significantly associated with: not being treatment-naïve, younger age, being located in the USA, being a participant in an earlier study, and being classified as obese compared with normal weight. A pattern to identify nocebo responders did not emerge, although some prognostic variables were associated with a greater probability of nocebo response. There was some evidence to support the role of expectancy as a cause of nocebo reactions.

Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study

Idiopathic pulmonary fibrosis (IPF) risk has a strong genetic component. Studies have implicated variations at several loci, including TERT, surfactant genes, and a single nucleotide polymorphism at chr11p15 (rs35705950) in the intergenic region between TOLLIP and MUC5B. Patients with IPF who have risk alleles at rs35705950 have longer survival from the time of IPF diagnosis than do patients homozygous for the non-risk allele, whereas patients with shorter telomeres have shorter survival times. We aimed to assess whether rare protein-altering variants in genes regulating telomere length are enriched in patients with IPF homozygous for the non-risk alleles at rs35705950. Between Nov 1, 2014, and Nov 1, 2016, we assessed blood samples from patients aged 40 years or older and of European ancestry with sporadic IPF from three international phase 3 clinical trials (INSPIRE, CAPACITY, ASCEND), one phase 2 study (RIFF), and US-based observational studies (Vanderbilt Clinical Interstitial Lung Disease Registry and the UCSF Interstitial Lung Disease Clinic registry cohorts) at the Broad Institute (Cambridge, MA, USA) and Human Longevity (San Diego, CA, USA). We also assessed blood samples from non-IPF controls in several clinical trials. We did whole-genome sequencing to assess telomere length and identify rare protein-altering variants, stratified by rs35705950 genotype. We also assessed rare functional variation in TERT exons and compared telomere length and disease progression across genotypes. We assessed samples from 1510 patients with IPF and 1874 non-IPF controls. 30 (3%) of 1046 patients with an rs35705950 risk allele had a rare protein-altering variant in TERT compared with 34 (7%) of 464 non-risk allele carriers (odds ratio 0·40 [95% CI 0·24-0·66], p=0·00039). Subsequent analyses identified enrichment of rare protein-altering variants in PARN and RTEL1, and rare variation in TERC in patients with IPF compared with controls. We expanded our study population to provide a more accurate estimation of rare variant frequency in these four loci, and to calculate telomere length. The proportion of patients with at least one rare variant in TERT, PARN, TERC, or RTEL1 was higher in patients with IPF than in controls (149 [9%] of 1739 patients vs 205 [2%] of 8645 controls, p=2·44 × 10-8). Patients with IPF who had a variant in any of the four identified telomerase component genes had telomeres that were 3·69-16·10% shorter than patients without a variant in any of the four genes and had an earlier mean age of disease onset than patients without one or more variants (65·1 years [SD 7·8] vs 67·1 years [7·9], p=0·004). In the placebo arms of clinical trials, shorter telomeres were significantly associated with faster disease progression (1·7% predicted forced vital capacity per kb per year, p=0·002). Pirfenidone had treatment benefit regardless of telomere length (p=4·24 × 10-8 for telomere length lower than the median, p=0·0044 for telomere length greater than the median). Rare protein-altering variants in TERT, PARN, TERC, and RTEL1 are enriched in patients with IPF compared with controls, and, in the case of TERT, particularly in individuals without a risk allele at the rs35705950 locus. This suggests that multiple genetic factors contribute to sporadic IPF, which might implicate distinct mechanisms of pathogenesis and disease progression. Genentech, National Institutes of Health, Francis Family Foundation, Pulmonary Fibrosis Foundation, Nina Ireland Program for Lung Health, US Department of Veterans Affairs.

Placebo and nocebo effects on itch : Methodological and clinical implications

Patients often experience positive (placebo) or negative (nocebo) treatment effects due to the positive or negative expectations they have about the treatment. Placebo and nocebo effects have only relatively recently received attention for itch. Experimental studies indicate that, in line with research in other areas, such as pain, learning via verbal suggestion and conditioning plays akey role in placebo and nocebo effects on itch. Results on contagious itch emphasize the role of observational learning and suggest that itch sensations might be particularly susceptible to suggestion and therefore placebo and nocebo effects. Substantial itch reductions in the placebo arms of clinical trials suggest that placebo effects are also important for clinical practice. In this article, an overview is given of how placebo and nocebo effects on itch can optimally be used in research and for the treatment of itch.

Identifying combinatorial biomarkers by association rule mining in the CAMD Alzheimer's database

The concept of combinatorial biomarkers was conceived when it was noticed that simple biomarkers are often inadequate for recognizing and characterizing complex diseases. Here we present an algorithmic search method for complex biomarkers which may predict or indicate Alzheimer's disease (AD) and other kinds of dementia. We show that our method is universal since it can describe any Boolean function for biomarker discovery. We applied data mining techniques that are capable to uncover implication-like logical schemes with detailed quality scoring. The new SCARF program was applied for the Tucson, Arizona based Critical Path Institute's CAMD database, containing laboratory and cognitive test data for 5821 patients from the placebo arm of clinical trials of large pharmaceutical companies, and consequently, the data is much more reliable than numerous other databases for dementia. The results of our study on this larger than 5800-patient cohort suggest beneficial effects of high B12 vitamin level, negative effects of high sodium levels or high AST (aspartate aminotransferase) liver enzyme levels to cognition. As an example for a more complex and quite surprising rule: Low or normal blood glucose level with either low cholesterol or high serum sodium would also increase the probability of bad cognition with a 3.7 multiplier. The source code of the new SCARF program is publicly available at http://pitgroup.org/static/scarf.zip.

The Role of Ethnicity in Alzheimer's Disease: Findings From The C-PATH Online Data Repository.

Ethnic minorities seem to be at an increased risk of Alzheimer's disease (AD). However, little is known about ethnic differences and the risks of early onset AD (EOAD). Cognitive function changes over time and odds of EOAD by ethnicity were analyzed by the mixed model and the logistic regression. Information on demographics, self-reported co-morbidities, cognitive functions (MMSE and ADAS-COG), and ApoE genotypes were collected for 6,500 subjects with AD obtained from the placebo arm of clinical trials; this data was examined by ethnicities: Caucasian, Asian, African American, Hispanic, and other minorities--including Native Alaskans, Americans, and Hawaiians. Of the total subjects, Caucasians accounted for 89.0% , followed by 4.7% Asians, 2.7% African Americans, 2.4% Hispanics, and 1.2% Native Americans, Alaskans, and Hawaiians. Age, gender, EOAD status, co-morbidities, family history of AD, and ApoE genotypes were significantly different by ethnicity. ApoE ɛ2 allele is possibly overrepresented in the Native Americans, Africans, Hawaiians, and African Americans. A significant interaction with time, ethnicity, and cognitive performance was found, indicating more cognitive deterioration in other minorities than Caucasians for mini-mental state (p < 0.01). After adjusting for co-morbidities and gender, the odds of EOAD among African Americans (OR: 1.6, 95% CI: 1.1-2.4) and Native Alaskans, Americans, and Hispanics (OR: 2.1, 95% CI: 1.2-3.5) were significantly higher, compared with Caucasians. Ethnicity may impact AD through age of onset, co-morbidities, family history, ApoE gene status, and cognitive change over time. The greater odds of EOAD among African Americans, Alaskans, and Hawaiians suggest that some ethnicities may be at risk of AD at a younger age.

The placebo effect in thyroid cancer: a meta-analysis.

The natural history of advanced thyroid malignancies is largely unknown. The outcome of patients included in the placebo arm of clinical trials could be reflective of their therapy-free evolution. To analyze the response rate, symptoms and adverse effects of locally advanced or metastatic differentiated (DTC) and medullary thyroid cancer (MTC) in patients treated with placebo in clinical trials. PubMed (MEDLINE) and SCOPUS databases were searched through September 2015 to identify high-quality randomized controlled clinical trials. We included studies that recruited patients with DTC or MTC with a placebo arm. We conducted a meta-analysis for each category of response rate, adherence to treatment, and adverse events. An empirical Bayesian random-effect model was used. We identified five clinical trials. DTC and MTC were independently analyzed. In the placebo arm, no complete response was observed; partial response occurred in 1.6% (0.6-3) and 6.4% (3.4-10.3) of DTC and MTC respectively; stable disease was described in 40.5% (34.6-46.9) and 53.9% (44.3-64.4) of DTC and MTC respectively. DTC reached a disease control rate of 42.3% (36.2-48.9) and MTC of 60.2 (50.1-71.4). Treatment discontinuation rate was 3.5% (1.9-5.5) in DTC and 5.7% (3.0-9.4) in MTC. Rate of dose reduction was 7.3% (4.8-10.5) in DTC and 6.2% (3.3-10.0) in MTC. This meta-analysis provides extensive data on the response rate and adverse effects of locally advanced or metastatic DTC and MTC in patients treated with placebo. These results may be used for comparisons with results from clinical trials without a placebo arm.

Intravenous immune globulin: another disappointing treatment for recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) occurs in about 1% of couples attempting pregnancy. The majority of cases are unexplained and there are no treatments proven to improve outcomes in idiopathic cases. This is extremely frustrating for patients and clinicians and has led to the widespread use of therapies with uncertain efficacy. High quality data are difficult to obtain because many couples (and their physicians) are unwilling to consider randomisation to placebo arms of clinical trials. In turn, this perpetuates the use of unproven interventions. Many cases of RPL are thought to be due to abnormal inflammation in gestational tissues. Indeed, there is considerable evidence for this in animal models (Sharma. Int J Dev Biol 2014;58:219). However, clear pathophysiologic pathways in humans are lacking. Nonetheless, suppression of inflammation is a biologically plausible treatment for RPL. In this issue of BJOG, Christiansen and coworkers report the results of a randomised controlled trial of intravenous immune globulin (IVIG) and placebo in women with secondary (prior birth reaching 28 weeks’ gestation) RPL (Christiansen BJOG; 2014;122:501–9). Participants received about 0.4 mg/kg of IVIG starting with a positive pregnancy test, with repeat doses on a serial basis until 15 weeks’ gestation in ongoing pregnancies. There was no difference in live births in women treated with IVIG or placebo. The study had numerous strengths including women with at least four losses, enrollment early in gestation and only after normally rising quantitative human chorionic gonadotropins, the use of albumin as a placebo, and a relatively large number of patients. It is noteworthy that maternal side effects including skin rash and headaches were increased in women receiving IVIG. In addition, rare but serious complications of IVIG such as anaphylaxis and haemolytic anaemia may occur. Also, IVIG is quite expensive and cumbersome to receive. Accordingly, IVIG cannot be recommended for the treatment of idiopathic RPL. An interesting secondary outcome was a 10-day increase in average gestational length in pregnancies treated with IVIG. Although this finding may have been due to chance, it is possible that immunosuppression decreases the risk of preterm birth. Low dose aspirin (with anti-inflammatory properties) also has been associated with a decrease in preterm birth (Duley et al. Cochrane Database Syst Rev 2007;18:CD004659) and this observation deserves further study. Results of recent trials for the treatment of women with RPL have been disappointing. For example, low dose aspirin and heparins do not reduce the risk of pregnancy loss (Kaandorp et al. N Engl J Med 2010;362:1586). On the other hand, studies such as the one by Christiansen and colleagues are encouraging. They demonstrate that it is possible to conduct high-quality, ethical trials in women with RPL. Only through similar studies will it be possible to identify novel causes of and effective treatments for RPL. Bob Silver has no conflicts to declare.