The significance of "nonsignificance" in randomized controlled studies: a discussion inspired by a double-blinded study on St. John's Wort (Hypericum perforatum L.) for premenstrual symptoms

Objectives: This study aimed to investigate the efficacy of St. John's wort extract (SJW) as a treatment for premenstrual symptoms. Design: The study was a randomized, double-blinded, placebo-controlled trial, with two parallel treatment groups. After a no-treatment baseline cycle, volunteers were randomized to either SJW or placebo for a further two menstrual cycles. Settings/location: A postal trial conducted from The University of Reading, Berkshire, England. Subjects: One hundred and sixty-nine (169) normally menstruating women who experienced recurrent premenstrual symptoms were recruited onto the study. One hundred and twenty-five (125) completed the protocol and were included in the analysis. Interventions: Six hundred milligrams (600) mg of SJW (standardized to contain 1800 mug of hypericin) or placebo (containing lactose and cellulose). Outcome measure: A menstrual diary was used to assess changes in premenstrual symptoms. The anxiety-related subgroup of symptoms of this instrument was used as the primary outcome measure. Results: After averaging the effects of treatment over both treatment cycles it was found that there was a trend for SJW to be superior to placebo. However, this finding was not statistically significant. Conclusion: The possibility that this nonsignificant finding resulted from insufficient statistical power in the study, rather than a lack of efficacy of SJW, is discussed. Following this discussion the recommendation is made that, in future, similar studies should be powered to detect a minimum clinically relevant difference between treatments.

The significance of "nonsignificance" in randomized controlled studies: a discussion inspired by a double-blinded study on St. John's Wort (Hypericum perforatum L.) for premenstrual symptoms

Objectives: This study aimed to investigate the efficacy of St. John's wort extract (SJW) as a treatment for premenstrual symptoms. Design: The study was a randomized, double-blinded, placebo-controlled trial, with two parallel treatment groups. After a no-treatment baseline cycle, volunteers were randomized to either SJW or placebo for a further two menstrual cycles. Settings/location: A postal trial conducted from The University of Reading, Berkshire, England. Subjects: One hundred and sixty-nine (169) normally menstruating women who experienced recurrent premenstrual symptoms were recruited onto the study. One hundred and twenty-five (125) completed the protocol and were included in the analysis. Interventions: Six hundred milligrams (600) mg of SJW (standardized to contain 1800 mug of hypericin) or placebo (containing lactose and cellulose). Outcome measure: A menstrual diary was used to assess changes in premenstrual symptoms. The anxiety-related subgroup of symptoms of this instrument was used as the primary outcome measure. Results: After averaging the effects of treatment over both treatment cycles it was found that there was a trend for SJW to be superior to placebo. However, this finding was not statistically significant. Conclusion: The possibility that this nonsignificant finding resulted from insufficient statistical power in the study, rather than a lack of efficacy of SJW, is discussed. Following this discussion the recommendation is made that, in future, similar studies should be powered to detect a minimum clinically relevant difference between treatments.

Randomized controlled trial of full and brief cognitive-behaviour therapy and wait-list for paediatric obsessive-compulsive disorder

Background: Reviews and practice guidelines for paediatric obsessive-compulsive disorder (OCD) recommend cognitive-behaviour therapy (CBT) as the psychological treatment of choice, but note that it has not been sufficiently evaluated for children and adolescents and that more randomized controlled trials are needed. The aim of this trial was to evaluate effectiveness and optimal delivery of CBT, emphasizing cognitive interventions. Methods: A total of 96 children and adolescents with OCD were randomly allocated to the three conditions each of approximately 12 weeks duration: full CBT (average therapist contact: 12 sessions) and brief CBT (average contact: 5 sessions, with use of therapist-guided workbooks), and wait-list/delayed treatment. The primary outcome measure was the child version of the semi-structured interviewer-based Yale-Brown Obsessive Compulsive Scale. Clinical Trial registration: http://www.controlled-trials.com/ISRCTN/; unique identifier: ISRCTN29092580. Results: There was statistically significant symptomatic improvement in both treatment groups compared with the wait-list group, with no significant differences in outcomes between the two treatment groups. Controlled treatment effect sizes in intention-to-treat analyses were 2.2 for full CBT and 1.6 for brief CBT. Improvements were maintained at follow-up an average of 14 weeks later. Conclusions: The findings demonstrate the benefits of CBT emphasizing cognitive interventions for children and adolescents with OCD and suggest that relatively lower therapist intensity delivery with use of therapist-guided workbooks is an efficient mode of delivery.

Cognitive behaviour therapy for low self-esteem: A preliminary randomized controlled trial in a primary care setting

Background and Objectives Low self-esteem (LSE) is associated with psychiatric disorder, and is distressing and debilitating in its own right. Hence, it is frequent target for treatment in cognitive behavioural interventions, yet it has rarely been the primary focus for intervention. This paper reports on a preliminary randomized controlled trial of cognitive behaviour therapy (CBT) for LSE using Fennell’s (1997) cognitive conceptualisation and transdiagnostic treatment approach ( [Fennell, 1997] and [Fennell, 1999]). Methods Twenty-two participants were randomly allocated to either immediate treatment (IT) (n = 11) or to a waitlist condition (WL) (n = 11). Treatment consisted of 10 sessions of individual CBT accompanied by workbooks. Participants allocated to the WL condition received the CBT intervention once the waitlist period was completed and all participants were followed up 11 weeks after completing CBT. Results The IT group showed significantly better functioning than the WL group on measures of LSE, overall functioning and depression and had fewer psychiatric diagnoses at the end of treatment. The WL group showed the same pattern of response to CBT as the group who had received CBT immediately. All treatment gains were maintained at follow-up assessment. Limitations The sample size is small and consists mainly of women with a high level of educational attainment and the follow-up period was relatively short. Conclusions These preliminary findings suggest that a focused, brief CBT intervention can be effective in treating LSE and associated symptoms and diagnoses in a clinically representative group of individuals with a range of different and co-morbid disorders.

Energy compensation following consumption of sugar-reduced products: a randomized controlled trial

PURPOSE: Consumption of sugar-reformulated products (commercially available foods and beverages that have been reduced in sugar content through reformulation) is a potential strategy for lowering sugar intake at a population level. The impact of sugar-reformulated products on body weight, energy balance (EB) dynamics and cardiovascular disease risk indicators has yet to be established. The REFORMulated foods (REFORM) study examined the impact of an 8-week sugar-reformulated product exchange on body weight, EB dynamics, blood pressure, arterial stiffness, glycemia and lipemia. METHODS: A randomized, controlled, double-blind, crossover dietary intervention study was performed with fifty healthy normal to overweight men and women (age 32.0 ± 9.8 year, BMI 23.5 ± 3.0 kg/m2) who were randomly assigned to consume either regular sugar or sugar-reduced foods and beverages for 8 weeks, separated by 4-week washout period. Body weight, energy intake (EI), energy expenditure and vascular markers were assessed at baseline and after both interventions. RESULTS: We found that carbohydrate (P < 0.001), total sugars (P < 0.001) and non-milk extrinsic sugars (P < 0.001) (% EI) were lower, whereas fat (P = 0.001) and protein (P = 0.038) intakes (% EI) were higher on the sugar-reduced than the regular diet. No effects on body weight, blood pressure, arterial stiffness, fasting glycemia or lipemia were observed. CONCLUSIONS: Consumption of sugar-reduced products, as part of a blinded dietary exchange for an 8-week period, resulted in a significant reduction in sugar intake. Body weight did not change significantly, which we propose was due to energy compensation.

The effect of selective decontamination of the digestive tract on mortality in multiple trauma patients: a multicenter randomized controlled trial

Objective: Evaluation of selective decontamination of the digestive tract (SDD) on late mortality in ventilated trauma patients in an intensive care unit (ICU). Methods: A multicenter, randomized controlled trial was undertaken in 401 trauma patients with Hospital Trauma Index-Injury Severity Score of 16 or higher. Patients were randomized to control (n = 200) or SDD (n = 201), using polymyxin E, tobramycin, and amphotericin B in throat and gut throughout ICU treatment combined with cefotaxime for 4 days. Primary endpoint was late mortality excluding early death from hemorrhage or craniocerebral injury. Secondary endpoints were infection and organ dysfunction. Results: Mortality was 20.9% with SDD and 22.0% in controls. Overall late mortality was 15.3% (57/372) as 29 patients died from cerebral injury, 16 SDD and 13 control. The odds ratio (95% confidence intervals) of late mortality for SDD relative to control was 0.75 (0.40-1.37), corresponding to estimates of 13.4% SDD and 17.2% control. The overall infection rate was reduced in the test group (48.8% vs. 61.0%). SDD reduced lower airway infections (30.9% vs. 50.0%) and bloodstream infections due to aerobic Gram-negative bacilli (2.5% vs. 7.5%). No difference in organ dysfunction was found. Concluson: This study demonstrates that SDD significantly reduces infection in multiple trauma, although this RCT in 401 patients was underpowered to detect a mortality benefit.

Flavonoids and cognitive function: a review of human randomized controlled trial studies and recommendations for future studies

Evidence in support of the neuroprotective effects of flavonoids has increased significantly in recent years, although to date much of this evidence has emerged from animal rather than human studies. Nonetheless, with a view to making recommendations for future good practice, we review 15 existing human dietary intervention studies that have examined the effects of particular types of flavonoid on cognitive performance. The studies employed a total of 55 different cognitive tests covering a broad range of cognitive domains. Most studies incorporated at least one measure of executive function/working memory, with nine reporting significant improvements in performance as a function of flavonoid supplementation compared to a control group. However, some domains were overlooked completely (e.g. implicit memory, prospective memory), and for the most part there was little consistency in terms of the particular cognitive tests used making across study comparisons difficult. Furthermore, there was some confusion concerning what aspects of cognitive function particular tests were actually measuring. Overall, while initial results are encouraging, future studies need to pay careful attention when selecting cognitive measures, especially in terms of ensuring that tasks are actually sensitive enough to detect treatment effects.

A double-blind, randomized, controlled crossover trial of glutamine supplementation in home parenteral nutrition

Objective: Studies suggest clinical benefit of glutamine-supplemented parenteral nutrition. The aim was to determine if the inclusion of 10 g of glutamine as part of the nitrogen source of home parenteral nutrition (HPN) reduces infectious complications. Subjects/Methods: Thirty-five patients on HPN were recruited and 22 completed the study. Patients were randomized to receive either standard HPN or glutamine-supplemented HPN. Patients were assessed at randomization, 3 and 6 months later then they were crossed over to the alternative HPN and reassessed at 3 and 6 months. Assessments included plasma amino acid concentrations, intestinal permeability and absorption, nutritional status, oral and parenteral intake, quality of life, routine biochemistry and haematology. Results: No difference was seen between the groups at randomization. No difference was detected between the treatment phases for infective complications (55% in the standard treatment phase and 36% in the glutamine-supplemented phase P 0.67). There were no differences in nutritional status, intestinal permeability, plasma glutamine concentrations or quality of life. Conclusion: Although limited by the sample size, the study has shown that glutamine as part of the nitrogen source of parenteral nutrition can be given to patients on HPN for 6 months without any adverse effects.

Can a short period of micronutrient supplementation in older institutionalized people improve response to influenza vaccine? A randomized, controlled trial

OBJECTIVES: To test the hypothesis that a micronutrient supplement can improve seroconversion after influenza immunization in older institutionalized people. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Nursing and residential homes in Liverpool, United Kingdom. PARTICIPANTS: One hundred sixty-four residents aged 60 and older from 31 homes were initially randomized; of these, 119 (72.6%) completed the study. INTERVENTION: Participants were randomized to receive a micronutrient supplement providing the reference nutrient intake for all vitamins and trace elements or identical placebo. Tablets were taken over an 8-week period during September and October 2000; influenza vaccine was administered 4 weeks after their commencement. MEASUREMENTS: The hemagglutination-inhibiting antibody response as defined by a fourfold or greater titer rise over 4 weeks and assessed separately for each of the three antigens contained in the 2000/2001 influenza vaccine (A/New Caledonia/20/99 (H1N1), A/Moscow/10/99 (H3N2), B/Beijing/184/93 (B)). RESULTS: Despite a significant increase in serum concentrations of vitamins A, C, D-3, E, folate, and selenium in the supplemented group, there was no significant difference between groups (supplemented vs placebo, respectively) in the proportion of participants seroconverting to H1N1 (41% vs 49%, P=.374), H3N2 (49% vs 58%, P=.343), or B (41% vs 40%, P=.944). CONCLUSION: A micronutrient supplement providing the reference nutrient intake administered over 8 weeks had no beneficial effect on antibody response to influenza vaccine in older people living in long-term care.

Prebiotic evaluation of cocoa-derived flavanols in healthy humans by using a randomized, controlled, double-blind, crossover intervention study

BACKGROUND: The absorption of cocoa flavanols in the small intestine is limited, and the majority of the flavanols reach the large intestine where they may be metabolized by resident microbiota. OBJECTIVE: We assessed the prebiotic potential of cocoa flavanols in a randomized, double-blind, crossover, controlled intervention study. DESIGN: Twenty-two healthy human volunteers were randomly assigned to either a high-cocoa flavanol (HCF) group (494 mg cocoa flavanols/d) or a low-cocoa flavanol (LCF) group (23 mg cocoa flavanols/d) for 4 wk. This was followed by a 4-wk washout period before volunteers crossed to the alternant arm. Fecal samples were recovered before and after each intervention, and bacterial numbers were measured by fluorescence in situ hybridization. A number of other biochemical and physiologic markers were measured. RESULTS: Compared with the consumption of the LCF drink, the daily consumption of the HCF drink for 4 wk significantly increased the bifidobacterial (P < 0.01) and lactobacilli (P < 0.001) populations but significantly decreased clostridia counts (P < 0.001). These microbial changes were paralleled by significant reductions in plasma triacylglycerol (P < 0.05) and C-reactive protein (P < 0.05) concentrations. Furthermore, changes in C-reactive protein concentrations were linked to changes in lactobacilli counts (P < 0.05, R(2) = -0.33 for the model). These in vivo changes were closely paralleled by cocoa flavanol-induced bacterial changes in mixed-batch culture experiments. CONCLUSION: This study shows, for the first time to our knowledge, that consumption of cocoa flavanols can significantly affect the growth of select gut microflora in humans, which suggests the potential prebiotic benefits associated with the dietary inclusion of flavanol-rich foods. This trial was registered at clinicaltrials.gov as NCT01091922.

Acute ingestion of beetroot bread increases endothelium-independent vasodilation and lowers diastolic blood pressure in healthy men: a randomized controlled trial

Dietary nitrate, from beetroot, has been reported to lower blood pressure (BP) by the sequential reduction of nitrate to nitrite and further to NO in the circulation. However, the impact of beetroot on microvascular vasodilation and arterial stiffness is unknown. In addition, beetroot is consumed by only 4.5% of the UK population, whereas bread is a staple component of the diet. Thus, we investigated the acute effects of beetroot bread (BB) on microvascular vasodilation, arterial stiffness, and BP in healthy participants. Twenty-three healthy men received 200 g bread containing 100 g beetroot (1.1 mmol nitrate) or 200 g control white bread (CB; 0 g beetroot, 0.01 mmol nitrate) in an acute, randomized, open-label, controlled crossover trial. The primary outcome was postprandial microvascular vasodilation measured by laser Doppler iontophoresis and the secondary outcomes were arterial stiffness measured by Pulse Wave Analysis and Velocity and ambulatory BP measured at regular intervals for a total period of 6 h. Plasma nitrate and nitrite were measured at regular intervals for a total period of 7 h. The incremental area under the curve (0-6 h after ingestion of bread) for endothelium-independent vasodilation was greater (P = 0.017) and lower for diastolic BP (DBP; P = 0.032) but not systolic (P = 0.99) BP after BB compared with CB. These effects occurred in conjunction with increases in plasma and urinary nitrate (P < 0.0001) and nitrite (P < 0.001). BB acutely increased endothelium-independent vasodilation and decreased DBP. Therefore, enriching bread with beetroot may be a suitable vehicle to increase intakes of cardioprotective beetroot in the diet and may provide new therapeutic perspectives in the management of hypertension.

Randomized controlled trial of parent-enhanced CBT compared with individual CBT for obsessive-compulsive disorder in young people

Objective: Obsessive-compulsive disorder (OCD) in young people can be effectively treated with Cognitive Behavior Therapy (CBT). Practice guidelines in the United Kingdom recommend that CBT be delivered with parental or family involvement; however, there is no evidence from randomized trials that this enhances effectiveness. The aim of this trial was to assess if CBT with high parental involvement was more effective than CBT with low parental involvement (individual CBT) in reducing symptoms of OCD. Method: Fifty young people ages 12–17 years with OCD were randomly allocated to individual CBT or parent-enhanced CBT. In parent-enhanced CBT parents attended all treatment sessions; in individual CBT, parents attended only Sessions 1, 7, and the final session. Participants received up to 14 sessions of CBT. Data were analyzed using intent-to-treat and per-protocol methods. The primary outcome measure was the Children’s Yale-Brown Obsessive Compulsion Scale (Scahill et al., 1997). Results: Both forms of CBT significantly reduced symptoms of OCD and anxiety. Change in OCD symptoms was maintained at 6 months. Per-protocol analysis suggested that parent-enhanced CBT may be associated with significantly larger reductions in anxiety symptoms. Conclusions: High and low parental involvement in CBT for OCD in young people were both effective, and there was no evidence that 1 method of delivery was superior on the primary outcome measure. However, this study was small. Future trials should be adequately powered and examine interactions with the age of the young person and comorbid anxiety disorders.

Magnetic resonance imaging of a randomized controlled trial investigating predictors of recovery following psychological treatment in adolescents with moderate to severe unipolar depression: study protocol for Magnetic Resonance - Improving Mood with Psychoanalytic and Cognitive Therapies (MR-IMPACT)

Background Major depressive disorders (MDD) are a debilitating and pervasive group of mental illnesses afflicting many millions of people resulting in the loss of 110 million working days and more than 2,500 suicides per annum. Adolescent MDD patients attending NHS clinics show high rates of recurrence into adult life. A meta-analysis of recent research shows that psychological treatments are not as efficacious as previously thought. Modest treatment outcomes of approximately 65% of cases responding suggest that aetiological and clinical heterogeneity may hamper the better use of existing therapies and discovery of more effective treatments. Information with respect to optimal treatment choice for individuals is lacking, with no validated biomarkers to aid therapeutic decision-making. Methods/Design Magnetic resonance-Improving Mood with Psychoanalytic and Cognitive Therapies, the MR-IMPACT study, plans to identify brain regions implicated in the pathophysiology of depressions and examine whether there are specific behavioural or neural markers predicting remission and/or subsequent relapse in a subsample of depressed adolescents recruited to the IMPACT randomised controlled trial (Registration # ISRCTN83033550). Discussion MR-IMPACT is an investigative biomarker component of the IMPACT pragmatic effectiveness trial. The aim of this investigation is to identify neural markers and regional indicators of the pathophysiology of and treatment response for MDD in adolescents. We anticipate that these data may enable more targeted treatment delivery by identifying those patients who may be optimal candidates for therapeutic response.

Flavonoid-rich fruits and vegetables improve microvascular reactivity and inflammatory status in men at risk of cardiovascular disease – FLAVURS: a randomized controlled trial

BACKGROUND: Observed associations between increased fruit and vegetable (F&V) consumption, particularly those F&Vs that are rich in flavonoids, and vascular health improvements require confirmation in adequately powered randomized controlled trials. OBJECTIVE: This study was designed to measure the dose-response relation between high-flavonoid (HF), low-flavonoid (LF), and habitual F&V intakes and vascular function and other cardiovascular disease (CVD) risk indicators. DESIGN: A single-blind, dose-dependent, parallel randomized controlled dietary intervention study was conducted. Male and female low-F&V consumers who had a ≥1.5-fold increased risk of CVD (n = 174) were randomly assigned to receive an HF F&V, an LF F&V, or a habitual diet, with HF and LF F&V amounts sequentially increasing by 2, 4, and 6 (+2, +4, and +6) portions/d every 6 wk over habitual intakes. Microvascular reactivity (laser Doppler imaging with iontophoresis), arterial stiffness [pulse wave velocity, pulse wave analysis (PWA)], 24-h ambulatory blood pressure, and biomarkers of nitric oxide (NO), vascular function, and inflammation were determined at baseline and at 6, 12, and 18 wk. RESULTS: In men, the HF F&V diet increased endothelium-dependent microvascular reactivity (P = 0.017) with +2 portions/d (at 6 wk) and reduced C-reactive protein (P = 0.001), E-selectin (P = 0.0005), and vascular cell adhesion molecule (P = 0.0468) with +4 portions/d (at 12 wk). HF F&Vs increased plasma NO (P = 0.0243) with +4 portions/d (at 12 wk) in the group as a whole. An increase in F&Vs, regardless of flavonoid content in the groups as a whole, mitigated increases in vascular stiffness measured by PWA (P = 0.0065) and reductions in NO (P = 0.0299) in the control group. CONCLUSION: These data support recommendations to increase F&V intake to ≥6 portions daily, with additional benefit from F&Vs that are rich in flavonoids, particularly in men with an increased risk of CVD. This trial was registered at www.controlled-trials.com as ISRCTN47748735.

Apolipoprotein e genotype has a modest impact on the postprandial plasma response to meals of varying fat composition in healthy men in a randomized controlled trial

BACKGROUND:Apolioprotein E (APOE) genotype is reported to influence a person's fasting lipid profile and potentially the response to dietary fat manipulation. The impact of APOE genotype on the responsiveness to meals of varying fat composition is unknown. OBJECTIVE:We examined the effect of meals containing 50 g of fat rich in saturated fatty acids (SFAs), unsaturated fatty acids (UNSATs), or SFAs with fish oil (SFA-FO) on postprandial lipemia. METHOD:A randomized, controlled, test meal study was performed in men recruited according to the APOE genotype (n = 10 APOE3/3, n = 11 APOE3/E4). RESULTS:For the serum apoE response (meal × genotype interaction P = 0.038), concentrations were on average 8% lower after the UNSAT than the SFA-FO meal in APOE4 carriers (P = 0.015) only. In the genotype groups combined, there was a delay in the time to reach maximum triacylglycerol (TG) concentration (mean ± SEM: 313 ± 25 vs. 266 ± 27 min) and higher maximum nonesterified fatty acid (0.73 ± 0.05 vs. 0.60 ± 0.03 mmol/L) and glucose (7.92 ± 0.22 vs. 7.25 ± 0.22 mmol/L) concentrations after the SFA than the UNSAT meal, respectively (P ≤ 0.05). In the Svedberg flotation rate 60-400 TG-rich lipoprotein fraction, meal × genotype interactions were observed for incremental area under the curve (IAUC) for the TG (P = 0.038) and apoE (P = 0.016) responses with a 58% lower apoE IAUC after the UNSAT than the SFA meal (P = 0.017) in the E4 carriers. CONCLUSIONS:Our data indicate that APOE genotype had a modest impact on the postprandial response to meals of varying fat composition in normolipidemic men. The physiologic importance of greater apoE concentrations after the SFA-rich meals in APOE4 carriers may reflect an impact on TG-rich lipoprotein clearance from the circulation. This trial was registered at clinicaltrials.gov as NCT01522482.