Acute response to cholinergic challenge predicts long-term response to galantamine treatment in patients with Alzheimer's disease.

AIMS: Cholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer's disease (AD) patients, but are associated with multiple side effects and only 20-40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of administration of a single dose of galantamine on central nervous system (CNS) functioning in mild to moderate AD patients and its potential to predict long-term treatment response. METHODS: This study consisted of a challenge and treatment phase. In the challenge phase, a single dose of 16 mg galantamine was administered to 50 mild to moderate AD patients in a double-blind, placebo-controlled cross-over fashion. Acute PD effects were monitored up to 5 hours after administration with use of the NeuroCart CNS test battery and safety and pharmacokinetics were assessed. In the treatment phase, patients were treated with open-label galantamine according to regular clinical care. After 6 months of galantamine treatment, patients were categorized as either responder or as non-responder based on their minimental state examination (MMSE), neuropsychiatric inventory (NPI) and disability assessment in dementia (DAD) scores. An analysis of covariance was performed to study the difference in acute PD effects during the challenge phase between responders and non-responders. RESULTS: A single dose of galantamine significantly reduced saccadic reaction time (-0.0099; 95% CI = -0.0195, -0.0003; P = .0430), absolute frontal EEG parameters in alpha (-14.9; 95% CI = -21.0, -8.3; P = .0002), beta (-12.6; 95% CI = -19.4, -5.3; P = .0019) and theta (-17.9; 95% CI = -25.0, -10.0; P = .0001) frequencies. Relative frontal (-1.669; 95% CI = -2.999, -0.339; P = .0156) and occipital (-1.856; 95% CI = -3.339, -0.372; P = .0166) EEG power in theta frequency and relative occipital EEG power in the gamma frequency (1.316; 95% CI = 0.158, 2.475; P = .0273) also increased significantly compared to placebo. Acute decreases of absolute frontal alpha (-20.4; 95% CI = -31.6, -7.47; P = .0046), beta (-15.7; 95% CI = -28.3, -0.93; P = .0390) and theta (-25.9; 95% CI = -38.4, -10.9; P = .0024) EEG parameters and of relative frontal theta power (-3.27%; 95% CI = -5.96, -0.58; P = .0187) on EEG significantly distinguished responders (n = 11) from non-responders (n = 32) after 6 months. CONCLUSIONS: This study demonstrates that acute PD effects after single dose of galantamine are correlated with long-term treatment effects and that patients who demonstrate a reduction in EEG power in the alpha and theta frequency after a single administration of galantamine 16 mg will most likely respond to treatment.

Safety, tolerability and pharmacokinetic characterisation of DACRA KBP-042 in healthy male subjects.

There is a need for antidiabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was (a) to evaluate safety and tolerability, (b) to evaluate pharmacokinetics and (c) to assess indications of receptor engagement of single ascending doses of KBP-042, a dual amylin and calcitonin receptor agonist (DACRA) that has shown promising preclinical data, with superior activity in terms of typical amylin-induced responses including reduction of food intake, weight loss and gluco-regulatory capacities. A randomised double-blind placebo-controlled single ascending dose study was performed with six dose levels of KBP-042 (5, 7.5, 10, 20, 20 (evening), 40 ug) in healthy male adults. KBP-042 or placebo was administered as a single dose after an overnight fast, followed by a standardized lunch after 4 hours. KBP-042 was associated with dose-dependent complaints of nausea and vomiting, with a lack of tolerability at doses of 20 µg and above. Doses of 5-40 µg KBP-042 behaved according to a linear pharmacokinetic profile. Indications of target receptor engagement were observed at the level of glucose control and lowering of bone resorption, compared to placebo. The results of this study showed that doses up to 40 µg were safe, although tolerability was not present at the highest doses. The study confirmed target receptor engagement at the studied doses.

Proof of pharmacology of Org 48775-0, a p38 MAP kinase inhibitor, in healthy volunteers.

AIM: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of the highly selective oral p38alpha/beta mitogen-activated protein (MAP) kinase inhibitor Org 48,775-0 in a first-in-human study. METHODS: In the single ascending dosing (SAD) study, an oral dose of Org 48,775-0 (0.3-600 mg) was evaluated in healthy males. In the multiple ascending dosing (MAD) study, levels of 30, 70 and 150 mg were dosed for six consecutive days, twice daily. Both studies were performed in a double-blind, randomized, placebo-controlled, cross-over fashion and evaluated pharmacokinetics, pharmacodynamics (ex vivo inhibition of lipopolysaccharide [LPS]-induced tumor necrosis factor (TNFα) release) and routine clinical and laboratory data. Pharmacokinetic and pharmacodynamic parameters of Org 48,775-0 were compared between healthy males and postmenopausal females, and the effect of a standardized fat meal was evaluated. RESULTS: All adverse events observed in the SAD (16; dizziness and headache, diarrhoea and catheter-related phlebitis) and MAD (43; mainly somnolence, dizziness, headache and nasopharyngitis) cohorts were mild, transient and completely reversible. Pharmacokinetics were linear up to single doses of 400 mg. Median Tmax ranged from 0.5 to 1.8 hours, geometric mean for T1/2 from 7.0 to 14.4 hours. Org 48,775-0 doses equal to and greater than 30 mg significantly inhibited LPS-induced TNFα release (42.3%; 95% CI = -65.2, -4.3) compared to placebo. In the MAD study, Org 48,775-0 treatment inhibited LPS-induced TNFα release during the entire steady-state period. Levels of inhibition amounted 30-75% for 30 mg, 53-80% for 70 mg and 77-92% for 150 mg Org 48,775-0. CONCLUSION: Org 48,775-0 has the capacity to significantly inhibit MAP kinase activity in humans without safety concerns.

Clinical trial simulations of the interaction between cannabidiol and clobazam and effect on drop-seizure frequency.

With this study, we aim to test the hypothesis that the effect of cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome and Dravet syndrome could be attributed to a drug-drug interaction with clobazam. We performed clinical trial simulations for the effect of 20 mg/kg/day cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome. We assumed that patients taking 10 or 20 mg clobazam would have a 2- to 7-fold increase in N-desmethylclobazam exposure, whereas patients not taking clobazam would have a median reduction in drop-seizure frequency and a variability in the percent reduction similar to the placebo group. The results show that the effect of cannabidiol on the median reduction in drop-seizure frequency in patients with Lennox-Gastaut syndrome may be explained by a drug-drug interaction with clobazam. This may have important implications for the use of cannabidiol and its Food and Drug Administration registration.

No synergistic effect of subtherapeutic doses of donepezil and EVP-6124 in healthy elderly subjects in a scopolamine challenge model.

INTRODUCTION: Donepezil is a widely used cholinesterase inhibitor in the management of Alzheimer's disease. Despite large-scaled evidence for its efficacy, elevated peripheral ACh levels often lead to side effects and are dose limiting. The present exploratory study is designed to determine the potentiation of the effects of donepezil by cotreatment with EVP-6124, an alpha-7 nicotinic agonist, to reduce scopolamine-induced cognitive deficits in healthy elderly subjects. Secondary objectives are to explore safety and pharmacokinetic and pharmacodynamics effects of EVP-6124 alone and in combination with donepezil compared to placebo. METHODS: A phase I randomized, single-center, placebo-controlled, double-blind, five-way, partial crossover study was performed with donepezil 2.5, 5 mg or placebo combined with EVP-6124 0.3, 1, 2, 4 mg or placebo in three cohorts of healthy elderly subjects in a scopolamine (0.3 mg i.v.) challenge test. Safety, pharmacokinetic, and pharmacodynamics outcomes were assessed. RESULTS: A total of 36 subjects completed the study. Donepezil pharmacokinetic parameters were similar with and without EVP-6124. Effective dose combinations were donepezil/EVP-6124(5/2 mg) and donepezil/EVP-6124 (5/0.3 mg) and showed improvements of the delayed recall of the Visual Verbal Learning Test (1.2; CI = 0.1-2.3) and reaction time during the two-back condition of the N-back (-42; CI = -77, -8), respectively. Overall, no marked reversal of scopolamine effects was observed. DISCUSSION: This study shows no synergistic effect of subtherapeutic doses of donepezil and EVP-6124 in a scopolamine challenge model in healthy elderly subjects. Dosing of scopolamine and the combination of donepezil and EVP-6124 requires further study.

Cost-effectiveness of healthy eating and/or physical activity promotion in pregnant women at increased risk of gestational diabetes mellitus: economic evaluation alongside the DALI study, a European multicenter randomized controlled trial.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with perinatal health risks to both mother and offspring, and represents a large economic burden. The DALI study is a multicenter randomized controlled trial, undertaken to add to the knowledge base on the effectiveness of interventions for pregnant women at increased risk for GDM. The purpose of this study was to evaluate the cost-effectiveness of the healthy eating and/or physical activity promotion intervention compared to usual care among pregnant women at increased risk of GDM from a societal perspective. METHODS: An economic evaluation was performed alongside a European multicenter-randomized controlled trial. A total of 435 pregnant women at increased risk of GDM in primary and secondary care settings in nine European countries, were recruited and randomly allocated to a healthy eating and physical activity promotion intervention (HE + PA intervention), a healthy eating promotion intervention (HE intervention), or a physical activity promotion intervention (PA intervention). Main outcome measures were gestational weight gain, fasting glucose, insulin resistance (HOMA-IR), quality adjusted life years (QALYs), and societal costs. RESULTS: Between-group total cost and effect differences were not significant, besides significantly less gestational weight gain in the HE + PA group compared with the usual care group at 35-37 weeks (-2.3;95%CI:-3.7;-0.9). Cost-effectiveness acceptability curves indicated that the HE + PA intervention was the preferred intervention strategy. At 35-37 weeks, it depends on the decision-makers' willingness to pay per kilogram reduction in gestational weight gain whether the HE + PA intervention is cost-effective for gestational weight gain, whereas it was not cost-effective for fasting glucose and HOMA-IR. After delivery, the HE + PA intervention was cost-effective for QALYs, which was predominantly caused by a large reduction in delivery-related costs. CONCLUSIONS: Healthy eating and physical activity promotion was found to be the preferred strategy for limiting gestational weight gain. As this intervention was cost-effective for QALYs after delivery, this study lends support for broad implementation. TRIAL REGISTRATION: ISRCTN ISRCTN70595832 . Registered 2 December 2011.

External validity of randomized controlled trials in older adults, a systematic review.

BACKGROUND: To critically assess the external validity of randomized controlled trials (RCTs) it is important to know what older adults have been enrolled in the trials. The aim of this systematic review is to study what proportion of trials specifically designed for older patients report on somatic status, physical and mental functioning, social environment and frailty in the patient characteristics. METHODS: PubMed was searched for articles published in 2012 and only RCTs were included. Articles were further excluded if not conducted with humans or only secondary analyses were reported. A random sample of 10% was drawn. The current review analyzed this random sample and further selected trials when the reported mean age was ≥ 60 years. We extracted geriatric assessments from the population descriptives or the in- and exclusion criteria. RESULTS: In total 1396 trials were analyzed and 300 trials included. The median of the reported mean age was 66 (IQR 63-70) and the median percentage of men in the trials was 60 (IQR 45-72). In 34% of the RCTs specifically designed for older patients somatic status, physical and mental functioning, social environment or frailty were reported in the population descriptives or the in- and exclusion criteria. Physical and mental functioning was reported most frequently (22% and 14%). When selecting RCTs on a mean age of 70 or 80 years the report of geriatric assessments in the patient characteristics was 46% and 85% respectively but represent only 5% and 1% of the trials. CONCLUSION: Somatic status, physical and mental functioning, social environment and frailty are underreported even in RCTs specifically designed for older patients published in 2012. Therefore, it is unclear for clinicians to which older patients the results can be applied. We recommend systematic to transparently report these relevant characteristics of older participants included in RCTs.

An Internet-Based Physical Activity Intervention to Improve Quality of Life of Inactive Older Adults: A Randomized Controlled Trial.

BACKGROUND: Increasing physical activity is a viable strategy for improving both the health and quality of life of older adults. OBJECTIVE: The aim of this study was to assess if an Internet-based intervention aimed to increase physical activity was effective in improving quality of life of inactive older adults. In addition, we analyzed the effect of the intervention on quality of life among those participants who successfully reached their individually targeted increase in daily physical activity as indicated by the intervention program, as well as the dose-response effect of increasing physical activity on quality of life. METHODS: The intervention was tested in a randomized controlled trial and was comprised of an Internet program-DirectLife (Philips)-aimed at increasing physical activity using monitoring and feedback by accelerometry and feedback by digital coaching (n=119). The control group received no intervention (n=116). Participants were inactive 60-70-year-olds and were recruited from the general population. Quality of life and physical activity were measured at baseline and after 3 months using the Research ANd Development 36-item health survey (RAND-36) and wrist-worn triaxial accelerometer, respectively. RESULTS: After 3 months, a significant improvement in quality of life was seen in the intervention group compared to the control group for RAND-36 subscales on emotional and mental health (2.52 vs -0.72, respectively; P=.03) and health change (8.99 vs 2.03, respectively; P=.01). A total of 50 of the 119 participants (42.0%) in the intervention group successfully reached their physical activity target and showed a significant improvement in quality of life compared to the control group for subscales on emotional and mental health (4.31 vs -0.72, respectively; P=.009) and health change (11.06 vs 2.03, respectively; P=.004). The dose-response analysis showed that there was a significant association between increase in minutes spent in moderate-to-vigorous physical activity (MVPA) and increase in quality of life. CONCLUSIONS: Our study shows that an Internet-based physical activity program was effective in improving quality of life in 60-70-year-olds after 3 months, particularly in participants that reached their individually targeted increase in daily physical activity. TRIAL REGISTRATION: Nederlands Trial Register: NTR 3045; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3045 (Archived by WebCite at http://www.webcitation.org/6fobg2sjJ).

An economic evaluation alongside a randomized controlled trial evaluating an individually tailored lifestyle intervention compared with usual care in people with familial hypercholesterolemia.

BACKGROUND: Cost-effectiveness analyses provide insight in the use of lifestyle interventions. To evaluate the cost-effectiveness of a lifestyle intervention compared to usual care in people with Familial Hypercholesterolemia, 340 people with FH were randomized to the intervention or control group. LDL cholesterol, quality of life and costs were measured at 0 and 12 months. Cost-effectiveness analyses were performed from a healthcare perspective using bootstrapping techniques. RESULTS: Non-significant decreases in LDL cholesterol and quality of life were found. The mean between-group difference in costs was €-237 (95% CI -1,386 to 130). The incremental cost-effectiveness ratios were 1,729 per 1 mmol/l LDL cholesterol and 145,899 per QALY gained. Assumed that the small non-significant decrease in LDL cholesterol is attributed to the intervention, the probability of cost-effectiveness of the intervention compared to usual care was 91% per 1 mmol/l LDL cholesterol reduction and 75% per QALY gained at a ceiling ratio of €20,000. CONCLUSIONS: The intervention is not cost-effective. TRIAL REGISTRATION: NTR1899, date 07-07-2009.

Characteristics of randomized controlled trials designed for elderly: a systematic review.

OBJECTIVES: To quantify the proportion of randomized controlled trials (RCTs) specifically designed for elderly, and to assess their characteristics, as compared to RCTs not specifically designed for elderly. DESIGN: Review and synthesis of published literature. MEASUREMENTS: We searched PubMed for articles published in the year 2012. We included RCTs. Articles were excluded if not conducted with human subjects or if findings of secondary analyses were reported. A random sample of 10% was drawn and of this selection the following trial characteristics were extracted: sample size, disease category, age of sample, and age-related inclusion criteria. Clinical trials were defined to be specifically designed for elderly if a lower age cut-off of ≥ 55 years was used, or when participants had an average age of ≥ 70 years. RESULTS: The search strategy yielded 26,740 articles, from which a random sample was drawn, resulting in 2375 articles. After exclusion, data was extracted from 1369 publications. Of these 1369 RCTs, 96 (7%) were specifically designed for elderly. In comparison with trials not designed for older adults, trials designed for elderly contained a significantly larger median number of participants (125 vs. 80, p = 0.008) significantly more trials designed for elderly fell into the disease categories eye (6% vs. 2%, p = 0.005), musculoskeletal (13% vs. 7%, p = 0.023) and circulatory system (16% vs. 9%, p = 0.039). No significant difference was observed with regard to the other disease categories. CONCLUSION: There is a low proportion of RCTs specifically designed for elderly. As older patients will increasingly form the majority in medical practice, there is an urgent need for stronger evidence for the formulation of treatment guidelines specifically for older adults.

Dose-response effects of a Web-based physical activity program on body composition and metabolic health in inactive older adults: additional analyses of a randomized controlled trial.

BACKGROUND: Low physical activity is a major risk factor for several age-related diseases. Recently, we showed in a randomized controlled trial that a 12-week Web-based intervention (Philips DirectLife) to increase physical activity was effective in increasing physical activity levels and metabolic health in an inactive population aged 60-70 years. OBJECTIVE: The goal of this paper was to assess how many participants successfully reached the physical activity level as targeted by the intervention and what the effects of the intervention on body composition and metabolic health in these successful individuals were to provide insight in the maximum attainable effect of the intervention. METHODS: Among the 235 participants in a randomized controlled trial of the Actief en Gezond Oud (AGO) study, we assessed the effects of the intervention on metabolic parameters in those who had successfully reached their personalized physical activity target compared with the entire intervention group. Furthermore, we studied the dose-response effect of increase in physical activity on metabolic outcome within the intervention group. RESULTS: Of the intervention group, 50 of 119 (42.0%) participants successfully reached the physical activity target (corresponding to a 10% increased daily physical activity on average). This group showed markedly higher effects of the intervention compared to the entire intervention group, with greater decreases in body weight (2.74 vs 1.49 kg), waist circumference (3.74 vs 2.33 cm), insulin resistance (HOMA index: 0.23 vs 0.20), and in cholesterol/HDL ratio (0.39 vs 0.20) and Framingham risk score (0.90% vs 0.54%). We found that men compared to women were more likely to be successful. The dose-response analysis showed that there was a significant association between increase in minutes spent in moderate-to-vigorous activity and body weight loss, BMI reduction, waist circumference reduction, HDL cholesterol increasing, and cholesterol/HDL ratio lowering. CONCLUSIONS: Of the intervention group, 42.0% (50/119) reached their daily physical activity end goal, which was associated with a markedly better effect on body composition and metabolic health compared to the effect in the entire intervention group. In this population, men are more likely to be successful in increasing physical activity. Findings demonstrate that improving the effect of such physical activity interventions requires finding new ways to increase the proportion of the population reaching the targeted goal. TRIAL REGISTRATION: Dutch Trial Registry: NTR 3045; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3045 (Archived by WebCite at http://www.webcitation.org/6KPw52dCc).

The value of (pre)school playgrounds for children's physical activity level: a systematic review.

The (pre)school environment is an important setting to improve children's health. Especially, the (pre)school playground provides a major opportunity to intervene. This review presents an overview of the existing evidence on the value of both school and preschool playgrounds on children's health in terms of physical activity, cognitive and social outcomes. In addition, we aimed to identify which playground characteristics are the strongest correlates of beneficial effects and for which subgroups of children effects are most distinct. In total, 13 experimental and 17 observational studies have been summarized of which 10 (77%) and 16 (94%) demonstrated moderate to high methodological quality, respectively. Nearly all experimental studies (n = 11) evaluated intervention effects on time spent in different levels of physical activity during recess. Research on the effects of (pre)school playgrounds on cognitive and social outcomes is scarce (n = 2). The experimental studies generated moderate evidence for an effect of the provision of play equipment, inconclusive evidence for an effect of the use of playground markings, allocating play space and for multi-component interventions, and no evidence for an effect of decreasing playground density, the promotion of physical activity by staff and increasing recess duration on children's health. In line with this, observational studies showed positive associations between play equipment and children's physical activity level. In contrast to experimental studies, significant associations were also found between children's physical activity and a decreased playground density and increased recess duration. To confirm the findings of this review, researchers are advised to conduct more experimental studies with a randomized controlled design and to incorporate the assessment of implementation strategies and process evaluations to reveal which intervention strategies and playground characteristics are most effective.

Effects of a web-based intervention on physical activity and metabolism in older adults: randomized controlled trial.

BACKGROUND: Lack of physical activity leads to detrimental changes in body composition and metabolism, functional decline, and increased risk of disease in old age. The potential of Web-assisted interventions for increasing physical activity and improving metabolism in older individuals holds great promise but to our knowledge it has not been studied. OBJECTIVE: The goal of our study was to assess whether a Web-based intervention increases physical activity and improves metabolic health in inactive older adults. METHODS: We conducted a 3-month randomized, waitlist-controlled trial in a volunteer sample of 235 inactive adults aged 60-70 years without diabetes. The intervention group received the Internet program Philips DirectLife, which was directed at increasing physical activity using monitoring and feedback by accelerometer and digital coaching. The primary outcome was relative increase in physical activity measured objectively using ankle- and wrist-worn accelerometers. Secondary outcomes of metabolic health included anthropometric measures and parameters of glucose metabolism. RESULTS: In total, 226 participants (97%) completed the study. At the ankle, activity counts increased by 46% (standard error [SE] 7%) in the intervention group, compared to 12% (SE 3%) in the control group (P(difference)<.001). Measured at the wrist, activity counts increased by 11% (SE 3%) in the intervention group and 5% (SE 2%) in the control group (P(difference)=.11). After processing of the data, this corresponded to a daily increase of 11 minutes in moderate-to-vigorous activity in the intervention group versus 0 minutes in the control group (P(difference)=.001). Weight decreased significantly more in the intervention group compared to controls (-1.5 kg vs -0.8 kg respectively, P=.046), as did waist circumference (-2.3 cm vs -1.3 cm respectively, P=.036) and fat mass (-0.6% vs 0.07% respectively, P=.025). Furthermore, insulin and HbA1c levels were significantly more reduced in the intervention group compared to controls (both P<.05). CONCLUSIONS: This was the first study to show that in inactive older adults, a 3-month Web-based physical activity intervention was effective in increasing objectively measured daily physical activity and improving metabolic health. Such Web-based interventions provide novel opportunities for large scale prevention of metabolic deregulation in our rapidly aging population.

Can multiple lifestyle behaviours be improved in people with familial hypercholesterolemia? Results of a parallel randomised controlled trial.

OBJECTIVE: To evaluate the efficacy of an individualised tailored lifestyle intervention on physical activity, dietary intake, smoking and compliance to statin therapy in people with Familial Hypercholesterolemia (FH). METHODS: Adults with FH (n = 340) were randomly assigned to a usual care control group or an intervention group. The intervention consisted of web-based tailored lifestyle advice and face-to-face counselling. Physical activity, fat, fruit and vegetable intake, smoking and compliance to statin therapy were self-reported at baseline and after 12 months. Regression analyses were conducted to examine between-group differences. Intervention reach, dose and fidelity were assessed. RESULTS: In both groups, non-significant improvements in all lifestyle behaviours were found. Post-hoc analyses showed a significant decrease in saturated fat intake among women in the intervention group (ß = -1.03; CI -1.98/-0.03). In the intervention group, 95% received a log on account, of which 49% logged on and completed one module. Nearly all participants received face-to-face counselling and on average, 4.2 telephone booster calls. Intervention fidelity was low. CONCLUSIONS: Individually tailored feedback is not superior to no intervention regarding changes in multiple lifestyle behaviours in people with FH. A higher received dose of computer-tailored interventions should be achieved by uplifting the website and reducing the burden of screening questionnaires. Counsellor training should be more extensive. TRIAL REGISTRATION: Dutch Trial Register NTR1899.

A systematic review of randomized controlled trials on the effectiveness of computer-tailored physical activity and dietary behavior promotion programs: an update.

BACKGROUND: A review update is necessary to document evidence regarding the effectiveness of computer-tailored physical activity and nutrition education. PURPOSE: The purpose of this study was to summarize the latest evidence on the effectiveness of computer-tailored physical activity and nutrition education, and to compare the results to the 2006 review. METHODS: Databases were searched for randomized controlled trials evaluating computer-tailored physical activity and nutrition education aimed at primary prevention in adults, published from September 2004 through June 2011. RESULTS: Compared to the findings in 2006, a larger proportion of studies found positive effects for computer-tailored programs compared to generic or no information, including those for physical activity promotion. Effect sizes were small and generally at short- or medium-term follow-up. CONCLUSIONS: The results of the 2006 review were confirmed and reinforced. Future interventions should focus on establishing larger effect sizes and sustained effects and include more generic health education control groups and objective measurements of dietary behavior.

From theory to practice: intervention fidelity in a randomized controlled trial aiming to optimize weight development during pregnancy.

BACKGROUND: Intervention fidelity is an increasingly important methodological concept in process evaluations. In this article, the authors investigated the intervention fidelity in a randomized controlled trial on excessive weight gain prevention in pregnancy. METHOD: A sample of 109 audiotaped counseling sessions, linked to 65 women in the intervention group of the New Life(style) trial, was drawn. The following criteria were quantitatively evaluated using a fidelity checklist: (a) reach, (b) dose, (c) adherence to study objectives, (d) adherence to underlying problem-solving treatment (PST) theory, and (e) counselor competence. RESULTS: A total of 60.4% received all counseling sessions. The dose of intervention components was generally moderate (50.9% to 60.4%), and the dose of PST components was low (17.3%). Adherence to study objectives was moderate (64.2%) and adherence to PST theory was low (43.2%). The counselors sufficiently stimulated the participant to optimize lifestyle (54.2% of the sessions), provided positive feedback (50.5%), and left the initiative regarding problem solving to the participant (71%). One of the two counselors performed significantly better on all measured criteria (p < .001). CONCLUSIONS: Intervention fidelity in the New Life(style) trial was generally low to moderate. In future interventions, it is recommended to put more emphasis on counselor recruitment, training, and intervention protocol contents. Fellow researchers are encouraged to embed a process evaluation into all study stages, taking into account all essential process elements, and to link process outcomes to more distal, health outcomes.

Is the process of delivery of an individually tailored lifestyle intervention associated with improvements in LDL cholesterol and multiple lifestyle behaviours in people with familial hypercholesterolemia?

BACKGROUND: More insight in the association between reach, dose and fidelity of intervention components and effects is needed. In the current study, we aimed to evaluate reach, dose and fidelity of an individually tailored lifestyle intervention in people with Familial Hypercholesterolemia (FH) and the association between intervention dose and changes in LDL-Cholesterol (LDL-C), and multiple lifestyle behaviours at 12-months follow-up. METHODS: Participants (n = 181) randomly allocated to the intervention group received the PRO-FIT intervention consisting of computer-tailored lifestyle advice (PRO-FIT*advice) and counselling (face-to-face and telephone booster calls) using Motivational Interviewing (MI). According to a process evaluation plan, intervention reach, dose delivered and received, and MI fidelity were assessed using the recruitment database, website/counselling logs and the Motivational Interviewing Treatment Integrity (MITI 3.1.1.) code. Regression analyses were conducted to explore differences between participant and non-participant characteristics, and the association between intervention dose and change in LDL-C, and multiple lifestyle behaviours. RESULTS: A 34% (n = 181) representative proportion of the intended intervention group was reached during the recruitment phase; participants did not differ from non-participants (n = 623) on age, gender and LDL-C levels. Of the participants, 95% received a PRO-FIT*advice log on account, of which 49% actually logged on and completed at least one advice module. Nearly all participants received a face-to-face counselling session and on average, 4.2 telephone booster calls were delivered. None of the face-to-face sessions were implemented according to MI guidelines. Overall, weak non-significant positive associations were found between intervention dose and LDL-C and lifestyle behaviours. CONCLUSIONS: Implementation of the PRO-FIT intervention in practice appears feasible, particularly PRO-FIT*advice, since it can be relative easily implemented with a high dose delivered. However, only less than half of the intervention group received the complete intervention-package as intended. Strategies to let participants optimally engage in using web-based computer-tailored interventions like PRO-FIT*advice are needed. Further, more emphasis should be put on more extensive MI training and monitoring/supervision.

No significant improvement of cardiovascular disease risk indicators by a lifestyle intervention in people with familial hypercholesterolemia compared to usual care: results of a randomised controlled trial.

BACKGROUND: People with Familial Hypercholesterolemia (FH) may benefit from lifestyle changes supporting their primary treatment of dyslipidaemia. This project evaluated the efficacy of an individualised tailored lifestyle intervention on lipids (low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), total cholesterol (TC) and triglycerides), systolic blood pressure, glucose, body mass index (BMI) and waist circumference in people with FH. METHODS: Adults with FH (n = 340), recruited from a Dutch cascade screening program, were randomly assigned to either a control group or an intervention group. The personalised intervention consisted of web-based tailored lifestyle advice and personal counselling. The control group received care as usual. Lipids, systolic blood pressure, glucose, BMI, and waist circumference were measured at baseline and after 12 months. Regression analyses were conducted to examine differences between both groups. RESULTS: After 12 months, no significant between-group differences of cardiovascular disease (CVD) risk indicators were observed. LDL-C levels had decreased in both the intervention and control group. This difference between intervention and control group was not statistically significant. CONCLUSIONS: This project suggests that an individually tailored lifestyle intervention did not have an additional effect in improving CVD risk indicators among people with FH. The cumulative effect of many small improvements in all indicators on long term CVD risk remains to be assessed in future studies. TRIAL REGISTRATION: NTR1899 at ww.trialregister.nl.

A tailored lifestyle intervention to reduce the cardiovascular disease risk of individuals with Familial Hypercholesterolemia (FH): design of the PRO-FIT randomised controlled trial.

BACKGROUND: Because of a high cardiovascular disease (CVD) risk in people with Familial Hypercholesterolemia (FH), early prevention of cardiovascular disease is important for health gain and cost reduction. This project focuses on the development and evaluation of an innovative intervention aiming to reduce CVD risk by promoting a healthy lifestyle among people with FH. METHODS: This project is designed as a randomised controlled trial in which individuals with FH will be assigned randomly to a control or intervention group. In the intervention group (n = 200), participants will receive a personalized intervention which is a combination of web-based tailored lifestyle advice and personal counselling by a lifestyle coach. The control group (n = 200) will receive care as usual. Primary outcomes are biological indicators of CVD risk: systolic blood pressure, glucose, BMI, waist circumference and lipids (triglycerides, total, LDL and HDL cholesterol). Secondary outcomes are: healthy lifestyle behaviour (with regard to smoking, physical activity, dietary pattern and compliance to statin therapy) and psychological correlates and determinants of healthy lifestyle behaviour (knowledge, attitude, risk perception, social influence, self-efficacy, cues to action, intention and autonomy). Measurement will take place at baseline, and at 3 and 12 months after randomisation. Additionally, a throughout process-evaluation will be conducted to assess and monitor intervention implementation during the trial. DISCUSSION: Results of the PRO-FIT project will provide information about the effects and implementation of a healthy lifestyle intervention for individuals with FH. Our experiences with this intervention will be indicative about the suitability, feasibility and benefits of this approach for future interventions in other high-risk groups, such as Familial Combined Hypercholesterolemia (FCH) and diabetes. TRIAL REGISTRATION NUMBER: NTR1899.