High-precision stereotactic irradiation for focal drug-resistant epilepsy versus standard treatment: a randomized waitlist-controlled trial (the PRECISION trial).

INTRODUCTION: The standard treatment for patients with focal drug-resistant epilepsy (DRE) who are not eligible for open brain surgery is the continuation of anti-seizure medication (ASM) and neuromodulation. This treatment does not cure epilepsy but only decreases severity. The PRECISION trial offers a non-invasive, possibly curative intervention for these patients, which consist of a single stereotactic radiotherapy (SRT) treatment. Previous studies have shown promising results of SRT in this patient population. Nevertheless, this intervention is not yet available and reimbursed in the Netherlands. We hypothesize that: SRT is a superior treatment option compared to palliative standard of care, for patients with focal DRE, not eligible for open surgery, resulting in a higher reduction of seizure frequency (with 50% of the patients reaching a 75% seizure frequency reduction at 2 years follow-up). METHODS: In this waitlist-controlled phase 3 clinical trial, participants are randomly assigned in a 1:1 ratio to either receive SRT as the intervention, while the standard treatments consist of ASM continuation and neuromodulation. After 2-year follow-up, patients randomized for the standard treatment (waitlist-control group) are offered SRT. Patients aged ≥ 18 years with focal DRE and a pretreatment defined epileptogenic zone (EZ) not eligible for open surgery will be included. The intervention is a LINAC-based single fraction (24 Gy) SRT treatment. The target volume is defined as the epileptogenic zone (EZ) on all (non) invasive examinations. The seizure frequency will be monitored on a daily basis using an electronic diary and an automatic seizure detection system during the night. Potential side effects are evaluated using advanced MRI, cognitive evaluation, Common Toxicity Criteria, and patient-reported outcome questionnaires. In addition, the cost-effectiveness of the SRT treatment will be evaluated. DISCUSSION: This is the first randomized trial comparing SRT with standard of care in patients with DRE, non-eligible for open surgery. The primary objective is to determine whether SRT significantly reduces the seizure frequency 2 years after treatment. The results of this trial can influence the current clinical practice and medical cost reimbursement in the Netherlands for patients with focal DRE who are not eligible for open surgery, providing a non-invasive curative treatment option. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05182437. Registered on September 27, 2021.

Prevention of the metabolic syndrome in IGT subjects in a lifestyle intervention: results from the SLIM study.

BACKGROUND AND AIMS: The Study on Lifestyle intervention and Impaired glucose tolerance Maastricht (SLIM), a randomized controlled trial, directed at diet and physical activity in impaired glucose tolerant subjects was effective to improve glucose tolerance and prevent type 2 diabetes. The aim of this study was to determine the effects of the SLIM lifestyle intervention on the incidence and prevalence of the metabolic syndrome (MetS) during the active intervention and four years thereafter. METHODS AND RESULTS: MetS was diagnosed according to the NCEP ATP III criteria. At baseline, 66.4% of all participants (n = 146, age 57 ± 7 years, BMI 29.7 ± 3.6, 51.3% female) fulfilled the criteria for MetS. No significant difference in MetS prevalence was observed between the intervention (63.9%) and control group (68.9%). At the end of active intervention (average duration 4.2 ± 2.0 years), prevalence of MetS was significantly lower in the intervention group (52.6%, n = 57) compared to the control group (74.6%, n = 59) (p = 0.014). Furthermore, in participants without MetS at baseline, cumulative incidence of MetS was 18.2% in the intervention group at the end of active intervention, compared to 73.7% in the control group (Log-rank test, p = 0.011). Four years after stopping active intervention, the reduced incidence of MetS was maintained (Log-rank test, p = 0.002). CONCLUSION: In conclusion, a combined diet-and-exercise intervention to improve glucose tolerance, not only prevented type 2 diabetes, but also reduced the prevalence of MetS and prevented MetS development, showing the long-term impact of lifestyle intervention on cardiovascular risk reduction.

Predictors of lifestyle intervention outcome and dropout: the SLIM study.

BACKGROUND/OBJECTIVES: To evaluate the effect of a 4.1-year (range 3-6 years) lifestyle intervention according to general public health recommendations on glucose tolerance and dropout in a Dutch population with impaired glucose tolerance (IGT). SUBJECTS/METHODS: In the Study on Lifestyle intervention and Impaired glucose tolerance Maastricht, 147 Caucasian IGT subjects were randomized to an intervention group (INT: n=74; 38 male, 36 female) and control group (CON: n=73; 37 male, 36 female). Annually, subjects underwent measurements of body weight, anthropometry, glucose tolerance (oral glucose tolerance test), insulin resistance (homeostasis model assessment-insulin resistance), maximal aerobic capacity (VO(2) max), blood lipids and blood pressure. INT received individual advice regarding a healthy diet and physical activity. RESULTS: INT decreased their saturated fat intake, increased their carbohydrate intake (P<0.05) and VO(2) max (P=0.04) compared with CON. Body weight did not change significantly (P=0.20) between the groups. After an initial decrease, 2-h glucose levels overall increased in INT (+0.11 mmol/l), but significantly less than CON (+1.18 mmol/l; P=0.04). Diabetes incidence was lower in INT versus CON (30 versus 56%, P=0.04). Change in body weight was associated with change in 2-h glucose levels (ß=0.399 mmol/l per kg, P=0.02). Dropouts had a lower aerobic fitness and socioeconomic status, and a higher body mass index (BMI) and 2-h glucose compared with non-dropouts. CONCLUSIONS: Prolonged feasible changes in diet and physical activity prevent deterioration of glucose tolerance and reduce diabetes risk. Low socioeconomic status, low aerobic fitness and high BMI and 2-h glucose are indicative of dropout to the program.

Changes in transferrin are related to changes in insulin resistance: the SLIM study.

AIMS: To determine the effect of a lifestyle intervention on serum transferrin and ferritin levels and the relationship between changes in transferrin and ferritin and changes in glucose tolerance and insulin resistance. METHODS: Randomized controlled lifestyle intervention directed at a healthy diet and increased physical activity in subjects with impaired glucose tolerance. RESULTS: After 1 year, the change in ferritin levels in the intervention group as compared with the control group did not reach statistical significance (P = 0.06). Transferrin change was independently related to the change in homeostasis model assessment of insulin resistance and ferritin change was related to the change in 2-h free fatty acids. CONCLUSIONS: Changes in insulin sensitivity and postprandial lipid metabolism are related to changes in iron metabolism.

Impact of 3-year lifestyle intervention on postprandial glucose metabolism: the SLIM study.

OBJECTIVE: To determine the effect of a 3-year diet and exercise lifestyle intervention, based on general public health recommendations, on glucose tolerance, insulin resistance and metabolic cardiovascular risk factors in Dutch subjects with impaired glucose tolerance (IGT). METHODS: The study was a randomized controlled lifestyle intervention over 3 years. A total of 147 IGT subjects (75 male, 72 female) were randomized to the intervention (INT) group or control (CON) group; 106 subjects (52 INT, 54 CON) completed 3 years of intervention. Annually, glucose, insulin and free fatty acid (FFA) concentrations were determined fasting and after an oral glucose tolerance test. Measurements of body weight, serum lipids, blood pressure and maximal aerobic capacity were also performed. RESULTS: Analysis of those who completed the 3-year trial, showed that the lifestyle intervention improved body weight (INT -1.08 +/- 4.30 kg; CON +0.16 +/- 4.91 kg, P = 0.01), homeostatis model assessment index for insulin resistance and 2-h FFA. Two-hour glucose concentrations improved in the INT group, the difference being most pronounced after 1 year, with a return to baseline values after 3 years, from 8.59 +/- 1.55 to 8.55 +/- 0.34 mm; in contrast, 2-h glucose deteriorated in the CON group-from 8.46 +/- 1.84 to 9.35 +/- 2.50 mm (P = 0.02). In the INT group, diabetes incidence was reduced by 58% (P = 0.025). CONCLUSION: Our lifestyle intervention showed a sustained beneficial effect on 2-h glucose concentrations, insulin resistance and 2-h FFA, even after 3 years. Our lifestyle intervention is effective, but for implementation more information is needed about factors influencing adherence.