Double-blind Placebo-controlled Crossover Trial Research Articles

The effect of paracetamol on care dependency and daily functioning in persons with advanced dementia living in long-term care facilities

BackgroundPain medication may have an impact on the quality of life (QoL) in persons with dementia, but may also influence care dependency and daily functioning. The aim of this study is to investigate the effect of regularly scheduled paracetamol on care dependency and daily functioning in persons with advanced dementia with low QoL living in long-term care facilities.MethodsThe Quality of life and Paracetamol In advanced Dementia (Q-PID) study was a (block) randomized double-blind placebo-controlled crossover trial with paracetamol and placebo across seventeen long-term care facilities across 9 care organizations in the western region of the Netherlands. Participants were ≥ 65 years, had advanced dementia (Global Deterioration Scale 5–7), and low QoL (QUALIDEM-6D score ≤ 70). Measurements were performed by nursing staff at the start and at the end of each treatment period of six weeks. Repeated linear mixed models were used to compute differences between randomization groups, with adjustment for period and order effects, and psychotropic use.ResultsNinety-five persons (mean age of 83.9 years, 57.4% female) were enrolled in the Q-PID study. The mean Care Dependency Scale total score was 37.8 (Standard Deviation [SD] 12.9) and the mean Katz-15 total score was 11.9 (SD 2.4). Repeated linear mixed models showed no difference in mean differences of care dependency (paracetamol − 1.0 [95% Confidence Interval (CI) -2.4-0.3], placebo + 0.1 [-1.3-1.5]), and daily functioning (paracetamol + 0.2 [95% CI -0.2-0.6], placebo + 0.1 [-0.3-0.4]).ConclusionsCompared to placebo, no effect of scheduled administration of paracetamol was found on care dependency and daily functioning in persons with advanced dementia with low QoL. Future research should focus on which specific items of care dependency need special attention to improve the care for persons with advanced dementia. A multi-domain approach is needed to enhance and/or maintain QoL of persons with advanced dementia.Trial registrationNetherlands Trial Register (NTR6766); http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6766; Trial registration date: 20/10/2017.

Acute effects of a chewable beetroot-based supplement on cognitive performance: a double-blind randomized placebo-controlled crossover clinical trial

BackgroundDietary nitrate (NO3−) has been shown to be useful as an ergogenic aid with potential applications in health and disease (e.g., blood pressure control). However, there is no consensus about the effects of dietary NO3− or beetroot (BR) juice supplementation on cognitive function.ObjectiveThe aim of this study was to evaluate the effects of a single dose of a chewable BR-based supplement on cognitive performance.MethodsA double-blind randomized placebo-controlled two-period crossover clinical trial was carried out based on the extension of the CONSORT guidelines for randomized crossover trials. A total of 44 participants (24 F; 20 M; 32.7 [12.5] years; 66.3 [9.0] kg; 170 [9.2] cm; 22.8 [1.4] kg/m2) were randomly allocated to receive first either four BR-based chewable tablets (BR-CT) containing 3 g of a Beta vulgaris extract (RedNite®) or four tablets of a placebo (maltodextrin). A 4-day washout period was used before crossover. Ninety minutes after ingestion of the treatments, a neuropsychological testing battery was administered in each period. The trial was registered at clinicaltrials.gov NCT05509075.ResultsSignificant improvements with moderate effect size were found on memory consolidation at the short and long term only after BR-CT supplementation via the Rey Auditory Verbal Learning Test immediate (+ 20.69%) and delayed (+ 12.34%) recalls. Likewise, enhancement on both frontal lobe functions (+ 2.57%) and cognitive flexibility (+ 11.16%) were detected after BR-CT. There was no significant change (p < 0.05) on verbal memory of short-term digits, working memory and information processing speed. Mixed results were found on mood and anxiety through the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI-Y1 and STAI-Y2); however, sequence and period effects were seen on STAI-Y2.ConclusionsThe acute administration of a chewable BR-based supplement improves certain aspects of cognitive function in healthy females and males, particularly memory capacity and frontal skills.

Immunomodulatory effects of fucoidan in recreationally active adult males undertaking 3-weeks of intensified training

ABSTRACT The aim of the current study was to determine whether daily fucoidan supplementation (Undaria pinnatifida extract containing >85% fucoidan, 1 g/day) for three-weeks in a double blind-placebo controlled cross-over trial (ACTRN12621000872831) could modulate alterations in faecal (calprotectin, lysozyme and IgA) and salivary (lactoferrin, lysozyme and IgA) markers of mucosal immune competence typically observed in response to both acute physical activity, and a period of intensified exercise training, in healthy recreationally active men (n = 12). Participants responded positively to the intensified training with 16–19% improvement in mean power that was not different between supplement groups. Faecal biomarkers and concentrations of lactoferrin, lysozyme and IgA from resting saliva samples were largely stable over the supplementation period. Concentrations of salivary biomarkers varied significantly over time in response to acute exercise, however differences between supplementation groups were modest. For salivary lysozyme, there was a trend for a lower magnitude of increase post-exercise (p = 0.08) and limited return towards pre-exercise in response to fucoidan. For salivary IgA, a greater acute exercise response was noted for IgA in response to fucoidan (~2.7-fold higher; p = 0.02). Different dosage and supplementation protocols and inclusion of additional immune markers should be considered in subsequent assessments of any potential benefits of fucoidan supplementation in healthy active adults.

Composition and distribution of lipoproteins after evolocumab in familial dysbetalipoproteinemia: A randomized controlled trial

Proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibodies (mAbs) reduce fasting and post fat load cholesterol in non-HDL and intermediate density lipoprotein (IDL) in familial dysbetalipoproteinemia (FD). However, the effect of PCSK9 mAbs on the distribution and composition of atherogenic lipoproteins in patients with FD is unknown. To evaluate the effect of the PCSK9 mAb evolocumab added to standard lipid-lowering therapy in patients with FD on fasting and post fat load lipoprotein distribution and composition. Randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. Patients received an oral fat load at the start and end of each treatment period. Apolipoproteins (apo) were measured with ultracentrifugation, gradient gel electrophoresis, retinyl palmitate and SDS-PAGE. PCSK9 mAbs significantly reduced particle number of all atherogenic lipoproteins, with a stronger effect on smaller lipoproteins than on larger lipoproteins (e.g. IDL-apoB 49%, 95%confidence interval (CI) 41-59 and very low-density lipoprotein (VLDL)-apoB 33%, 95%CI 16-50). Furthermore, PCSK9 mAbs lowered cholesterol more than triglyceride (TG) in VLDL, IDL and low-density lipoprotein (LDL) (e.g. VLDL-C 48%, 95%CI 29-63%; and VLDL-TG 20%, 95%CI 6.3-41%). PCSK9 mAbs did not affect the post fat load response of chylomicrons. PCSK9 mAbs added to standard lipid-lowering therapy in FD patients significantly reduced lipoprotein particle number, in particular the smaller and more cholesterol-rich lipoproteins (i.e. IDL and LDL). PCSK9 mAbs did not affect chylomicron metabolism. It seems likely that the observed effects are achieved by increased hepatic lipoprotein clearance, but the specific working mechanism of PCSK9 mAbs in FD patients remains to be elucidated.

Medical cannabinoids for painful symptoms in patients with severe dementia: a randomized, double-blind cross-over placebo-controlled trial protocol.

In an observational study in Geneva (Switzerland), we found that administering a standardized THC/CBD oil was feasible, safe, and beneficial in an elderly polymedicated population with severe dementia, behavioral troubles, and pain. Those findings need to be confirmed in a randomized clinical trial. The MedCanDem trial is a randomized, double-blind cross-over placebo-controlled trial to study the efficacy of cannabinoids in improving painful symptoms during severe dementia disorders in patients living in long-term care facilities in Geneva. This manuscript describes the MedCanDem trial protocol. Participants will be patients suffering from severe dementia associated with pain and behavioral troubles and living in long-term care facilities. We selected five facilities specialized in caring for severely demented patients in Geneva (Switzerland). A total of 24 subjects will be randomized 1:1 to the sequence study intervention/placebo or the sequence placebo/study intervention. Patients will receive study intervention treatment or placebo for eight weeks, and then after a one-week wash-out, treatments will be inversed for another eight weeks. The intervention will be a standardized THC/CBD 1:2 oil extract, and the placebo will be a hemp seed oil. The primary outcome is the reduction from the baseline of the Cohen-Mansfield score; secondary outcomes include the reduction in the Doloplus scale, the reduction of rigidity, the monitoring of concomitant drugs prescription and de-prescription, the safety assessment, and a pharmacokinetic evaluation. The primary and secondary outcomes will be assessed at the baseline, after 28 days, and at the end of both study periods. In addition, safety laboratory analysis, pharmacokinetic evaluation, and therapeutic drug monitoring for the cannabinoids will be evaluated through a blood sample analysis conducted at the beginning and the end of both study periods. This study will allow us to confirm the clinical results observed during the observational study. It represents one of the few studies aiming to prove natural medical cannabis efficacy in a population of non-communicating patients with severe dementia, experimenting with behavioral troubles, pain, and rigidity. The trial has Swissethics authorization (BASEC 2022-00999), and it is registered on clinicaltrials.gov (NCT05432206) and the SNCTP (000005168).

CE-452779-3 RANDOMIZED PLACEBO-CONTROLLED TRIAL OF FLECAINIDE IN PATIENTS WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited arrhythmia disorder with a high risk of ventricular tachycardia (VT) or ventricular fibrillation (VF), and implantable cardioverter defibrillators (ICD) remain the palliative therapy of choice. We conducted an NIH-funded pilot clinical trial hypothesizing flecainide administration is more effective than placebo in reducing the burden of ventricular premature beats (VPBs) in ARVC patients. The study was designed as a randomized double-blinded placebo-controlled crossover trial in ARVC patients with administration of 100 mg bid of flecainide or matching placebo for 4 weeks each with a washout period. The primary specific aim was to determine whether flecainide administration is associated with a significant reduction of number of VPBs in comparison to placebo, measured on 7-day Zio-Patch ECG monitoring. Inclusion criteria required ARVC diagnosis with the 2010 ARVC Task Force Criteria at the age of at least 18 years, implanted ICD, and over 500 VPBs on a diagnostic 24-hour Holter recording. Patients were required to be treated with beta-blockers. Patients on other antiarrhythmic treatment required washout with reconfirmation of over 500 VPBs per 24 hour off antiarrhythmic medication. The effect of flecainide on log2(VPB rate) was analyzed using a weighted linear mixed effects analysis of variance model with fixed effects for treatment and period and a random effect for subject, with wights proportional to teh Zio-Patch monitoring time. There were 22 patients with ARVC and an ICD enrolled with a mean age 45+/-13 years, including 12 females. There were 19 patients with at least one Zio-Patch recording and 17 with both recordings. The Table includes details of arrhythmias on placebo and on flecainide. The mean and median number of VPBs/day was significantly lower on flecainide than placebo. At least 50% reduction in VPBs/day was observed in 79% and at least 75% reduction in 53% of patients. The primary analysis showed that flecainide reduced the VPB rate by 72% (p < 0.0001, 95% CI: 56-82%), adjusted for the period effect. There were 2 subjects with pro-arrhythmic response, but flecainide was safe for most of study patients. This is the first randomized clinical trial testing antiarrhythmic management in ARVC patients. Flecainide signficantly reduced the VPB rate and NSVT/VT/VF rate supporting clinical use of this medication in ARVC patients.

S-57-3: GUT MICROBIAL METABOLITES LOWER 24-HOUR SYSTOLIC BLOOD PRESSURE IN HYPERTENSIVE PATIENTS

Objective: Clinical evidence supports that dietary fibre intake lowers blood pressure (BP). Dietary fibres remain intact until they reach the colon. There, they are fermented by gut microbial communities to produce metabolites, particularly short-chain fatty acids (SCFAs). Previous studies, including our own, have demonstrated that supplementation with the SCFAs acetate and butyrate lower BP in experimental models. However, whether dietary supplementation with SCFAs in humans elicits the same reduction in BP is undetermined. We aimed to establish whether a SCFAs-enriched dietary supplement lowers 24-hour BP in participants with essential hypertension. Design and method: Twenty untreated hypertensive participants, diagnosed by 24-hour BP using a Mobil-O-Graph device, were recruited for a phase II randomized placebo-controlled double-blind crossover trial. Participants were randomized to receive a daily intervention of 40 g/day of acetylated and butyrylated high amylose maize starch (HAMSAB) or 40 g/day of regular flour or cornflour (placebo). The dietary intervention lasted three weeks, with a three-week washout period following completion. The primary endpoint was a change in 24-hour systolic BP. Secondary endpoints included SCFA levels and changes in gut microbiome. Results: Participants were on average 55.8 ± 11.2 (mean ± SD) years of age, had a body mass index (BMI) of 25.7 ± 2.5km2/m, and 30% were female. The baseline 24-hour systolic BP was 136 ± 6mmHg. The dietary intervention was well-tolerated and had high acceptability with 93% compliance. There was no difference in 24-hour systolic BP between the baseline visits (P = 0.55) and the placebo (P = 0.18). After 3-weeks on the HAMSAB diet, the placebo-subtracted treatment 24-hour systolic BP difference was 6.1 ± 9.9mmHg (P = 0.027). These observations were independent of age, sex, BMI and study arm. Day and night systolic BP were reduced by 6.5 ± 12.3mmHg (P = 0.01) and 5.7 ± 9.8mmHg (P = 0.02), respectively, and 24-h central BP by 7.2 ± 14.7 mmHg (P = 0.005). There was no change in stroke volume, cardiac output or heart rate; however, HAMSAB reduced total vascular resistance (P = 0.049). Compared to the placebo, the HAMSAB diet elevated acetic and butyric acid levels by 7.8-fold (P = 0.016). HAMSAB also shifted the gut microbial ecosystem (P = 0.037) and increased the prevalence of the acetate and butyrate producers Parabacteroides distasonis and Ruminococcus gauvreauii (q-value &lt; 0.05). Conclusions: We observed a clinically relevant reduction in 24-hour systolic BP in participants with essential hypertension treated with the gut microbial-derived metabolites acetate and butyrate. These metabolites may represent a novel option for lowering BP. Low fibre diets and reduced gut microbial metabolites may be one of the principal reasons for the hypertension epidemic in Western countries.

Randomized double-blind placebo-controlled crossover trial with pyridostigmine in spinal muscular atrophy types 2-4.

Hereditary proximal spinal muscular atrophy causes weakness and increased fatigability of repetitive motor functions. The neuromuscular junction is anatomically and functionally abnormal in patients with spinal muscular atrophy. Pharmacological improvement of neuromuscular transmission may therefore represent a promising additional treatment strategy. We conducted a Phase II, monocentre, placebo-controlled, double-blind, cross-over trial with the acetylcholinesterase inhibitor pyridostigmine in treatment-naïve patients with spinal muscular atrophy types 2-4. We investigated the safety and efficacy of pyridostigmine on fatigability and motor function. Each participant received pyridostigmine and a placebo for 8 weeks, in random order. Primary outcomes were the repeated nine-hole peg test for fatigability and motor function measure. Secondary outcomes were patient-reported effects, endurance shuttle test combined scores and adverse events. We included 35 patients. For the repeated nine-hole peg test, the mean difference was 0.17 s/trial (95% confidence interval: -1.17-1.49; P = 0.8), favouring placebo, and for the motor function measure, 0.74% (95% confidence interval: 0.00-1.49; P = 0.05), favouring pyridostigmine. Around 74% of patients reported medium-to-large beneficial effects of pyridostigmine on fatigability, compared with 29.7% in the placebo arm. This was paralleled by a reduced dropout risk of 70% on the endurance shuttle test combined scores (hazard ratio: 0.30; 95% confidence interval: 0.15-0.58) under pyridostigmine. Adverse events, mostly mild and self-limiting, occurred more frequently under pyridostigmine. No serious adverse events related to the study medication were observed. Patients with spinal muscular atrophy tolerated pyridostigmine well. There were no significant differences in primary outcomes, but the self-reported reduction of fatigability and improved endurance shuttle test combined score performance suggest that pyridostigmine may be useful as an additional therapy to survival motor neuron-augmenting drugs. Trial registration number: EudraCT: 2011-004369-34, NCT02941328.

Effects of Descurainia sophia on Oxidative Stress Markers and Thirst Alleviation in Hemodialysis Patients: A Randomized Double-Blinded Placebo-Controlled Cross-Over Clinical Trial.

Patients undergoing hemodialysis (HD) are regularly exposed to oxidative stress and inflammation and may suffer from thirst distress with no definitive treatment to address these complications. Descurainia sophia (DS) has been used to alleviate thirst in traditional Persian medicine. This study aimed to assess the effectiveness of DS on oxidation factors and thirst score in HD patients. This study was conducted on fifty-three HD patients referred to Tehran Shahid Modarres hospital. The patients were randomly divided into two groups: Group 1 received DS for six weeks, then underwent four weeks of washout period followed by six weeks of placebo treatment, while group 2 received placebo initially followed by treatment with DS. Biochemistry, malondialdehyde (MDA), and total antioxidant capacity (TAC) were measured in four phases: at the beginning, before washout, after washout, and at the end of the study. The patient's body weight was recorded at the start of each session to assess interdialytic weight gain. Thirst scores also were measured using a visual analog scale. A total of 53 patients, including 23 (43.4%) male and 30 (56.6%) female subjects, were included in the study. The results showed a reduction in thirst score (p=0.001), cholesterol levels (p=0.046), triglycerides (0.003), and MDA (p < 0.001) following the four-week administration of DS treatment in HD patients. The mean levels of TAC were increased (p < 0.001), and calcium, as well as Na+, remained unchanged (p > 0.05). Also, a significant decrease in the patient's weight was observed (p value <0.001). This effect persisted after shifting to a placebo. However, the two groups had no significant difference (p value = 0.539). DS powder-mixed syrup may benefit HD patients by facilitating free radical scavenging and alleviating thirst distress with minimal adverse effects. The seeds could therefore be utilized as a complementary therapy for hemodialysis patients.

Effect of evolocumab on fasting and post fat load lipids and lipoproteins in familial dysbetalipoproteinemia

Familial dysbetalipoproteinemia (FD) is the second most common monogenic lipid disorder (prevalence 1 in 850-3500), characterized by postprandial remnant accumulation and associated with increased cardiovascular disease (CVD) risk. Many FD patients do not achieve non-HDL-C treatment goals, indicating the need for additional lipid-lowering treatment options. To evaluate the effect of the PCSK9 monoclonal antibody evolocumab added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in patients with FD. A randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. At the start and end of each treatment period patients received an oral fat load. The primary endpoint was the 8-hour post fat load non-HDL-C area under the curve (AUC). Secondary endpoints included fasting and post fat load lipids and lipoproteins. In total, 28 patients completed the study. Mean age was 62±9 years and 93% had an Ɛ2Ɛ2 genotype. Evolocumab reduced the 8-hour post fat load non-HDL-C AUC with 49% (95%CI 42-55) and apolipoprotein B (apoB) AUC with 47% (95%CI 41-53). Other fasting and absolute post fat load lipids and lipoproteins including triglycerides and remnant-cholesterol were also significantly reduced by evolocumab. However, evolocumab did not have significant effects on the rise above fasting levels that occurred after consumption of the oral fat load. Evolocumab added to standard lipid-lowering therapy significantly reduced fasting and absolute post fat load concentrations of non-HDL-C, apoB and other atherogenic lipids and lipoproteins in FD patients. The clinically significant decrease in lipids and lipoproteins can be expected to translate into a reduction in CVD risk in these high-risk patients.

Enriched enrollment randomized double-blind placebo-controlled cross-over trial with phenytoin cream in painful chronic idiopathic axonal polyneuropathy (EPHENE): a study protocol

BackgroundPatients with chronic idiopathic axonal polyneuropathy (CIAP) can have neuropathic pain that significantly impacts quality of life. Oral neuropathic pain medication often has insufficient pain relief and side effects. Topical phenytoin cream could circumvent these limitations.The primary objectives of this trial are to evaluate (1) efficacy in pain reduction and (2) safety of phenytoin cream in patients with painful CIAP. The main secondary objective is to explore the usefulness of a double-blind placebo-controlled response test (DOBRET) to identify responders to sustained pain relief with phenytoin cream.MethodsThis 6-week, enriched enrollment randomized double-blind, placebo-controlled triple cross-over trial compares phenytoin 20%, 10% and placebo cream in 48 participants with painful CIAP. Enriched enrollment is based on a positive DOBRET in 48 participants who experience within 30 minutes ≥2 points pain reduction on the 11-point numerical rating scale (NRS) in the phenytoin 10% cream applied area and ≥1 point difference in pain reduction on the NRS between phenytoin 10% and placebo cream applied area, in favour of the former. To explore whether DOBRET has predictive value for sustained pain relief, 24 DOBRET-negative participants will be included.An open-label extension phase is offered with phenytoin 20% cream for up to one year, to study long-term safety.The main inclusion criteria are a diagnosis of CIAP and symmetrical neuropathic pain with a mean weekly pain score of ≥4 and <10 on the NRS.The primary outcome is the mean difference between phenytoin 20% versus placebo cream in 7-day average pain intensity, as measured by the NRS, over week 2 in DOBRET positive participants.Key secondary outcomes include the mean difference in pain intensity between phenytoin 10% and phenytoin 20% cream, and between phenytoin 10% and placebo cream. Furthermore, differences between the 3 interventions will be evaluated on the Neuropathic Pain Symptom Inventory, EuroQol EQ5-5D-5L, and evaluation of adverse events.DiscussionThis study will provide evidence on the efficacy and safety of phenytoin cream in patients with painful CIAP and will give insight into the usefulness of DOBRET as a way of personalized medicine to identify responders to sustained pain relief with phenytoin cream.Trial registrationClinicalTrials.gov NCT04647877. Registered on 1 December 2020.

Effect of evolocumab versus placebo added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in familial dysbetalipoproteinemia

Abstract Background Familial Dysbetalipoproteinemia (FD) is the second most common genetic lipid disorder (prevalence ranging from 1 in 1000–2500), characterized by impaired postprandial lipoprotein clearance and associated with increased cardiovascular (CVD) risk. The majority of FD patients do not achieve non-HDL-cholesterol treatment goals, indicating the medical need for additional lipid-lowering treatment options. Purpose To evaluate the effect of the PCSK9 monoclonal antibody evolocumab added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in FD patients. Methods A randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12 week treatment periods. At the start and end of each treatment period FD patients received an oral fat load. The primary endpoint was the 8 hour post fat load non-HDL-cholesterol level expressed as area under the curve (AUC). Levels of other fasting and post fat load lipids and (apo)lipoproteins were assessed with ultracentrifugation, polyacrylamide gels, retinyl palmitate and SDS-PAGE. Results In total, 28 patients completed the study. Mean age was 62±9 years and 93% had an ɛ2ɛ2 genotype. Compared with placebo, evolocumab reduced fasting non-HDL-cholesterol with 51% (95% CI 43–57) and the 8 hours post fat load non-HDL-cholesterol AUC with 49% (95% CI 42–55). Fasting triglyceride levels were reduced with 24% (95% CI 14–37) and the 8 hours post fat load triglyceride AUC was reduced with 22% (95% CI 11–29). Except for HDL-cholesterol, all fasting and 8 hour post fat load lipids and (apo)lipoproteins were significantly reduced by evolocumab, including apolipoprotein B (8 hour post fat load AUC reduction 47% (95% CI 41–53) and remnant cholesterol (8 hour post fat load AUC reduction 49% (95% CI −38 to 59)), compared with placebo. After treatment with evolocumab, 89% of patients achieved their non-HDL-cholesterol treatment goal compared with 36% after placebo. Conclusion Evolocumab added to standard lipid-lowering therapy significantly reduced fasting and post fat load non-HDL-cholesterol and other atherogenic lipids and lipoproteins in FD patients. This is the largest clinical trial in FD to date and the first to investigate evolocumab in this very high-risk group. The large decrease in fasting and post fat load lipids and lipoproteins will likely lower CVD risk in these patients. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): AmgenThis project was funded by Amgen for an investigator-initiated research project. The University Medical Center Utrecht was the sponsor of the study. The financial funder had no role in the design, collection of the data, conduct of the analyses or reporting of the study results.

Water-Soluble Tomato Concentrate, a Potential Antioxidant Supplement, Can Attenuate Platelet Apoptosis and Oxidative Stress in Healthy Middle-Aged and Elderly Adults: A Randomized, Double-Blinded, Crossover Clinical Trial.

Increased oxidative stress and platelet apoptotic in middle-aged and elderly adults are important risk factors for atherosclerotic cardiovascular disease (ASCVD). Therefore, it is of great significance to control the oxidative stress and platelet apoptosis in middle-aged and elderly adults. Previous acute clinical trials have shown that water-soluble tomato concentrate (WSTC) from fresh tomatoes could exert antiplatelet benefits after 3 h or 7 h, but its effects on platelet apoptosis and oxidative stress are still unknown, especially in healthy middle-aged and elderly adults. This current study aimed to examine the efficacies of WSTC on platelet apoptosis and oxidative stress in healthy middle-aged and elderly adults via a randomized double-blinded placebo-controlled crossover clinical trial (10 weeks in total). A total of 52 healthy middle-aged and elderly adults completed this trial. The results showed that WSTC could increase the serum total antioxidant capacity levels (p < 0.05) and decrease the serum malondialdehyde levels (p < 0.05) after a 4-week WSTC supplementation in healthy middle-aged and elderly adults. Platelet endogenous reactive oxygen species generation (p < 0.05), mitochondrial membrane potential dissipation (p < 0.05) and phosphatidylserine exposure (p < 0.05) were attenuated. In addition, our present study also found that WSTC could inhibit platelet aggregation and activation induced by collagen or ADP after intervention (p < 0.05), while having no effects on adverse events (p > 0.05). The results suggest that WSTC can inhibit oxidative stress and its related platelet apoptosis, which may provide a basis for the primary prevention of WSTC in ASCVD.

Improved Plasma Lipids, Anti-Inflammatory Activity, and Microbiome Shifts in Overweight Participants: Two Clinical Studies on Oral Supplementation with Algal Sulfated Polysaccharide.

Seaweed polysaccharides in the diet may influence both inflammation and the gut microbiome. Here we describe two clinical studies with an Ulva sp. 84-derived sulfated polysaccharide—“xylorhamnoglucuronan” (SXRG84)—on metabolic markers, inflammation, and gut flora composition. The first study was a double-blind, randomized placebo-controlled trial with placebo, and either 2 g/day or 4 g/day of SXRG84 daily for six weeks in 64 overweight or obese participants (median age 55 years, median body mass index (BMI) 29 kg/m2). The second study was a randomized double-blind placebo-controlled crossover trial with 64 participants (median BMI 29 kg/m2, average age 52) on placebo for six weeks and then 2 g/day of SXRG84 treatment for six weeks, or vice versa. In Study 1, the 2 g/day dose exhibited a significant reduction in non-HDL (high-density lipoprotein) cholesterol (−10% or −0.37 mmol/L, p = 0.02) and in the atherogenic index (−50%, p = 0.05), and two-hour insulin (−12% or −4.83 mU/L) showed trends for reduction in overweight participants. CRP (C-reactive protein) was significantly reduced (−27% or −0.78 mg/L, p = 0.03) with the 4 g/day dose in overweight participants. Significant gut flora shifts included increases in Bifidobacteria, Akkermansia, Pseudobutyrivibrio, and Clostridium and a decrease in Bilophila. In Study 2, no significant differences in lipid measures were observed, but inflammatory cytokines were improved. At twelve weeks after the SXRG84 treatment, plasma cytokine concentrations were significantly lower than at six weeks post placebo for IFN-γ (3.4 vs. 7.3 pg/mL), IL-1β (16.2 vs. 23.2 pg/mL), TNF-α (9.3 vs. 12.6 pg/mL), and IL-10 (1.6 vs. 2.1 pg/mL) (p < 0.05). Gut microbiota abundance and composition did not significantly differ between groups (p > 0.05). Together, the studies illustrate improvements in plasma lipids and an anti-inflammatory effect of dietary SXRG84 that is participant specific.

Levetiracetam in Alzheimer's Disease: Do Epileptologists Already Have the Cure?

Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial Vossel K, Ranasinghe KG, Beagle AJ, et al. JAMA Neurol. 2021;78(11):1345-1354. doi:10.1001/jamaneurol.2021.3310.Importance:Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).Objective:To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.Design, setting, and participants:The Levetiracetam for Alzheimer’s Disease–Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination.Interventions:Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence.Main outcomes and measures:The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer’s Disease Assessment Scale—Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity.Results:Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, .07 points; 95% CI, −.18 to .32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, .2–14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = .11; P = .02). There were no treatment discontinuations because of adverse events.Conclusions and relevance:In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD.

Effects of trazodone on behavioral and physiological signs of stress in dogs during veterinary visits: a randomized double-blind placebo-controlled crossover clinical trial.

To determine whether a single dose of trazodone administered to dogs before a veterinary visit reduced their behavioral and physiologic signs of stress and owners' stress during veterinary visits. 20 dogs and their owners. In this randomized double-blinded placebo-controlled crossover clinical trial, dogs with a history of anxiety during veterinary visits were scheduled for 2 veterinary visits 1 week apart and randomly assigned to receive a single oral dose of either trazodone (9 to 12 mg/kg) or a placebo 90 minutes before transport to the veterinary clinic for alternate visits between September 21 and November 3, 2019. For each visit, we collected and assessed owner-completed surveys of dog stress score (DSS) and owner stress score; various investigator-reported scores, including from video-recorded behavior analyses; and patient-related physiologic data. Dogs treated with trazodone versus placebo had lower mean DSSs, assessed by owners for physical examination and assessed by video analysis for time spent in the examination room; lower mean SD of normal-to-normal intervals, root mean square of successive heartbeat interval difference, and respiratory rate; and higher mean heart rate. No meaningful differences were observed in other behavioral or physiologic outcomes, including serum cortisol concentrations. A single dose of trazodone before transport reduced signs of stress during veterinary visits for dogs in the present study and may be useful as an anti-anxiety medication for similarly affected dogs, potentially resulting in higher-quality clinical examinations and improved patient welfare.

Opioids and obstructive sleep apnea.

Freire C, Sennes LU, Polotsky VY. Opioids and obstructive sleep apnea. J Clin Sleep Med. 2022;18(2):647-652.

Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity

Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD). To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD. The Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini-Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination. Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence. The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer's Disease Assessment Scale-Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity. Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, 0.07 points; 95% CI, -0.18 to 0.32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, 0.2-14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = 0.11; P = .02). There were no treatment discontinuations because of adverse events. In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD. ClinicalTrials.gov Identifier: NCT02002819.

Preliminary finding of a randomized, double-blind, placebo-controlled, crossover study to evaluate the safety and efficacy of 5-hydroxytryptophan on REM sleep behavior disorder in Parkinson’s disease

PurposeAltered serotonergic neurotransmission may contribute to the non-motor features commonly associated with Parkinson’s disease (PD) such as sleep disorders. The 5-hydroxytryptophan (5-HTP) is the intermediate metabolite of l-tryptophan in the production of serotonin and melatonin. The purpose of this study was to compare the effects of 5-HTP to placebo on REM sleep behavior disorder (RBD) status in patients with PD.MethodsA single-center, randomized, double-blind placebo-controlled crossover trial was performed in a selected population of 18 patients with PD and RBD. The patients received a placebo and 50 mg of 5-HTP daily in a crossover design over a period of 4 weeks.Results5-HTP produced an increase in the total percentage of stage REM sleep without a related increase of RBD episodes, as well as a marginal, non-significant reduction in both arousal index and wake after sleep onset. The self-reported RBD frequency and clinical global impression (CGI) were improved during 5-HTP and placebo treatment in comparison to baseline. 5-HTP significantly improved our patients’ motor experiences of daily living as rated by the Unified Parkinson’s Disease Rating Scale (UPDRS) part II.ConclusionsThis study provides evidence that 5-HTP is safe and effective in improving sleep stability in PD, contributing to ameliorate patients’ global sleep quality. Larger studies with higher doses and longer treatment duration are needed to corroborate these preliminary findings.

An Investigation of Levetiracetam in Alzheimer\u2019s Disease (ILiAD): a double-blind, placebo-controlled, randomised crossover proof of concept study

BackgroundAlthough Alzheimer’s disease affects around 800,000 people in the UK and costs almost £23 billion per year, currently licenced treatments only offer modest benefit at best. Seizures, which are more common in patients with Alzheimer’s disease than age matched controls, may contribute to the loss of nerve cells and abnormal brain discharges can disrupt cognition. This aberrant electrical activity may therefore present potentially important drug targets. The anti-seizure medication levetiracetam can reduce abnormal cortical discharges and reverse memory deficits in a mouse model of Alzheimer’s disease. Levetiracetam has also been shown to improve memory difficulties in patients with mild cognitive impairment, a precursor to Alzheimer’s disease. Clinical use of levetiracetam is well-established in treatment of epilepsy and extensive safety data are available. Levetiracetam thus has the potential to provide safe and efficacious treatment to help with memory difficulties in Alzheimer’s disease.MethodsThe proposed project is a proof of concept study to test whether levetiracetam can help cognitive function in people with dementia. We plan to recruit thirty patients with mild to moderate Alzheimer’s disease with no history of previous seizures or other significant co-morbidity. Participants will be allocated to a double-blind placebo-controlled crossover trial that tests levetiracetam against placebo. Standardised scales to assess cognition and a computer-based touchscreen test that we have developed to better detect subtle improvements in hippocampal function will be used to measure changes in memory. All participants will have an electroencephalogram (EEG) at baseline. The primary outcome measure is a change in the computer-based touchscreen cognitive task while secondary outcomes include the effect of levetiracetam on mood, quality of life and modelling of the EEG, including time series measures and feature-based analysis to see whether the effect of levetiracetam can be predicted. The effect of levetiracetam and placebo will be compared within a given patient using the paired t-test and the analysis of covariance adjusting for baseline values.DiscussionThis is the first study to evaluate if an anti-seizure medication can offer meaningful benefit to patients with Alzheimer’s disease. If this study demonstrates at least stabilisation of memory function and/or good tolerability, the next step will be to rapidly progress to a larger study to establish whether levetiracetam may be a useful and cost-effective treatment for patients with Alzheimer’s disease.Trial registrationClinicalTrials.govNCT03489044. Registered on April 5, 2018.