Moamba, Mozambique

Effectiveness of the RISE Intervention

Rationale: People who have suffered a stroke are at high risk of functional decline, recurrent stroke and premature mortality. High amounts of sedentary behaviour, accumulated in prolonged bouts and low amounts of moderate to vigorous physical activity increase the risk of cardiovascular disease. Based on earlier research it is expected that a healthier balance in the 24h activity pattern (sedentary time, physical activity and sleep) reduces the risk of a second cardiovascular event. To support patients with stroke to strike the balance in their 24h activity pattern, a behavioural change coaching intervention focusing on reducing and interrupting their sedentary time was designed. A pilot study has been performed, and the RISE intervention seems feasible in reducing sedentary behaviour in people after stroke. Objective: To determine the effectiveness of the RISE intervention on preventing major adverse cardiovascular effects (MACE), after discharge from acute hospital care in community dwelling people after first-ever stroke, who have a sedentary movement behavioural pattern. In addition, the effects on 24h activity pattern, cost-effectiveness, and usability of the RISE intervention will be investigated. Study design: In this clinical randomized controlled trial, participants with first-ever stroke and a sedentary movement pattern will be included and randomly assigned to either the experimental group who will receive RISE intervention and usual care or the control group who will receive usual care. Primary and secondary outcomes will be measured at baseline, post-treatment (four months), and six, nine, and 12 months post-randomisation. Study population: People aged over 18, who return home after acute care with a first-ever stroke, who are independent in walking with or without a walking aid, will be included in the RISE intervention study. Intervention (if applicable): Participants will receive the RISE intervention, a 15-weeks blended behavioural intervention, where a primary care physiotherapist coaches participants on striking the balance in their 24h activity pattern, with a focus on reducing and interrupting their sedentary time. This will subsequently lead to an increase in physical activity. Next to that, insights into their personal sleep pattern, sleep hygiene rules and advices will be provided. Primary care physiotherapists coach people with a first-ever stroke in their home setting by using behaviour change techniques and the RISE eCoaching system. The RISE eCoaching system consists of 1) an activity monitor, 2) a smartphone application that provides real-time feedback and contains e-learning modules, 3) a monitoring dashboard for the physiotherapist. Participants receive participatory support from someone from their social network (e.g., partner or close friend) who joins them in the intervention (see image 1). Participants in the control group receive usual care, according to hospital specific guidelines. Main study parameters/endpoints: Effectiveness of RISE intervention on preventing major adverse cardiovascular events. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The burden and risk of participating in the RISE intervention are considered low. The participants will receive a blended coaching intervention to reduce and interrupt their sedentary behaviour. The blended intervention includes ten face-to-face or online sessions of a primary care physiotherapist, wearing an activity monitor during the intervention period, and support from the smartphone application. During the intervention people will be encouraged to sit less and move more. The participant will participate in a baseline and post intervention measurements. This includes wearing an activity monitor, questionnaires and performing physical tests. All measurements are non-invasive. Participants can shower and perform all other daily activities while wearing the activity monitor. The other measurements will take about 3.5 hours in total, and will be carried out online or at people's homes. Included participants are physically capable of performing these physical activities and are coached by a physiotherapist. Therefore, the risk involved in participating is low. Additional burden of the intervention is low since visits of the physiotherapist will be at home or online The possible benefits of participating in the study are: 1) insights in own movement behaviour and 2) (if someone is randomized to the RISE intervention group) the RISE intervention may help to reduce sedentary time, which may lower the risk on recurrent stroke.

Virtual Reality Training for Aggression Control

In an earlier pilot study the Virtual Reality Aggression Prevention Training (VRAPT), developed by Klein Tuente, was explored and refined for a prison-based population. Changes were made and the training was adjusted to Virtual Reality Training Aggression Control (VR-TRAC). In this study the effectiveness of VR-TRAC will be explored. The main goal of this randomized controlled trial is to investigate the effectiveness of VR-TRAC (Virtual Reality TRaining for Aggression Control) for reducing aggression in a prison-based population. The study-design is a single-blind randomized controlled trial, comparing VR-TRAC to waiting-list control condition (WL). 128 male detainees with aggression regulation problems in the last month (measured with the Aggression Questionnaire [AQ]) and a minimum age of 18 years, recruited from the Penitentiary Institution (P.I.) Vught, the Netherlands will participate in this study. They are randomly allocated to VR-TRAC or control condition WL. The treatment group fills in questionnaires, participates in role-plays and follows the VR-TRAC. The control group filles in the same questionnaires as the treatment group and also participates in the role-plays, but does not participate in the VR-TRAC. Participants receive Care As Usual (CAU) when necessary. CAU in prison consists of treatment with the main focus to stabilize a disrupted psychological state (such as pharmacological treatment, supportive contact or a transfer to a Penitentiary Psychiatric Centre where necessary interventions are applied to stabilize the disorder). The training consists of 16 twice-weekly sessions, with a duration of 60 minutes each. The first four sessions focus on the early stages of information processing (what is happening and what does it mean). Session five through eight focus on the late information processing stages (what goals am I trying to achieve, what options do I have to react, what am I going to do, and what is the reaction or behavior). Session 10 through 15 combines the early and late stages, as all newly learned behavior will be incorporated in the interactive scenarios. To train the aforementioned stages, different aggressive-inducing situations are practiced in VR. To measure the effect of VR-TRAC on aggression, three different types of measurements are used: staff observation, self-report and performance-based. Firstly, through staff-observation, using weekly scores of the Observation Scale for Aggressive Behaviour (OSAB) throughout the study period. Secondly, individual changes are measured through self-report measurements. The questionnaires will be scored on three different moments during the study: before the treatment starts, at the end of the treatment, and two- months after the treatment ended. Four questionnaires will be used to measure different types of aggression, namely the Aggression Questionnaire (AQ) (which will also be used as a screening measurement), Difficulties in Emotion Regulation (DERS), the Novaco Anger Scale and Provocation Inventory (NAS-PI), and the Reactive-Proactive Questionnaire (RPQ). To measure impulsiveness the Barratt Impulsiveness Scale (BIS-11) will be used. One questionnaire, the Short Anger Measure (SAM), will be used to measure feelings of anger in the last week. It consists of 12 short items measuring feelings of anger. The questionnaire will be scored weekly and starts four weeks before the treatment starts and will end four weeks after the last treatment. Participants are also asked to answer some questions to evaluate the session through the SRS (Session Rating Scale). Two additional self-report questionnaires will be conducted, one on childhood trauma with the Adverse Childhood Experiences (ACE) and one on substance abuse with the Addiction for Triage & Evaluation (MATE), Lastly, to measure the effectiveness of the skills trained in the VR-TRAC, performance-based assessments (role-play tests and vignettes) will be conducted before and after the treatment period.

Rewards for Cannabis Abstinence-study

Feasibility of Self-treatment of Painful Diabetic Neuropathy Using Electrical Vasomotor Nerve Stimulation

DOSAGE Study: Upfront Dose-Reduced Chemotherapy in Older Patients with Metastatic Colorectal Cancer

Treating older adults with chemotherapy remains a challenge, as they are strongly underrepresented in clinical trials and no robust guidelines for treating older patients exist. Moreover, older adults are at increased risk of chemotherapy-related toxicity, resulting in decreased quality of life (QoL), increased hospital admissions and high health care costs. Therefore, the aim of the DOSAGE study is to demonstrate that upfront dose-reduced chemotherapy in patients with metastasized colorectal cancer is non-inferior to full-dose treatment with regard to progression-free survival (PFS). Treatment plans (monotherapy or doublet chemotherapy) will be based on expected risk of treatment toxicity for the individual patient (according to the Geriatric 8 (G8) questionnaire). The investigators expect that this treatment strategy will lead to less grade ≥3 toxicity, less early treatment continuation and hospitalizations and a better QoL and physical functioning. The DOSAGE study is a phase III, open-label, non-inferiority, randomized controlled clinical trial in patients aged ≥70 years with metastasized colorectal cancer eligible for palliative chemotherapy. All participating patients will undergo geriatric screening by the G8 questionnaire and will be classified as "low risk of toxicity" (G8-score of 15 or higher) or "high risk of toxicity" (G8-score of 14 or lower or judged as "high toxicity risk" by their treating oncologist). Patients classified as low risk will be randomized between a fluoropyrimidine and oxaliplatin in either full-dose, or with an upfront dose-reduction of 25%. Patients classified as high risk will be randomized between fluoropyrimidine monotherapy in either full-dose or upfront dose-reduction. Addition of targeted treatment (bevacizumab or epidermal growth factor receptor (EGFR) inhibition) is allowed. Patients with a moderate renal impairment (GFR 30- 50 mL/min) will be treated with 25% reduced starting dose of capecitabine when randomized for full dose treatment and treated with 40% reduced starting dose when randomized for upfront dose reduction. Primary outcome is PFS. Secondary endpoints include grade ≥3 toxicity, QoL, physical functioning, overall survival, number of treatment cycles, dose reductions, hospital admissions, cumulative received dosage and cost-effectiveness. Given a non-inferiority margin of 8 weeks, 587 patients will be included (293/292 patients per arm).

Pain in Endometriosis And the Relation to Lifestyle

Cough Reduction in IPF with Nalbuphine ER

This is a multi-center randomized, double-blind, placebo-controlled, parallel, 4-arm study. After meeting eligibility during the Screening Period, subjects will be randomized (1:1:1:1) to one of four treatment arms. - Arm 1: Placebo - Arm 2: 27 mg nalbuphine ER - Arm 3: 54 mg nalbuphine ER - Arm 4: 108 mg nalbuphine ER Each arm will be titrated to their fixed dose during the blinded 2-week Titration period according to Table: Dosing Scheme, followed by the 4-week Fixed Dose Period for a total of 6 weeks on drug. Subjects will be taken off study drug at the end of the Fixed Dose Period and followed off treatment for an additional 2 weeks.

Rhu-pGSN for Acute Respiratory Distress Syndrome (ARDS)

Potential subjects hospitalized with pneumonia or other infections are to be screened within 24 hours of diagnosis of ARDS. The Sponsor aims to identify as early as possible patients in the hospital who have developed acute hypoxemic respiratory failure within 7 days of the precipitating infection (often fever, rigors, chills, increased heart rate, increased respiratory rate, pain, cough, etc.) leading to ARDS resulting in mechanical or noninvasive ventilation or high-flow nasal oxygen (HFNO) supplementation with ≥50% O2 at a flow rate of ≥30 L/min. Patients who do not qualify for the study at the initial screening visit because of mild ARDS may subsequently progress to moderate-to-severe ARDS and should be reassessed at least daily for the 7 days following the precipitating infection. Once informed consent is obtained, the following assessments/procedures will be performed: 1. Confirm the potential participant has acute hypoxemic respiratory failure qualifying as moderate-to-severe ARDS for ≤48 hours following a suspected or confirmed infection within the preceding week. Moderate-to-severe ARDS is defined by the calculated or estimated ratio of arterial pressure of O2 to the fraction of inspired O2 [P/F ratio] ≤150. The P/F ratio will be computed from the most recent arterial blood gas obtained no more than 12 hours earlier than randomization. For potential subjects on high-flow nasal oxygen with ≥50% O2 at a flow rate of ≥30 L/min, the P/F ratio will be estimated assuming 50% delivered O2. If eligible and entered in the trial, the following steps should be taken. 2. Record medical history, including concomitant medications and current clinical status. Specify the site and etiology (if known) of infection, indicating if the lung ("direct ARDS") or another organ ("indirect ARDS") is the primary site of infection. 3. Perform pregnancy test (urine or blood) for women of childbearing potential if not already performed during the current hospitalization. 4. Collect pretreatment blood samples for measurement of baseline pGSN and analysis of antibodies against pGSN. 5. Perform physical examination and document results of the chest x-ray (CXR) and/or computed tomography (CT) scan, if CXR is inadequate if not already available as per SOC. 6. Obtain blood and sputum cultures and electrocardiogram (EKG) per SOC (if not already performed). Document the site of infection by collecting specimens as indicated: sputum (bacterial, viral, and mycobacterial, as indicated) and blood cultures, sputum Gram-stains, antigen detection on respiratory and urine specimens, and syndromic nucleic acid amplification tests (NAATs) on respiratory specimens (including a viral and other respiratory pathogen polymerase chain reaction [PCR] panel), where possible. Other specimens from possible sites of infection (e.g., urine, intra-abdominal drainage, skin or soft-tissue abscesses) should be cultured when available. 7. Measure routine lab tests at local (hospital) laboratory per local custom/SOC collect aliquots f- blood for subsequent biomarker assays (including, but not limited to C-reactive protein [CRP], procalcitonin, interleukin [IL]1β, IL6, IL10, and tumor necrosis factor [TNF]) for analysis at the central laboratory. 8. If eligibility criteria are satisfied, the subject will be randomized 1:1 (rhu-pGSN:placebo) by site to a treatment group and treated within 12 hours of randomization and no later than 48 hours after the diagnosis of moderate-to-severe ARDS. Randomized subjects will receive the assigned dose of rhu-pGSN or an equal volume of visibly indistinguishable sterile saline placebo as soon as possible but beginning no later than 48 hours after the diagnosis of moderate-to-severe ARDS. After reconstitution, rhu-pGSN is not to be kept at room temperature for >2 hours prior to beginning study drug administration. A single loading dose of rhu-pGSN at 24 mg/kg followed by 5 daily doses of rhu-pGSN at 12 mg/kg of measured or estimated actual body weight starting 24 hours after the loading dose or an equal volume of indistinguishable saline placebo will be administered. A window of ±2 hours will be allowed around dosing times. Study drug is administered by an IV push through a 0.2 μm filter. The syringe, filter, and extension tubing for administration of study drug are to be connected as close to the subjects as possible. The primary efficacy endpoint of all-cause mortality will be assessed at Day 28. All-cause mortality will also be assessed on Days 7 and 14. Discharged subjects will undergo follow-up evaluation on Days 14 and 28, preferably but not necessarily in person. Survival at Day 60 will be confirmed by telephonic contact or after 3 failed attempts, review of hospital and public records that document survival or death. Screening laboratory and other tests may be used as baseline values and do not need to be repeated if performed within 24 hours prior to randomization unless otherwise dictated by SOC. However, the blood sample for analysis of pGSN levels is to be repeated if not collected within 15 minutes before initiating the first dose of study drug. Repeat CXRs and/or CT scans and labs/cultures are to be obtained during the hospitalization if/when indicated by SOC. On Days 1 (predose) and 28, blood samples for analysis of antibodies against pGSN are to be collected, if possible. Repeat blood and other cultures should be obtained per SOC. An independent Data and Safety Monitoring Board (DSMB) consisting of at least 2 physicians and 1 statistician with appropriate scientific and medical expertise will be formed, and its roles and responsibilities will be described in the DSMB charter. The DSMB will perform 5 periodic reviews of safety data emphasizing deaths and SAEs and will monitor stopping rules to pause enrollment. There will be no pause on enrollment during the planned unblinded periodic reviews. These reviews will be performed after the first 50, 100, 200, 300, and 400 subjects in the Safety Analysis Set have either completed 28 days of follow-up, have died, or have discontinued from the study prior to completing 28 days of follow-up. DSMB members will be provided with unblinded data. Based on the results of each of the planned periodic reviews, the study will be paused only if there is a relative increase of 25 percentage points in the incidence of death or SAEs in the rhu-pGSN treatment group compared to the placebo group. A futility analysis will be performed at the 300-subject review. The Sponsor will take appropriate action based on the recommendation of the DSMB. The DSMB will also review expedited reports of any SAEs throughout the study and may request additional looks at safety data at their discretion. Enrollment will continue during all safety analyses unless otherwise recommended by the DSMB chair.

Effects of Preoperative Multidisciplinary Team Meetings for High-risk, Adult, Noncardiac Surgical Patients

Due to the increase in life expectancy and improved care for patients suffering from a chronic disease, the number of complex patients requiring a surgical intervention is increasing. It is important to balance the potential benefits of this surgical treatment against the risk of permanent loss of functional capacity and quality of life due to complications. European and US guidelines on perioperative care all recommend preoperative multidisciplinary team meetings for high-risk noncardiac surgical patients. However, the evidence underlying a benefit of a preoperative MDT meeting is absent and recommendations are based on expert opinion. Moreover, considerable practice variation is currently present. This study will assess the efficacy of implementation of a preoperative structured multidisciplinary team (sMDT) meeting to optimize perioperative management for high risk noncardiac surgical patients. The hypothesis is that implementation of preoperative sMDT meetings for high risk noncardiac surgical patients results in less serious adverse events, is more cost-effective, and improves quality of life and functional outcome at six months, compared to preoperative care as usual (control). A preoperative structured Multidisciplinary Team (sMDT) meeting for high risk noncardiac surgical patients will be implemented in each participating center (n=14) throughout the study. In the sMDT meeting, patients' treatment plan and alternatives will be discussed by the anesthesiologist, surgical specialist and other relevant consultants or (specialized) nurses. The primary outcome is Serious adverse events (SAEs) according to the Clavien Dindo classification grade 3 or more, at 6 months following surgery or following the preoperative sMDT meeting in case of nonsurgical management. Secondary outcomes are: functional outcome (12-item WHO Disability Assessment Schedule), survival, quality of life (WHOQOL BREF), patients' regret (including interview at 6 months), societal costs (iMCQ and iPCQ, Electronic Medical Record (EMR) data, EQ5D-5L), alterations in perioperative management and sMDT performance (MDT-MOT), and facilitators and barriers (using structured interviews health care professionals). Most secondary outcomes will be assessed at baseline, 30 days, 3, 6 and 12 months. Subgroup analyses will take place for e.g. age groups (approximate quintiles), patient sex, size of hospital, intent of surgery, BMI categories (underweight, normal, overweight, obese, ≥super obese), ASA physical status, frailty, MET score, smoking behavior, alcohol use, comorbidity index score, planned postoperative destination, educational attainment, and employment status. For detailed description, see below.

A Study of Donanemab (LY3002813) in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ 5)

TRAILBLAZER-ALZ 5 is a Phase 3, double-blind, placebo-controlled study to evaluate the safety and efficacy of donanemab in participants with early symptomatic AD (prodromal AD and mild dementia due to AD) with the presence of brain tau pathology.