Flemming Island, Florida

Transversus Abdominis Plane Blocks With and Without Dexamethasone

Advances in minimally invasive surgery have reduced postoperative morbidity and enhanced recovery. Despite increased use of minimally invasive techniques, postoperative pain remains a challenging aspect of surgical treatment of colorectal diseases and is typically treated with multimodal analgesia, yet the backbone of analgesia continues to be opioid therapy. As analgesics, opioids are effective but fraught with side effects, including delay in return of bowel function, sedation, and potential for dependency. Minimally invasive colorectal surgery has dramatically improved postoperative outcomes, resulting in significantly shorter length of stay, pain, and overall cost. Despite the advances in multimodal analgesia and enhanced-recovery pathways, the optimal strategy for perioperative analgesia has not yet been defined, and there may be a role for expanded use of regional anesthesia in minimally invasive surgery. Regional anesthesia, specifically the transversus abdominis plane block, has been shown to reduce postoperative pain and opioid requirements even in the context of minimally invasive surgery. Surgeon-performed, laparoscopically placed TAP blocks are equivalent, or perhaps superior, to ultrasound-guided TAP blocks . Long-acting local anesthetics, specifically liposomal bupivacaine, have been shown to prolong the effect of TAP blocks over non-liposomal bupivacaine , and has also suggested a reduced length of stay and less overall cost, despite the high cost of the formulation. These findings suggest improved outcomes can be expected if a longer block is achieved. Liposomal bupivacaine is not available and Canada and is very costly. Regional anesthetic supplemented with dexamethasone, a potent corticosteroid, has shown improved efficacy and prolonged duration of anesthetic in other regional anesthetic techniques. The investigators hypothesize that addition of dexamethasone to bupivacaine can prolong the duration of block to be similar to that achieved with liposomal bupivacaine, but at a much lower cost. Ample evidence exists validating TAP block as an effective adjunct to minimally invasive surgery. Robust data also support the additional benefit of dexamethasone in regional anesthesia. No studies have been published specifically assessing any benefit of combining dexamethasone with local anesthetic to improve the TAP block, and none can be found registered at clinicaltrials.gov. This will be the first such trial to evaluate a promising technique that could reduce postoperative pain and opioid requirements. If found to be effective, this technique would profoundly impact surgical practice around the world. The investigators propose a multi-centre randomized, single-blinded, controlled trial, enrolling 60 patients. Royal University Hospital in Saskatoon, Saskatchewan will be the primary site, with potential to include at least one additional site. Planning is currently underway to run a second trial site at St. Paul's Hospital, Vancouver, British Columbia. The study investigators maintain a collaborative research relationship with the Division of Colorectal Surgery at the University of British Columbia, and there is potential to leverage this relationship to increase the power and relevance of the trial. Patients older than 18 years scheduled to undergo elective or urgent inpatient minimally invasive colorectal resection will be recruited. The type and site of extraction incision will be at the surgeon's preference. Exclusion criteria include conversion to laparotomy, perforated viscus, peritonitis, acute diverticulitis, death within 72 hours, and preoperative opioid use. The primary outcome will be total opioid consumption in the first 48 hours after surgery. Secondary outcomes will be time in the PACU and length of stay in hospital. A computer-generated random number table will be used to randomize patients to receive either conventional TAP (n=30) or TAP-DEX (n=30). Allocation will be performed in a 1:1 ratio. Group allocation will be revealed to the operating surgeon in order to administer the correct solution, but blinded to patient and study investigators, PACU staff, and ward staff. Trial participants will undergo their planned procedures as clinically indicated. Eligible procedures include laparoscopic low anterior resection, anterior resection, and segmental colectomy. At completion of the surgery, patients will undergo surgeon-placed laparoscopic TAP blocks using 1mL/kg of 0.25% bupivacaine with epinephrine 1:200,000, placed at two locations per side along the anterior axillary line between the costal margin and the iliac crest. The dexamethasone group will have 16mg dexamethasone added to the solution. Intravenous dexamethasone will not be given for prevention of postoperative nausea and vomiting. General anesthetic technique will be at the preference of the anesthesiologist. Statistical Analysis Data collection: A blinded, centralized, third-party research assistant will carry out data collection. Postoperative opioid consumption will be quantified through chart review as well as assessment of PCA usage 48 hours following the operation. Recording the doses of opioids administered in the medication administration record (MAR) is standard practice by PACU nursing staff at the study institution. PCA pumps automatically document cumulative opioids administered and can easily be checked at the bedside. Data will be entered and recorded into an encrypted Microsoft Excel spreadsheet. The study intends to enroll a sample size of 60 patients, with 30 patients in each group, using a power of 80% and alpha set at 5%, to detect a detect a difference of 25% (delta=-0.25) under a normal distribution. Given that the standard deviation of 1 is 0.341 under a normal distribution, the sample size was calculated using a 'power of two means" test with a commercially available software (STATA ®). This same sample size, and power calculation, has been used in several trials before . There is an anticipated reduction from 32mg hydromorphone equivalents in the TAP group to less than 25mg in the TAP-DEX group. Thus, the investigators are confident that enrolling 60 patients will be sufficient to detect at least a 25% difference. Primary outcome: The primary outcome will be total opioid use, in morphine equivalents, in the post-anesthetic recovery unit and the first 48 hours after surgery, Opioid equivalents will be calculated using http://opioidcalculator.practicalpainmanagement.com/conversion.php. Secondary Outcome: Secondary outcomes will include time of stay in the PACU and length of stay in hospital. An interim analysis will be performed after 50% enrolment for evaluation of superiority of either treatment.

Clinical Study of Fianlimab in Combination With Cemiplimab Versus Pembrolizumab in Adolescent and Adult Patients With Previously Untreated Unresectable Locally Advanced or Metastatic Melanoma

Treatment of Ligneous Conjunctivitis in Children With Plasminogen Deficiency

This study will enroll one patient with recurrent ligneous conjunctivitis at University of Saskatchewan, Saskatchewan Health Authority in Saskatoon. BACKGROUND: Congenital plasminogen deficiency is an extremely rare autosomal recessive disorder that leads to formation of extravascular fibrin rich pseudomembranes in various organ systems including central nervous system, gastrointestinal, respiratory and otopharyngeal tracts (1, 2, 3). Conjunctival involvement in the form of recurrent woody growths underneath the eyelid (ligneous conjunctivitis) is the most common manifestation (5, 6). The symptoms are most severe in infants and children, where it may lead to central nervous system (CNS) hydrocephalus, respiratory failure or blindness, depending on the organ system involved (3,4) The conjunctival pseudomembranes recur after excision and show a poor response to topical steroids, cyclosporine, or autologous serum administration. These lesions can lead to conjunctival scarring, ptosis, loss of visual acuity and ultimately blindness5,6. Plasminogen replacement (in the form of topical drops of plasminogen concentrate or allogenic plasma) has proven to be the most effective modality in preventing growth of these lesions and is required by most patients to prevent end organ damage. RATIONALE: More than 200 cases of plasminogen deficiency have been reported in literature.(14) Plasminogen replacement (in the form of intraocular drops of plasminogen concentrate or donor plasma) has proven to be the most effective modality in preventing growth of these lesions and is required by most patients to prevent end organ damage (7-20). Plasminogen concentrate is not an option as plasminogen concentrates are not available in Canada. There is one company that produces plasminogen concentrate in North America that is currently not supplying any products on compassionate basis and there are no open clinical trials. Another company (Kedrion) produces it in Italy though it is also not providing on compassionate basis. It is significantly cost prohibitive. Cost: 2800 Euros per ml of concentrate. The product needs to be applied to affected conjunctiva 3-8 times per day for ~3-12 months. Heparin Therapy alone: Case report data shows utilization of Heparin therapy alone for ligneous conjunctivitis in children which led to orbital inflammation and cellulitis with only partial control of lesion (2). Sustained control of these lesions has only been achieved with administration of plasminogen (Intravenous [IV]/local) or plasma (as a source of plasminogen) alone or in conjunction with other therapies (such as membrane resection, heparin etc (7-13), (15-20). TRIAL OBJECTIVES AND PURPOSE: 1. Determine safety of topical administration of aliquoted allogeneic plasma to the affected eye. 2. Determine efficacy of topical administration of aliquoted allogenic plasma. TRIAL TREATMENTS: The allogenic plasma will be aliquoted into 3 ml aliquots and placed in 7 ml vials/bottles. The vials will be frozen at -18 degree Celsius or lower temperature. To administer, the vial/bottle will be warmed to room temperature (15-30 degree Celsius). 1-2 drops of aliquoted donor plasma will be administered to the affected eye every 1-5 hours per day daily at maximum. The administration of plasma drops can change in frequency based on the clinical assessment of ligneous conjunctivitis and response to therapy. STUDY DURATION The treatment administration period will be 2 to 6 months. The duration of study participation, including follow-up, will be approximately 24 months. STUDY VARIABLES The following data will be collected for this study: 1. Size of pseudomembranous conjunctival lesion 2. Visual acuity of the affected eye 3. Development of strabismus or other visual defects in affected eye 4. Medical history 5. Physical exam 6. Blood group (ABO, RhD) and antibody screen results 7. Details of any adverse events All data will be collected on the data collection form. The participant's medical record will be considered to be a source document for the medical history. The lab report will be considered the source document for the lab tests. STOPPING RULES AND DISCONTINUATION CRITERIA Criteria for discontinuation 1. Patient does not want to continue the study 2. Patient has a significant adverse reaction to plasma drops 3. Patient has no response to therapy after 6 months of intervention. This is defined as: 1. No change in the size of pseudomembranes after 6 months of topical allogenic plasma administration performed according to recommendations (with/without surgical excision) 2. Increase in the size of pseudomembranous lesions despite recommended use of aliquoted allogenic plasma 3. Development of new pseudomembranous lesions in the eye receiving topical allogenic plasma 4. More effective therapies (liquid plasminogen concentrate IV/Intra-ocular) become available in Canada 5. Plasma drops can no longer be provided MONITORING OF PARTICIPANT COMPLIANCE Participant compliance will be assessed by maintaining adequate drug dispensing logs and return records. Participants will be asked to return all unused study drug in the provided container at each visit as a measure of drug accountability and patient compliance. ASSESSMENT OF SAFETY Safety Parameters include: 1. Direct clinical monitoring of patient during initial 5 intra-ocular plasma administrations 2. Communication with the patient and family at least on a weekly basis while receiving intra-ocular plasma. 3. Source plasma collected from donors who are negative for transfusion transmissible infections 4. Source plasma cultured before release to facility to ensure no bacterial contamination 5. Clear guidance to parents about situations where plasma administration should be stopped, and clinical care accessed. 6. Communication to the pediatric hematology service available 24/7 in case of any issues with plasma administration 7. Close liaison with pediatric ophthalmologist who will also monitor response and potential complications ADVERSE EVENTS and MITIGATION STRATEGIES According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Serious Adverse Events A serious adverse event is any adverse event that meets any of the following criteria: 1. Fatal (i.e., the adverse event actually causes or leads to death) 2. Life threatening (i.e., the adverse event, in the view of the investigator, places the patient at immediate risk of death). This does not include any adverse event that had it occurred in a more severe form, or was allowed to continue, might have caused death 3. Requires or prolongs inpatient hospitalization 4. Results in persistent or significant disability/incapacity (i.e., the adverse event results in substantial disruption of the patient's ability to conduct normal life functions) 5. Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug 6. Significant medical event in the investigator's judgment (e.g., may jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed above). RISK MITIGATION STRATEGIES 1. Loss of patient privacy and confidentiality: 1. All patient information will be recorded in hospital electronic medical record systems which have adequate protections in place to prevent unauthorized spread of patient information. 2. The data collected for clinical trial will be maintained in University Operated Redcap which will be password protected and have access limited to the study personnel. 2. Serious or severe adverse reaction to topical applications of aliquoted plasma (irritation, inflammation, infection etc.) 1. Initial few (~3-5) topical administrations will be closely monitored in the hospital to assess for any adverse events with nursing and physician oversight. 2. Patient/Family will be permitted to use the topical plasma independently at home only after 3-5 administrations have been monitored in hospital, parents are comfortable with storage and administration process and adverse events have been managed appropriately. 3. In case of any adverse event such as irritation or inflammation etc. patient/family will be able to contact the responsible physician or their service at any time. Appropriate treatment strategies will be undertaken immediately for such events. Processes will be developed to prevent the adverse event from occurring in future if therapy can be continued and the event is non-fatal and non-life/limb threatening. All adverse events will be reported to the manufacturer (Canadian Blood Services). STATISTICS Statistical Methods Descriptive statistics for categorical and continuous variables will be used based on data points obtained and their distribution. Paired T test (or equivalent non-parametric test) will be used to determine difference in baseline and post intervention plasminogen levels at 4 weeks, 2 months, 3 months, 6 months till 24 months. A p-value of 0.05 will be considered significant. All data analyses will be conducted in Statistical software SAS version 9.4. PLANNED PARTICIPANT ENROLLMENT One patient and 3 family members will be enrolled in this study currently. The rationale is that this is an extremely rare disorder with less than 5 patients in entire Canada and only one known patient in Saskatchewan. DATA ACCOUNTABILITY Missing values will not be substituted by estimated values but will be treated as missing in the statistical evaluation. All data from patients randomised in the study will be included in all listings, plots, summary tables, and statistical analyses.

Pole Walking Intervention in Retirement Communities

Pole walking provides an attractive form of exercise therapy for older adults. It is a simple, well-tolerated and effective means to improve overall functional fitness in older adults. Pole walking has improved upper and lower body muscle strength, cardiovascular endurance, and flexibility in community dwelling older adults. It has been positively associated with balance, functional mobility, muscle strength, and aerobic exercise capacity in older adults. Pole walking is considered to offer a safe format for walking as poles provide support and help with balance and thus, contribute to confidence in being active. However, there has not yet been a study assessing the feasibility of pole walking intervention in older adults living in independent living/retirement communities. This study is a patient-oriented pilot intervention. Our target is to include 50 independent living/retirement community's residents. Pole walking exercises are based on ongoing, patient-oriented Nordic Walking intervention, tailored for participants and progressive in nature. Training sessions will be led by trained peer/staff/student-instructors. Training sessions will be held outdoors, 2-3 times a week, for 20-60 min/session, over 12 weeks.

A Study of Tucatinib With Trastuzumab and mFOLFOX6 Versus Standard of Care Treatment in First-line HER2+ Metastatic Colorectal Cancer

Stretching vs Walking for Lowering Blood Pressure

Hypertension or high blood pressure is a prevalent and leading risk factor for heart disease and stroke afflicting seven million people in Canada and costing our health system approximately $20 billion annually. The prevailing exercise recommendation for people with hypertension is to perform aerobic training (i.e. brisk walking) as a non-pharmacological way to moderately reduce blood pressure. Evidence from several recent studies indicates flexibility training may accrue more positive changes in blood pressure than aerobic training. Additional recent studies show stretching can reduce arterial stiffness and sympathetic nervous system activation, suggesting physiological mechanisms by which blood pressure might be reduced through exercises designed mostly to improve flexibility. The purpose of this study is to determine if a 6-month flexibility program is superior to aerobic training for reducing 24-hour blood pressure measurements, improving measures of vascular function (i.e. arterial stiffness), and improving the ratio of parasympathetic to sympathetic nervous system activation. This study involves a randomized controlled trial of 96 men and women presenting with either high-normal blood pressure (systolic 130 to 139 mmHg or diastolic 85 to 89 mmHg) or stage 1 hypertension (systolic 140 to 159 mmHg or diastolic 90 to 99 mmHg) stratified by blood pressure (i.e. either high normal or stage 1 hypertension), sex, and age (≥55y or <55y) and randomized to one of two groups for six months duration: 1) a flexibility program (30 minutes of stretching per day); or 2) an aerobic training program (30 minutes of brisk walking per day). Assessments pre- and post-intervention and three months later include: 24-hour ambulatory blood pressure, arterial stiffness, and heart rate variability. .

Aggressive Smoking Cessation Trial (ASAP)

Background and Importance: People who smoke are at an elevated risk of developing cardiovascular disease (CVD). Those who have an acute coronary syndrome (ACS), including myocardial infarction and unstable angina, and continue to smoke have a 35% increased risk of reinfarction or death compared with those who quit. Our previous smoking cessation trials have established varenicline (Champix) as the "gold standard" for patients with CVD. However, more than 50% of patients motivated to quit who receive varenicline for 12 weeks immediately post-ACS will return to smoking within 6 months. Therefore, more effective smoking cessation strategies are needed. Based on newly available data from randomized controlled trials (RCTs), including our E3 Trial, which suggest that nicotine e-cigarettes are more efficacious for smoking cessation than other nicotine replacement therapies and counseling alone, the investigators propose to combine varenicline and nicotine e-cigarettes (aggressive smoking cessation therapy). The proposed aggressive therapy is a novel approach needed now to increase abstinence in people at elevated cardiovascular risk. Goal(s)/Research Aims: The Aggressive Smoking Cessation Therapy Among People at Elevated Cardiovascular Risk (ASAP) Trial is a 5-year, multi-centre RCT that will assess the efficacy, safety, and tolerability of aggressive smoking cessation therapy among people at elevated cardiovascular risk. The specific aims are: 1. To assess the efficacy of combination therapy (varenicline and nicotine e-cigarettes) versus varenicline alone for 12 weeks, in terms of biochemically-validated 7-day point prevalence and continuous smoking abstinence, and ≥50% reduction in daily cigarette consumption at 24 and 52 weeks among people at elevated cardiovascular risk. 2. To describe the safety and tolerability of varenicline combined with nicotine e-cigarettes, in terms of serious adverse events (SAEs), adverse events (AEs), treatment discontinuation due to side effects, and therapy adherence over the 12-week treatment period. Methods/Approaches/Expertise: A total of 798 participants will be randomized 1:1 to: (1) varenicline and nicotine e-cigarettes (aggressive smoking cessation therapy), or (2) varenicline alone for 12 weeks, with follow-up of 52 weeks. Both arms will receive individual smoking cessation counseling. Participants randomized to aggressive therapy (varenicline and nicotine e-cigarette) will be given funds to cover the purchase of e-cigarettes and nicotine cartridges. Funds will be provided at baseline for the first 4 weeks of e-cigarette use. Participants who follow the e-cigarette purchasing instructions and provide receipts at subsequent clinic visits will be provided additional funds at week 4 (for weeks 4 to 8) and reimbursed at week 12 (for weeks 8 to 12). Participants will begin varenicline (titrated to 1.0 mg twice daily) and counseling at baseline, and e-cigarette use (if applicable) after the baseline visit. Eligible people will have or be at elevated risk of developing CVD, self-identify as regular smokers (≥10 cigarettes/day for ≥1 year), and be motivated to quit. They will complete telephone follow-ups at weeks 1, 2, 8, and 18, and clinic visits at weeks 4, 12, 24, and 52. We will collect information about self-reported smoking, treatment adherence, and adverse events. Self-reported smoking abstinence will be biochemically-validated at clinic visits using exhaled carbon monoxide (≤10 ppm). The primary endpoint will be biochemically-validated 7-day point prevalence smoking abstinence at 24 weeks. With 399 participants per arm and an alpha of .05, the investigators will have 80% power to detect a ≥10% difference in abstinence at 24 weeks. The ASAP Trial will be conducted by a highly experienced team of researchers and enrolling centres, who have previously completed three smoking cessation RCTs, including two in cardiac patients. Expected Outcomes: Smoking cessation is essential to reduce morbidity and mortality in this high-risk patient population. ASAP will provide regulators, health care professionals, and smokers with important information about the efficacy of aggressive varenicline and nicotine e-cigarettes therapy for smoking cessation in people at an elevated cardiovascular risk.