The DIalysis Symptom COntrol-Restless Legs Syndrome (DISCO-RLS) Trial: A Protocol for a Randomized, Crossover, Placebo-Controlled Blinded Trial.

BACKGROUND: Restless legs syndrome (RLS) affects approximately 30% of patients with end-stage kidney disease and is associated with impaired sleep and health-related quality of life. Medications used to treat RLS in patients receiving dialysis may have an increased risk of adverse events with dose titration, and residual RLS symptoms are common despite the use of effective treatments. Randomized controlled trials of monotherapy and combination pharmacologic therapy for RLS in hemodialysis are needed. OBJECTIVE: To perform a randomized, crossover, placebo-controlled blinded trial of pharmacologic therapy for RLS in hemodialysis. DESIGN/SETTING: The DIalysis Symptom COntrol-Restless Legs Syndrome (DISCO-RLS) trial is a randomized, crossover, placebo-controlled blinded trial of fixed low-dose pharmacologic therapy in patients receiving hemodialysis in 10 centers across Canada. It uses patient partners in its design, conduct, and reporting. PARTICIPANTS: Adults receiving thrice-weekly hemodialysis for at least 3 months with RLS of at least mild symptoms defined International Restless Legs Syndrome Study Group Rating Scale (IRLS) of 10 or more will enter a double placebo run-in period to exclude nonadherent participants and those unable to tolerate double placebo. Seventy-two participants who completed the run-in period will be randomized to 1 of 8 treatment sequences based on modeling with 4 treatment periods. METHODS: Each treatment period lasts 4 weeks and consists of ropinirole 0.5 mg daily and gabapentin 100 mg daily, both together or neither with a double dummy placebo control for each treatment. The primary outcome is the difference in change scores of the IRLS between study treatments. Secondary outcomes are the differences in change scores of the Restless Legs Syndrome-6 Scale, patient global impression, 5-level EQ-5D version, and safety outcomes. RESULTS: This randomized, crossover, placebo-controlled blinded trial will evaluate the efficacy and safety of fixed low-dose combination of ropinirole and gabapentin in patients receiving hemodialysis with RLS. LIMITATIONS: Patients with chronic kidney disease not on dialysis, kidney transplant recipients and those receiving peritoneal dialysis or home hemodialysis are not included. The intervention's long term safety and efficacy including the risk of augmentation is not captured. CONCLUSION: This randomized crossover placebo controlled blinded trial will evaluate the efficacy and safety of fixed low-dose combination ropinirole and gabapentin in patients receiving hemodialysis with RLS. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03806530).

CONTEXTE: Le syndrome des jambes sans repos (SJSR) touche environ 30 % des patients atteints d'insuffisance rénale terminale (IRT) et est associé à des troubles du sommeil et à des altérations de la qualité de vie. Les médicaments employés pour traiter le SJSR chez les patients dialysés pourraient présenter un risque accru d'effets indésirables avec un ajustement de la dose, et les symptômes résiduels du SJSR sont fréquents malgré l'utilisation de traitements efficaces. Des essais contrôlés à répartition aléatoire examinant des traitements pharmacologiques en monothérapie ou en combinaison chez les patients hémodialysés sont nécessaires. OBJECTIF: Procéder à un essai croisé, en aveugle, réparti aléatoirement et contrôlé par placébo examinant un traitement pharmacologique contre le SJSR en contexte d'hémodialyse. CONCEPTION: DISCO-RLS (DIalysis Symptom COntrol-Restless Legs Syndrome) est un essai croisé, en aveugle, réparti aléatoirement et contrôlé par placébo examinant une faible dose fixe d'un médicament administré à des patients hémodialysés. L'essai fait appel à des patients-partenaires pour sa conception, sa conduite et ses rapports. CADRE: Dix centres à travers le Canada. SUJETS: Des adultes hémodialysés trois fois par semaine depuis plus de trois mois et présentant au moins des symptômes légers de SJSR, tels que définis par un score de 10 (score IRLS) ou plus sur l'échelle d'évaluation du groupe international d'étude sur le SJSR seront examinés lors d'une période de rodage à double placébo. Cette dernière permettra d'exclure les patients non adhérents et ceux qui ne tolèrent pas le double placébo. Parmi les patients qui complèteront la période de rodage, soixante-douze seront répartis aléatoirement dans une des huit séquences de traitement en fonction d'une modélisation avec quatre périodes de traitement. MESURES: Le principal résultat est l'observation d'une différence entre les traitements à l'étude dans les variations du score IRLS par rapport aux valeurs initiales. Les résultats secondaires incluent des différences dans les variations de scores sur l'échelle du SJSR (Restless Legs Syndrome-6 Scale), dans l'impression générale du patient, dans les résultats de la version à 5 niveaux du EQ-5D et dans les résultats d'innocuité. MÉTHODOLOGIE: Chaque période de traitement dure quatre semaines et consiste en l'administration quotidienne de 0,5 mg de ropinirole et de 100 mg de gabapentine, les deux ensembles ou aucun des deux, avec un double placébo comme témoin pour chaque traitement. LIMITES: Les patients non dialysés atteints de néphropathies chroniques, les receveurs d'une greffe rénale et les patients traités par dialyse péritonéale ou par hémodialyse à domicile sont exclus. L'efficacité et l'innocuité de l'intervention à long terme ne sont pas prises en compte. CONCLUSION: Cet essai croisé, en aveugle, réparti aléatoirement et contrôlé par placébo évaluera l'efficacité et l'innocuité d'une combinaison de ropinirole et de gabapentine à faible dose fixe chez les patients hémodialysés atteints du SJSR. ENREGISTREMENT DE L'ESSAI: ClinicalTrials.gov (NCT03806530).

Tranexamic acid and rosuvastatin in patients at risk of cardiovascular events after noncardiac surgery: a pilot of the POISE-3 randomized controlled trial.

BACKGROUND: Surgical bleeding is associated with postoperative cardiovascular complications. The efficacy and safety of tranexamic acid (TXA) in noncardiac surgery are still uncertain. Statins may prevent perioperative cardiovascular complications. We conducted a pilot to assess the feasibility of a perioperative trial of TXA and rosuvastatin. METHODS: Using a factorial design, we randomized patients at cardiovascular risk undergoing noncardiac surgery to intravenous TXA (1 g at the start and end of surgery) or placebo, and oral rosuvastatin (40 mg before and 20 mg daily for 30 days after surgery) or placebo. Feasibility outcomes included recruitment rates, follow-up, and compliance to interventions. Clinical outcomes were secondarily explored. RESULTS: After 3 months, we changed the design to a partial factorial due to the difficult recruitment of statin-naive patients. Over 6 months, 100 patients were randomized in the TXA trial (49 TXA, 51 placebo), 34 in the rosuvastatin trial (18 rosuvastatin, 16 placebo). Ninety-two percent (95% CI 80-98) of TXA and 86% (95% CI 74-94) of TXA-placebo patients received the 2 study doses. Thirty-three percent (95% CI 13-59) of rosuvastatin patients and 37% (95% CI 15-65) of rosuvastatin-placebo patients discontinued the study drug. A major cardiovascular complication occurred at 30 days in 1 TXA and 6 TXA-placebo patients, and 1 rosuvastatin and no rosuvastatin-placebo patients. CONCLUSIONS: Our pilot study supports the feasibility of a perioperative TXA trial in noncardiac surgery. Feasibility of a perioperative rosuvastatin trial is uncertain because of a high prevalence of statin use in the target population and concerns about compliance. TRIAL REGISTRATION: ClinicalTrials.govNCT02546648.

Perioperative Pregabalin and Intraoperative Lidocaine Infusion to Reduce Persistent Neuropathic Pain After Breast Cancer Surgery: A Multicenter, Factorial, Randomized, Controlled Pilot Trial.

Persistent postsurgical pain is defined as pain localized to the area of surgery of a duration of ≥2 months and is, unfortunately, a common complication after breast cancer surgery. Although there is insufficient evidence to support any preventative strategy, prior literature suggests the possible efficacy of intravenous lidocaine and perioperative pregabalin in preventing persistent pain after surgery. To determine feasibility of conducting a larger definitive trial, we conducted a multicenter 2 × 2 factorial, randomized, placebo-controlled pilot trial of 100 female patients undergoing breast cancer surgery. Patients were randomized to receive an intraoperative lidocaine infusion (1.5 mg/kg bolus followed by 2 mg/kg/h) or placebo and perioperative pregabalin (300 mg preoperatively, 75 mg twice daily for 9 days) or placebo. All feasibility criteria were surpassed; recruitment of 100 patients was accomplished within 42 weeks, with a follow-up rate of 100% and study drug compliance of ≥80%. At 3 months, 53% of patients reported persistent neuropathic pain. Although there was no interaction between lidocaine and pregabalin, lidocaine decreased the development of persistent neuropathic pain (43.1% vs 63.3%; relative risk = .68; 95% confidence interval = .47-1.0). Pregabalin did not reduce persistent pain (60% vs 46%; relative risk = 1.3; 95% confidence interval = .90-1.90) and neither pregabalin nor lidocaine impacted acute postoperative pain, opioid consumption, pain interference, or quality of life. Our pilot trial successfully demonstrated feasibility and provided promising data for conducting further trials of intraoperative lidocaine infusions during breast cancer surgeries. Clinical trial number: NCT02240199 PERSPECTIVE: This article reports the findings of a pilot randomized, controlled trial evaluating the effects of perioperative pregabalin and intraoperative lidocaine infusions in patients undergoing breast cancer surgery. This trial demonstrated the feasibility of conducting a larger trial and provided promising data that these interventions may decrease the development of persistent pain.