data safety monitoring board [keywords]
- [OP.8D.01] CONTROLLING AND LOWERING BLOOD PRESSURE WITH THE MOBIUSHD DEVICE: FIRST-IN-MAN INTERIM RESULTS (CALM-FIM STUDY). [Journal Article]
- J Hypertens 2016 Sep.:e105.
To evaluate the safety and performance of the MobiusHD system in patients with resistant hypertension.This is a multi-center (9 centers) non-randomized, first-in-man assessment of a nitinol self-expanding rectangular cuboid implant (MobiusHD) designed to increase carotid sinus arterial wall strain without impacting pulsatility or laminar flow. The geometric changes of the carotid sinus enhance baroreceptor sensitivity thus decreasing sympathetic activity and lowering BP. Patients with resistant hypertension (>3 antihypertensives, of which one is a diuretic, and office SBP >160 mmHg), without obstructive carotid disease received a unilateral carotid sinus MobiusHD implant. Incidence of serious adverse events and unanticipated adverse device effects were collected along with changes in blood pressure (BP) measured during 1.5-year follow-up.So far 31 patients, mean age 52 (range 21-76) years, of the anticipated 50 patients received a MobiusHD implant of which 9 patients had failed on renal denervation. Mean pretreatment office BP was 182/107 (±18/15) mmHg with a median of 4.4 prescribed antihypertensives [daily defined dose (DDD): 7.4]. During follow-up 3 patients had serious adverse events (as adjudicated by the data safety monitoring board) related to procedure or device: hypotension (n = 2) and closure device failure, requiring repair (n = 1). At 180 days, 17 of the 20 patients had a reduction in office SBP >10 mmHg and/or 24-hr SBP >5 mmHg. Eight of these 17 patients had a reduction in DDD of antihypertensive medications.(Figure is included in full-text article.): So far, implanting the MobiusHD device in patients with resistant hypertension seems to be safe and shows promising results in BP lowering.
- Targeted tissue perfusion versus macrocirculation-guided standard care in patients with septic shock (TARTARE-2S): study protocol and statistical analysis plan for a randomized controlled trial. [Journal Article]
- Trials 2016.:384.
Septic shock has a 90-day mortality risk of up to 50 %. The hemodynamic targets, including mean arterial pressure (MAP) are not based on robust clinical data. Both severe hypotension and high doses of vasopressors may be harmful. Hence, re-evaluation of hemodynamic targets in septic shock is relevant.The targeted tissue perfusion versus macrocirculation-guided standard care in patients with septic shock (TARTARE-2S) trial is a prospective, two-parallel-group, randomized, open-label, multicenter trial with assessor-blinded outcome evaluation. We will randomize at least 200 patients with septic shock in four European intensive care units (ICUs) to test whether a tissue perfusion-guided treatment strategy based on capillary refill time, peripheral temperature, arterial lactate concentrations, and accepting lower MAP levels, leads to a faster resolution of shock than macrocirculation target-guided standard care. The primary outcome measure is days alive in 30 days with normal arterial blood lactate (first value of <2 mmol/L) and without any inotropic or vasopressor agent. Secondary outcomes include individual components of the primary outcome, days alive without renal replacement, days alive without mechanical ventilation in 30 days, and new acute kidney injury. The sample size enables detection of a 13.5-h difference in the primary outcome with a type 1 error of 5 % and power of 80 %, assuming 25 % mortality and a mean of 650 h (SD 30) among the 30-day survivors. After 150 included patients the statistician masked for allocation group will recalculate the sample size potentially increasing the sample up to 300. The Data Safety and Monitoring Board (DSMB) will review the safety data after 100 patients.The TARTARE-2S trial will provide important clinical data on treatment targets in septic shock, evaluating the impact of clinical tissue perfusion-guided hemodynamic treatment on a surrogate outcome combining resolution of shock (hyperlactatemia and vasopressors/inotropes), and 30-day mortality.ClinicalTrials.gov: NCT02579525 . Registered on 19 October 2015.
- Chondroitin sulfate plus glucosamine sulfate shows no superiority over placebo in a randomized, double-blind, placebo-controlled clinical trial in patients with knee osteoarthritis. [JOURNAL ARTICLE]
- Arthritis Rheumatol 2016 Jul 31.
To assess the efficacy and safety of chondroitin sulfate (CS) plus glucosamine sulfate (GS) compared to placebo in patients with symptomatic knee osteoarthritis (KOA).A multicenter, randomized, double-blinded, placebo-controlled study was performed in 164 patients with Kellgren-Lawrence stages II-III KOA and moderate to severe pain (VAS: 62.1±11.3 mm). Patients were randomized to receive either CS (1200 mg) plus GS (1500 mg) or placebo in a single oral daily dose for 6 months. The mean change in VAS global pain was set as primary endpoint. Secondary outcomes included the mean change in the investigator global assessment, total WOMAC, pain and function subscales of WOMAC, OMERACT-OARSI 2004 responder rate, and rescue medication use. Adverse events were also recorded. A Data and Safety Monitoring Board was constituted to ensure patient safety and data accuracy.Intriguingly, CS+GS was inferior to placebo in reduction of joint pain for the modified intention-to-treat (mITT) population [11.8±2.4 mm (19%) vs 20.5±2.4 mm (33%); Δ= -8.7; -14.2%; p<0.03], but not for per-protocol completers. Placebo and CS+GS similarly improved total WOMAC, as well as pain and function WOMAC subscales in both mITT population and per-protocol completers. Neither the OMERACT-OARSI responder rate nor the use of rescue medication differed between both groups. Severe adverse events were uncommon and equally distributed.CS+GS failed to demonstrate superiority over placebo in reducing pain and function impairment in patients with symptomatic KOA at 6 months. Further research may contribute to fully elucidate the suitability of CS+GS combination as therapy in OA. This article is protected by copyright. All rights reserved.
- Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial. [JOURNAL ARTICLE]
- Clin Infect Dis 2016 Jul 20.
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1060 study demonstrated short-term superiority of lopinavir/ritonavir (LPV/r) over nevirapine (NVP) in antiretroviral therapy (ART), regardless of prior NVP exposure. However, NVP-based ART had a marginal benefit in CD4 percentage (CD4%) and growth. We compared 5-year outcomes from this clinical trial. Human immunodeficiency virus (HIV)-infected, ART-eligible children were enrolled into 2 cohorts based on prior NVP exposure and randomized to NVP- or LPV/r-based ART. The data safety monitoring board recommended unblinding results in both cohorts due to superiority of LPV/r for the primary endpoint: stopping randomized treatment, virologic failure (VF), or death by 6 months. Participants were offered a switch in regimens (if on NVP) and continued observational follow-up. We compared time to VF or death, death, and CD4% and growth changes using intention-to-treat analyses. Additionally, inverse probability weights were used to account for treatment switching and censoring. As of September 2014, 329 of the 451 (73%) enrolled participants were still in follow-up (median, 5.3 years; interquartile range [IQR], 4.3-6.4), with 52% on NVP and 88% on LPV/r as originally randomized. NVP arm participants had significantly higher risk of VF or death (adjusted hazard ratio [aHR], 1.90; 95% confidence interval [CI], 1.37-2.65) but not death alone (aHR, 1.65; 95% CI, .72-3.76) compared with participants randomized to LPV/r. Mean CD4% was significantly higher in the NVP arm up to 1 year after ART initiation, but not beyond. Mean weight-for-age z scores were marginally higher in the NVP arm, but height-for-age z scores did not differ. Similar trends were observed in sensitivity analyses. These findings support the current World Health Organization recommendation of LPV/r in first-line ART regimens for HIV-infected children. NCT00307151.
- Phase II trial of lenalidomide in HIV-infected patients with previously treated Kaposi's sarcoma: Results of the ANRS 154 Lenakap Trial. [JOURNAL ARTICLE]
- AIDS Res Hum Retroviruses 2016 Jul 12.
Purpose Lenalidomide, an oral immunomodulating agent, has shown promising activity in HIV-infected individuals with Kaposi's sarcoma (KS). Methods This single-arm, multicenter, open-label, Gehan's two-stage phase II trial evaluated the efficacy and safety of lenalidomide in HIV-infected patients with progressive KS despite previous chemotherapy (NCT01282047, ANRS 154 Lenakap trial). The primary endpoint was the rate of partial or complete responses (PR/CR) at W24, evaluated by both the study investigators and the patients using the Physical Global Assessment (PGA). ACTG criteria for KS treatment evaluation were used as a secondary endpoint. The data and safety monitoring board recommended that enrollments be halted on 24 April 2013 because of a lack of responses. Results We enrolled 12 antiretroviral-treated HIV-infected men with progressive KS despite previous chemotherapy. Their HIV plasma viral load was <50 copies/mL and their median CD4 cell count 444/mm3. One patient stopped taking lenalidomide because of hives at W1 and a second patient died at W7. The remaining 10 patients were assessable at W24, when none had PGA-defined CR or PR and one had ACTG-defined PR. There were no additional PGA responses at week 48, but an additional 3 patients had ACTG responses, for a total of 4 patients with ACTG PR at week 48 (40%; 95% confidence interval: 12.2-73.8). Fourteen grade 3-4 adverse events were considered at least possibly related to lenalidomide during a total of 101 cycles. Conclusion Lenalidomide was well tolerated in antiretroviral experienced patients with progressive KS previously treated with chemotherapy. The ACTG-defined response rate at W48 was 40%, while it was 0% using PGA criteria.
- Improving advance care planning for English-speaking and Spanish-speaking older adults: study protocol for the PREPARE randomised controlled trial. [Journal Article]
- BMJ Open 2016; 6(7):e011705.
Advance care planning (ACP) is a process that allows patients to identify their goals for medical care. Traditionally, ACP has focused on completing advance directives; however, we have expanded the ACP paradigm to also prepare patients to communicate their wishes and make informed decisions. To this end, we created an ACP website called PREPARE (http://www.prepareforyourcare.org) to prepare diverse English-speaking and Spanish-speaking older adults for medical decision-making. Here, we describe the study protocol for a randomised controlled efficacy trial of PREPARE in a safety-net setting. The goal is to determine the efficacy of PREPARE to engage diverse English-speaking and Spanish-speaking older adults in a full spectrum of ACP behaviours.We include English-speaking and Spanish-speaking adults from an urban public hospital who are ≥55 years old, have ≥2 chronic medical conditions and have seen a primary care physician ≥2 times in the last year. Participants are randomised to the PREPARE intervention (review PREPARE and an easy-to-read advance directive) or the control arm (only the easy-to-read advance directive). The primary outcome is documentation of an advance directive and/or ACP discussion. Secondary outcomes include ACP behaviour change processes measured with validated surveys (eg, self-efficacy, readiness) and a broad range of ACP actions (eg, choosing a surrogate, identifying goals for care, discussing ACP with clinicians and/or surrogates). Using blinded outcome ascertainment, outcomes will be measured at 1 week and at 3, 6 and 12 months, and compared between study arms using mixed-effects logistic regression and mixed-effects linear, Poisson or negative binomial regression.This study has been approved by the appropriate Institutional Review Boards and is guided by input from patient and clinical advisory boards and a data safety monitoring board. The results of this study will be disseminated to academic and community stakeholders.NCT01990235; NCT02072941; Pre-results.
- Sleeve gastrectomy versus Roux-en-Y gastric bypass for type 2 diabetes and morbid obesity: double-blind randomised clinical trial protocol. [Journal Article]
- BMJ Open 2016; 6(7):e011416.
Type 2 diabetes (T2D) in association with obesity is an increasing disease burden. Bariatric surgery is the only effective therapy for achieving remission of T2D among those with morbid obesity. It is unclear which of the two most commonly performed types of bariatric surgery, laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB), is most effective for obese patients with T2D. The primary objective of this study is to determine whether LSG or LRYGB is more effective in achieving HbA1c<6% (<42 mmol/mol) without the use of diabetes medication at 5 years.Single-centre, double-blind (assessor and patient), parallel, randomised clinical trial (RCT) conducted in New Zealand, targeting 106 patients. Eligibility criteria include age 20-55 years, T2D of at least 6 months duration and body mass index 35-65 kg/m(2) for at least 5 years. Randomisation 1:1 to LSG or LRYGB, used random number codes disclosed to the operating surgeon after induction of anaesthesia. A standard medication adjustment schedule will be used during postoperative metabolic assessments. Secondary outcomes include proportions achieving HbA1c<5.7% (39 mmol/mol) or HbA1c<6.5% (48 mmol/mol) without the use of diabetes medication, comparative weight loss, obesity-related comorbidity, operative complications, revision rate, mortality, quality of life, anxiety and depression scores. Exploratory outcomes include changes in satiety, gut hormone and gut microbiota to gain underlying mechanistic insights into T2D remission.Ethics approval was obtained from the New Zealand regional ethics committee (NZ93405) who also provided independent safety monitoring of the trial. Study commenced in September 2011. Recruitment completed in October 2014. Data collection is ongoing. Results will be reported in manuscripts submitted to peer-reviewed journals and in presentations at national and international meetings.ACTRN12611000751976, NCT01486680; Pre-results.
- What are the roles and valued attributes of a Trial Steering Committee? Ethnographic study of eight clinical trials facing challenges. [Journal Article]
- Trials 2016; 17(1):307.
Clinical trials oversight by a Trial Steering Committee (TSC) is mandated by Good Clinical Practice. This study used qualitative methods to explore the role and valued attributes of the TSC to inform planned updates of Medical Research Council guidance and TSC terms of reference.An ethnographic study was conducted during 2013-2014. TSC and Trial Management Group meetings from eight trials were observed and audio-recorded, and semi-structured interviews conducted with purposively sampled key informants: independent and non-independent TSC members, trial sponsor representatives, funder representatives and chief investigators. The selected trials were currently recruiting and dealing with challenging scenarios. Data were analysed thematically and findings triangulated and integrated to give a multi-perspective account of the role and valued attributes of a TSC.Eight TSC meetings and six Trial Management Group meetings were observed. Sixty-five interviews were conducted with 51 informants. The two main roles played by the TSC were quality assurance and patient advocacy. Quality assurance involved being a 'critical friend' or a provider of 'tough love'. Factors influencing the ability of the TSC to fulfil this role included the TSC Chair, other independent TSC members and the model of the TSC and its fit with the trial subject. The role of the TSC as an advocate for patient well-being was perceived as paramount. Two attributes of TSC members emerged as critical: experience (of running a trial, trial oversight or in a clinical/methodological area) and independence. While independence was valued for giving impartiality, the lack of consensus about its definition and strict requirements of some funders made it difficult to operationalise.We found tensions and ambiguities in the roles expected of TSCs and the attributes valued of TSC members. In particular, the requirements of independence and experience could conflict, impacting the TSCs' quality assurance role. Concerns were raised regarding whose interests are served by funders' criteria of independence; in particular, funders' selection of TSC members was thought to potentially inhibit TSCs' ability to fulfil their patient advocacy role. These findings should be incorporated in revising guidance and terms of reference for TSCs.
- Rapid Growth Of Antipsychotic Prescriptions For Children Who Are Publicly Insured Has Ceased, But Concerns Remain. [Journal Article]
- Health Aff (Millwood) 2016 Jun 1; 35(6):974-82.
The rapid growth of antipsychotic medication use among publicly insured children in the early and mid-2000s spurred new state efforts to monitor and improve prescription behavior. A starting point for many oversight initiatives was the foster care system, where most of the children are insured publicly through Medicaid. To understand the context and the effects of these initiatives, we analyzed patterns and trends in antipsychotic treatment of Medicaid-insured children in foster care and those in Medicaid but not in foster care. We found that the trend of rapidly increasing use of antipsychotics appears to have ceased since 2008. Children in foster care treated with antipsychotic medications are now more likely than other Medicaid-insured children to receive psychosocial interventions and metabolic monitoring for the side effects of the medications. However, challenges persist in increasing safety monitoring and access to psychosocial treatment. Development of specialized managed care plans for children in foster care represents a promising policy opportunity. New national quality measures for safe and judicious antipsychotic medication use are also now available to guide improvement. Oversight policies developed for foster care appear to have potential for adaptation to the broader population of Medicaid-covered children.
- Default options in advance directives: study protocol for a randomised clinical trial. [Journal Article]
- BMJ Open 2016; 6(6):e010628.
Although most seriously ill Americans wish to avoid burdensome and aggressive care at the end of life, such care is often provided unless patients or family members specifically request otherwise. Advance directives (ADs) were created to provide opportunities to set limits on aggressive care near life's end. This study tests the hypothesis that redesigning ADs such that comfort-oriented care is provided as the default, rather than requiring patients to actively choose it, will promote better patient-centred outcomes.This multicentre trial randomises seriously ill adults to receive 1 of 3 different ADs: (1) a traditional AD that requires patients to actively choose their goals of care or preferences for specific interventions (eg, feeding tube insertion) or otherwise have their care guided by their surrogates and the prevailing societal default toward aggressive care; (2) an AD that defaults to life-extending care and receipt of life-sustaining interventions, enabling patients to opt out from such care; or (3) an AD that defaults to comfort care, enabling patients to opt into life-extending care. We seek to enrol 270 patients who return complete, legally valid ADs so as to generate sufficient power to detect differences in the primary outcome of hospital-free days (days alive and not in an acute care facility). Secondary outcomes include hospital and intensive care unit admissions, costs of care, hospice usage, decision conflict and satisfaction, quality of life, concordance of preferences with care received and bereavement outcomes for surrogates of patients who die.This study has been approved by the Institutional Review Boards at all trial centres, and is guided by a data safety and monitoring board and an ethics advisory board. Study results will be disseminated using methods that describe the results in ways that key stakeholders can best understand and implement.NCT02017548; Pre-results.