Phase 2 trial of montelukast for prevention of pain in sickle cell disease.
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ABSTRACT:
SUBMITTER: Field JJ
PROVIDER: S-EPMC7094028 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
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Phase 2 trial of montelukast for prevention of pain in sickle cell disease.
Field Joshua J JJ Kassim Adetola A Brandow Amanda A Embury Stephen H SH Matsui Neil N Wilkerson Karina K Bryant Valencia V Zhang Liyun L Simpson Pippa P DeBaun Michael R MR
Blood advances 20200301 6
Cysteinyl leukotrienes (CysLTs) are lipid mediators of inflammation. In patients with sickle cell disease (SCD), levels of CysLTs are increased compared with controls and associated with a higher rate of hospitalization for pain. We tested the hypothesis that administration of the CysLT receptor antagonist montelukast would improve SCD-related comorbidities, including pain, in adolescents and adults with SCD. In a phase 2 randomized trial, we administered montelukast or placebo for 8 weeks. The ...[more]
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Project description:BackgroundThe up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease.MethodsIn this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed.ResultsA total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.ConclusionsIn patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361 .).
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Project description:BackgroundYoung children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA.MethodsThe Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3-7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry.DiscussionFindings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA.Trial registrationClinicalTrials.gov NCT04351698 . Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020.
| S-EPMC8502503 | biostudies-literature
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| S-EPMC4306369 | biostudies-other
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Project description:BACKGROUND:To improve the quality of care for children with sickle cell anemia in Kano, Nigeria, we initiated a standard care protocol in 2014 to manage children with strokes at Aminu Kano Teaching Hospital. METHODS:The standard care protocol requires that children with acute strokes be treated with hydroxyurea at a fixed dose of 20 mg/kg/day within two months of the stroke. RESULTS:Twenty-nine children with sickle cell anemia and initial stroke were identified based on clinical World Health Organization criteria from 2014 to 2017. Follow-up was a median of 1.04 years (interquartile range 0.43 to 1.83 years) to either July 2017 or a second stroke, corresponding to an initial stroke incidence rate of 0.88 per 100 patient-years. Eight children had a recurrent stroke, six of whom were prescribed hydroxyurea 20 mg/kg/day by two months after initial stroke. Two children died. Six of the recurrent strokes occurred within six months of the initial stroke, two before hydroxyurea prescription. The stroke recurrence rate was 17.4 events per 100 patient-years. Adherence was approximately 60%, partly because families had to pay for hydroxyurea. Stroke incidence is probably underestimated because despite formal training for stroke detection during the quality improvement period, no participant had assessment using a standardized pediatric stroke scale and neuroimaging was not available. CONCLUSIONS:In children with sickle cell anemia, a high rate of initial and recurrent strokes exists in a low-resource setting. Ongoing needs include training to detect strokes with an objective stroke assessment and government-supported free access to hydroxyurea for stroke prevention.
| S-EPMC6529264 | biostudies-literature
Project description:ImportanceSickle cell disease (SCD) is characterized by chronic pain and episodic acute pain caused by vasoocclusive crises, often requiring high doses of opioids for prolonged periods. In humanized mouse models of SCD, a synthetic cannabinoid has been found to attenuate both chronic and acute hyperalgesia. The effect of cannabis on chronic pain in adults with SCD is unknown.ObjectiveTo determine whether inhaled cannabis is more effective than inhaled placebo in relieving chronic pain in adults with SCD.Design, setting, and participantsThis pilot randomized clinical trial included participants with SCD with chronic pain admitted to a single inpatient clinical research center for 2 separate 5-day stays from August 2014 to April 2017. Participants inhaled either vaporized cannabis (4.4% Δ-9-tetrahydrocannabinol to 4.9% cannabidiol) 3 times daily or vaporized placebo cannabis. Pain and pain interference ratings using the Brief Pain Inventory were assessed throughout each 5-day period. Participants with SCD and chronic pain on stable analgesics were eligible to enroll. A total of 90 participants were assessed for eligibility; 56 participants were deemed ineligible, and 34 participants were enrolled. Of these, 7 participants dropped out before randomization. Of 27 randomized participants, 23 completed both treatment arms of the crossover study and were included in the final per protocol analysis. Data analysis was completed in June 2019, with the sensitivity analysis conducted in April 2020.InterventionsInhalation of vaporized cannabis plant (4.4% Δ-9-tetrahydrocannbinol to 4.9% cannabidiol) or placebo cannabis plant using a vaporizer 3 times daily for 5 days.Main outcomes and measuresDaily pain assessed with visual analog scale and Brief Pain Inventory.ResultsA total of 23 participants (mean [SD] age, 37.6 [11.4] years; 13 [56%] women) completed the trial. The mean (SD) difference in pain rating assessment between the cannabis and placebo groups was -5.3 (8.1) for day 1, -10.9 (7.0) for day 2, -16.5 (9.2) for day 3, -8.9 (6.7) for day 4, and -8.2 (8.1) for day 5; however, none of these differences were statistically significant. There was no statistically significant mean (SD) difference in pain interference ratings between cannabis and placebo between days 1 and 5 for interference in general activities (day 1: 0.27 [0.35]; day 5: -1.0 [0.5]), walking (day 1: 0.14 [0.73]; day 5: -0.87 [0.63]), sleep (day 1: 0.59 [0.74]; day 5: -1.3 [0.8]), or enjoyment (day 1: 0.23 [0.69]; day 5: -0.91 [0.48]), but there was a statistically significant mean (SD) difference in decrease in interference with mood (day 1: 0.96 [0.59]; day 5: -1.4 [0.6]; P = .02). No differences in treatment-related adverse effects were observed. Use of concomitant opioids was similar during both treatment periods.Conclusions and relevanceThis randomized clinical trial found that, compared with vaporized placebo, vaporized cannabis did not statistically significantly reduce pain and associated symptoms, except interference in mood, in patients with SCD with chronic pain.Trial registrationClinicalTrials.gov Identifier: NCT01771731.
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