Placebo-controlled Superiority Trial Research Articles

Effect of probiotic administration to breastfeeding mothers with very low birthweight neonates on some neonatal and maternal outcomes: study protocol for a randomised, double-blind, placebo-controlled trial

IntroductionPremature birth and very low birth weight (VLBW) are leading causes of neonatal mortality. Almost all premature infants experience hyperbilirubinaemia. Administering probiotics to breastfeeding mothers may positively affect infant outcomes....

The effect of UNIMMAP multiple micronutrient supplements versus iron-folic acid and placebo in anemia reduction among women of reproductive age in Kebribeyah Woreda, Somali Regional State, Ethiopia: a study protocol for a community-based individual RCT

BackgroundWomen of reproductive age (WRA) in developing countries are often at risk of micronutrient deficiencies due to inadequate intakes and excessive losses.ObjectiveThe purpose of this trial is to assess the effectiveness of United Nations International Multiple Micronutrient Antenatal Preparation-Multiple Micronutrient Supplements (UNIMMAP-MMS) versus iron-folic acid (IFA) among WRA in reducing anemia.MethodsThree parallel groups of WRA will participate in a community-based, individually randomized, double-blinded, placebo-controlled superiority trial. After consent, the sample of 375 mildly or moderately anemic women based on hemoglobin by Hemocue will be randomly assigned across two interventions and one control arm. Trial participants in intervention arms will receive UNIMMAP-MMS or IFA while those in the control arm will receive placebos twice a week for 17 weeks. The primary outcome will be a change in mean hemoglobin (Hb) concentrations. Outcome assessors and study participants will be blinded to the type of supplements and study arm.DiscussionThe World Health Organization (WHO) added UNIMMAP-MMS to its essential medicine lists in 2021 but recommended rigorous study. Several factors in addition to inadequate intakes of iron and folic acid contribute to the high prevalence of anemia among WRA in the Somali region. The findings of this study will provide evidence on the effect of UNIMMAP-MMS and IFA on Hb concentrations and anemia prevalence among anemic WRA.Trial registrationClinicalTrials.gov NCT05682261. Registered on January 12, 2023.

Perioperative intravenous lidocaine in thoracoscopic surgery for improved postoperative pain control: a randomized, placebo-controlled, double-blind, superiority trial.

Pain, including associated pain management, remains a burden on patients after thoracic surgery. Our objective was to investigate whether perioperative intravenous administration of lidocaine reduces postoperative morphine consumption and pain intensity after video-assisted thoracoscopic surgery (VATS). In this double-blind, placebo-controlled superiority trial, patients undergoing VATS with a planned duration of ≤90 minutes were randomized within an intention-to-treat setting. Patients received either intravenous lidocaine or placebo as a bolus of 1.5 mg/kg 30 minutes before incision, followed by a continuous infusion of 3.0 mg/kg/hour until 2 hours after skin closure. Pain and morphine consumption were evaluated when resting and when coughing 1, 2, 4, 8, 16, 24, and 48 hours after skin closure and in a follow-up 14, 90, and 180 days postoperatively. Twenty-eight patients were included in the lidocaine group, 24 in the placebo group. Patients' characteristics and preoperative pain scores were similar in both groups. When coughing, patients of the lidocaine group had less pain within 24 hours after skin closure than the placebo group (4.60±1.64 vs. 5.52±1.65; P=0.02). Morphine consumption was not statistically significantly lower in lidocaine group (18.22±12.87 vs. 21.26±9.39 mg; P=0.26). There were no significant differences between groups in secondary outcomes. Our results suggest that perioperative intravenous lidocaine administration reduces pain scores after VATS. The beneficial clinical effects are limited. Nevertheless, intravenous lidocaine may be helpful as part of a multimodal analgesia protocol or with patients in whom the use of other analgesics is contraindicated. ClinicalTrials.gov NCT03677817.

Reducing rebound pain severity after arthroscopic shoulder surgery under general anesthesia and interscalene block: a two-centre randomized controlled trial of pre-emptive opioid treatment compared with placebo.

Although a single-injection interscalene block provides effective early postoperative analgesia following shoulder surgery, patients may experience "rebound pain" when the block resolves. Our objective was to determine if oral hydromorphone (2 mg) given six hours after a single-injection interscalene block for arthroscopic shoulder surgery leads to a clinically significant reduction in the severity of rebound pain. After approval from research ethics boards, we conducted a two-centre, parallel-group, double-blind, randomized, placebo-controlled superiority trial. Patients received preoperative interscalene block, general anesthesia, and either hydromorphone or placebo six hours after the block. The primary outcome was the worst pain score in the first 24 hr postoperatively, measured on an 11-point (0-10) numerical rating scale. A total of 73 participants were randomly assigned to either the hydromorphone or placebo group. There was no statistically significant difference in the mean (standard deviation) worst pain score within 24 hr between the hydromorphone and placebo groups (6.5 [2.4] vs 5.9 [2.3]; mean difference, 0.6; 95% confidence interval, -0.5 to 1.8). Similarly, we did not find any significant difference in the pain trajectory, opioid use, or incidence of nausea and vomiting between the groups. The mean time to worst pain was 14.6 hr, and the mean time to first rescue analgesia was 11.3 hr after interscalene block. Hydromorphone 2 mg given six hours after interscalene block did not reduce the severity of rebound pain postoperatively compared with placebo in patients undergoing arthroscopic shoulder surgery. ClinicalTrials.gov (NCT02939209); registered 19 October 2016.

GO-Tibia: a masked, randomized control trial evaluating gentamicin versus saline in open tibia fractures

BackgroundThe rate of open tibia fractures is rapidly increasing across the globe due to a recent rise in road traffic accidents, predominantly in low- and low-middle-income countries. These injuries are orthopedic emergencies associated with infection rates as high as 40% despite the use of systemic antibiotics and surgical debridement. The use of local antibiotics has shown some promise in reducing the burden of infection in these injuries due to increasing local tissue availability; however, no trial has yet been appropriately powered to evaluate for definitive evidence and the majority of current studies have taken place in a high-resource countries where resources and the bio-burden may be different.MethodsThis is a prospective randomized, masked, placebo-controlled superiority trial designed to evaluate the efficacy of locally administered gentamicin versus placebo in the prevention of fracture-related infection in adults (age > 18 years) with primarily closeable Gustillo-Anderson class I, II, and IIIA open tibia fractures. Eight hundred ninety patients will be randomized to receive an injection of either gentamicin (treatment group) or saline (control group) at the site of their primarily closed open fracture. The primary outcome will be the occurrence of a fracture-related infection occurring during the course of the 12-month follow-up.DiscussionThis study will definitively assess the effectiveness of local gentamicin for the prevention of fracture-related infections in adults with open tibia fractures in Tanzania. The results of this study have the potential to demonstrate a low-cost, widely available intervention for the reduction of infection in open tibia fractures.Trial registrationClinicaltrials.gov NCT05157126. Registered on December 14, 2021.

Dihydroartemisinin-piperaquine or sulphadoxine-pyrimethamine for the chemoprevention of malaria in children with sickle cell anaemia in eastern and southern Africa (CHEMCHA): a protocol for a multi-centre, two-arm, double-blind, randomised, placebo-controlled superiority trial

BackgroundAn estimated 300,000 babies are born with sickle cell anaemia (SCA) annually. Affected children have chronic ill health and suffer premature death. Febrile illnesses such as malaria commonly precipitate acute crises in children with SCA. Thus, chemoprophylaxis for malaria is an important preventive strategy, but current regimes are either sub-optimally effective (e.g. monthly sulphadoxine-pyrimethamine, SP) or difficult to adhere to (e.g. daily proguanil). We propose dihydroartemisinin-piperaquine (DP) as the agent with the most potential to be used across Africa.MethodsThis will be a randomised, double-blind, parallel-group superiority trial of weekly single-day courses of DP compared to monthly single-day courses of SP in children with SCA. The study will be conducted in eastern (Uganda) and southern (Malawi) Africa using randomisation stratified by body weight and study centre. Participants will be randomised using an allocation of 1:1 to DP or SP. We will investigate the efficacy, safety, acceptability and uptake and cost-effectiveness of malaria chemoprevention with weekly courses of DP vs monthly SP in 548 to 824 children with SCA followed up for 12–18 months. We will also assess toxicity from cumulative DP dosing and the development of resistance. Participant recruitment commenced on 30 April 2021; follow-up is ongoing.DiscussionAt the end of this study, findings will be used to inform regional health policy. This manuscript is prepared from protocol version 2.1 dated 1 January 2022.Trial registrationThe trial was registered at ClinicalTrials.gov, NCT04844099. Registered on 08 April 2021.

Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients With Trauma at Risk of Massive Transfusion

Optimal transfusion strategies in traumatic hemorrhage are unknown. Reports suggest a beneficial effect of 4-factor prothrombin complex concentrate (4F-PCC) on blood product consumption. To investigate the efficacy and safety of 4F-PCC administration in patients at risk of massive transfusion. Double-blind, randomized, placebo-controlled superiority trial in 12 French designated level I trauma centers from December 29, 2017, to August 31, 2021, involving consecutive patients with trauma at risk of massive transfusion. Follow-up was completed on August 31, 2021. Intravenous administration of 1 mL/kg of 4F-PCC (25 IU of factor IX/kg) vs 1 mL/kg of saline solution (placebo). Patients, investigators, and data analysts were blinded to treatment assignment. All patients received early ratio-based transfusion (packed red blood cells:fresh frozen plasma ratio of 1:1 to 2:1) and were treated according to European traumatic hemorrhage guidelines. The primary outcome was 24-hour all blood product consumption (efficacy); arterial or venous thromboembolic events were a secondary outcome (safety). Of 4313 patients with the highest trauma level activation, 350 were eligible for emergency inclusion, 327 were randomized, and 324 were analyzed (164 in the 4F-PCC group and 160 in the placebo group). The median (IQR) age of participants was 39 (27-56) years, Injury Severity Score was 36 (26-50 [major trauma]), and admission blood lactate level was 4.6 (2.8-7.4) mmol/L; prehospital arterial systolic blood pressure was less than 90 mm Hg in 179 of 324 patients (59%), 233 patients (73%) were men, and 226 (69%) required expedient hemorrhage control. There was no statistically or clinically significant between-group difference in median (IQR) total 24-hour blood product consumption (12 [5-19] U in the 4F-PCC group vs 11 [6-19] U in the placebo group; absolute difference, 0.2 U [95% CI, -2.99 to 3.33]; P = .72). In the 4F-PCC group, 56 patients (35%) presented with at least 1 thromboembolic event vs 37 patients (24%) in the placebo group (absolute difference, 11% [95% CI, 1%-21%]; relative risk, 1.48 [95% CI, 1.04-2.10]; P = .03). Among patients with trauma at risk of massive transfusion, there was no significant reduction of 24-hour blood product consumption after administration of 4F-PCC, but thromboembolic events were more common. These findings do not support systematic use of 4F-PCC in patients at risk of massive transfusion. ClinicalTrials.gov Identifier: NCT03218722.

EBNEO commentary: Maternal high-dose DHA supplementation and neurodevelopment in infants born before 29 weeks' gestation.

This was a planned follow-up study of the Canadian multicentre, randomised, double-blind, placebo-controlled superiority trial, Maternal Omega-3 Supplementation to Reduce Bronchopulmonary Dysplasia in Very Preterm Infants (MOBYDIck). Enrolment in the primary study occurred from 2015 to 2018. A total of 457 infants were included in the final analysis.1, 2 At 18–22 months' corrected age, neurodevelopmental outcomes as assessed by Bayley-III cognitive, language, and motor composite scores were not statistically significant between the treatment and placebo groups.1 The rates of death before 18–22 months' corrected age, cerebral palsy, hearing impairment and visual impairment were also not statistically significant between the two groups.1 Some aspects may bias study results towards the null. First, approximately half the infants in both groups received intravenous docosahexaenoic acid (DHA). This was on average for 21–23 days, in the form of DHA-rich lipids. Second, there may have been additional enteral DHA supplementation in both groups. At 6 weeks postmenstrual age, infants received a median of 130–133 mL/kg/day of expressed breast milk.1 This suggests that many infants at this age were receiving supplemental nutrition, such as donor breast milk or formula. Formula frequently contains DHA.3 The use of fortifier, which also contains DHA, was not commented on.4 The total fatty acid levels in breast milk at 14 days post-delivery were, on average, similar between the groups. In the treatment group DHA composed on average 0.97% of total fatty acids in breast milk at 14 days post-delivery, and in the placebo group, 0.35%.1 The authors note the hypothesis that sole DHA supplementation may cause an imbalance between the long-chain polyunsaturated fatty acids (LCPUFAs), potentially negating the benefits of high-dose DHA supplementation.1 Indeed, expert consensus statements recommend that preterm infants are supplemented with multiple LCPUFAs, such as DHA and arachidonic acid.4, 5 Due to the lower frequency of severe intraventricular haemorrhage (IVH) in the DHA group, a post hoc sensitivity analysis excluding participants with severe IVH was completed. This did not change the primary findings. Subgroup analysis found that for neonates born <27 weeks' gestation, those in the treatment group had a higher language score (mean difference 5.06, 95% CI 0.08–10.03; p = 0.05). This analysis was not adjusted for the imbalance in frequency of IVH.1 Further study limitations are well documented by the authors. This includes a suboptimal sample size limiting study interpretation, as enrolment for the MOBYDIck trial was terminated early due to concern that DHA was associated with bronchopulmonary dysplasia.1 Additionally, the sample size was chosen for the primary outcome of the MOBYDIck trial, and therefore has limited ability to detect differences in the primary outcome of this study. Despite the theoretical benefit of LCPUFA supplementation for preterm infants, several randomised controlled trials and a Cochrane systematic review have found little, if any, clinical neurodevelopmental effect.4, 6-9 This study is important as there is limited data on very preterm and extremely preterm infants. Based on this trial, maternal supplementation with high-dose DHA in breastfed infants born before 29 weeks' gestational age does not improve neurodevelopmental outcomes at 18–22 months' corrected age. URL LINK: https://ebneo.org/ebneo-commentary-maternal-dha-and-nd DV wrote the initial draft with AK providing key input. All authors revised the paper for critical scientific content. Open access publishing facilitated by The University of Adelaide, as part of the Wiley - The University of Adelaide agreement via the Council of Australian University Librarians. AK receives funding from the Australian National Health and Medical Research Council (NHMRC) (APP1161379). The contents of this paper are solely the responsibility of the individual authors and do not reflect the views of the NHMRC. The authors have no conflicts of interest to declare.

Nighttime dexmedetomidine for delirium prevention in non-mechanically ventilated patients after cardiac surgery (MINDDS): a single-centre, parallel-arm, randomised, placebo-controlled superiority trial

The delirium-sparing effect of nighttime dexmedetomidine has not been studied after surgery. We hypothesised that a nighttime dose of dexmedetomidine would reduce the incidence of postoperative delirium as compared to placebo. This single-centre, parallel-arm, randomised, placebo-controlled superiority trial evaluated whether a short nighttime dose of intravenous dexmedetomidine (1μg/kg over 40min) would reduce the incidence of postoperative delirium in patients 60 years of age or older undergoing elective cardiac surgery with cardiopulmonary bypass. Patients were randomised to receive dexmedetomidine or placebo in a 1:1 ratio. The primary outcome was delirium on postoperative day one. Secondary outcomes included delirium within three days of surgery, 30-, 90-, and 180-day abbreviated Montreal Cognitive Assessment scores, Patient Reported Outcome Measures Information System quality of life scores, and all-cause mortality. The study was registered as NCT02856594 on ClinicalTrials.gov on August 5, 2016, before the enrolment of any participants. Of 469 patients that underwent randomisation to placebo (n=235) or dexmedetomidine (n=234), 75 met a prespecified drop criterion before the study intervention. Thus, 394 participants (188 dexmedetomidine; 206 placebo) were analysed in the modified intention-to-treat cohort (median age 69 [IQR 64, 74] years; 73.1% male [n=288]; 26·9% female [n=106]). Postoperative delirium status on day one was missing for 30 (7.6%) patients. Among those in whom it could be assessed, the primary outcome occurred in 5 of 175 patients (2.9%) in the dexmedetomidine group and 16 of 189 patients (8.5%) in the placebo group (OR 0.32, 95% CI: 0.10-0.83; P=0.029). A non-significant but higher proportion of participants experienced delirium within three days postoperatively in the placebo group (25/177; 14.1%) compared to the dexmedetomidine group (14/160; 8.8%; OR 0.58; 95% CI, 0.28-1.15). No significant differences between groups were observed in secondary outcomes or safety. Our findings suggested that in elderly cardiac surgery patients with a low baseline risk of postoperative delirium and extubated within 12h of ICU admission, a short nighttime dose of dexmedetomidine decreased the incidence of delirium on postoperative day one. Although non-statistically significant, our findings also suggested a clinical meaningful difference in the three-day incidence of postoperative delirium. National Institute on Aging (R01AG053582).

Cost-effectiveness of ursodeoxycholic acid in preventing new-onset symptomatic gallstone disease after Roux-en-Y gastric bypass surgery.

The aim was to evaluate the cost-effectiveness and cost-utility of ursodeoxycholic acid (UDCA) prophylaxis for the prevention of symptomatic gallstone disease after Roux-en-Y gastric bypass (RYGB) in patients without gallstones before surgery. Data from a multicentre, double-blind, randomized placebo-controlled superiority trial were used. Patients scheduled for laparoscopic RYGB or sleeve gastrectomy were randomized to receive 900 mg UDCA or placebo for 6 months. Indicated by the clinical report, prophylactic prescription of UDCA was evaluated economically against placebo from a healthcare and societal perspective for the subgroup of patients without gallstones before surgery who underwent RYGB. Volumes and costs of in-hospital care, out-of-hospital care, out-of-pocket expenses, and productivity loss were assessed. Main outcomes were the costs per patient free from symptomatic gallstone disease and the costs per quality-adjusted life-year (QALY). Patients receiving UDCA prophylaxis were more likely to remain free from symptomatic gallstone disease (relative risk 1.06, 95 per cent c.i. 1.02 to 1.11; P = 0.002) compared with patients in the placebo group. The gain in QALYs, corrected for a baseline difference in health utility, was 0.047 (95 per cent bias-corrected and accelerated (Bca) c.i. 0.007 to 0.088) higher (P = 0.022). Differences in costs were -€356 (95 per cent Bca c.i. €-1573 to 761) from a healthcare perspective and -€1392 (-3807 to 917) from a societal perspective including out-of-pocket expenses and productivity loss, both statistically non-significant, in favour of UDCA prophylaxis. The probability of UDCA prophylaxis being cost-effective was at least 0.872. UDCA prophylaxis after RYGB in patients without gallstones before surgery was cost-effective.

Coffee is more than just caffeine – a single-center, randomized, double-blinded, placebo-controlled superiority trial (CaCo trial)

Abstract Objective Avoidance of prolonged postoperative bowel paralysis after colorectal surgery is of major importance due to its significant clinical implications. Postoperative caffeine consumption appears to be a promising strategy. The aim of this study was to assess whether postoperative oral caffeine intake shortens bowel hypomotility after elective laparoscopic colorectal surgery. Methods This was a single-center, randomized, double-blinded, placebo-controlled superiority trial conducted from October 1st, 2015 to August 10th, 2020. Patients aged &amp;gt;=18 years with malignant or benign disease undergoing elective laparoscopic colectomy were included and assigned randomly before surgery to receive 3x daily either 100 mg caffeine or 200 mg caffeine or 250 mg corn starch (placebo) after the procedure. Substances were served in indistinguishable capsules three times daily before the meals. The primary endpoint was time to first bowel movement, measured from the time of wound closure to the patient's first defecation. Secondary endpoints included colonic transit time, time to tolerance of solid food, length of hospital stay and perioperative morbidity. Results A total of 60 patients were randomized, 20 to each group. Twenty-seven patients followed the protocol and were included in the per-protocol (PP) analysis. Baseline characteristics were similarly distributed among the groups. In intention-to-treat analysis, the time to first bowel movement in the caffeine 200 mg group was 67.9 h (standard deviation [SD] 19.2), in the caffeine 100 mg group 68.2 h (SD 32.2) and in the placebo group 67.3 h (SD 22.7) (p=0.887). PP analysis and measurement of colonic transit time (41.8 h [SD 21.7] in the caffeine 200 mg group, 34.2 h [SD 22.9] in the caffeine 100 mg group and 46.3 h [SD 20.6] in the placebo group, p=0.317) confirmed non-significant differences. The time to tolerance of solid food, length of hospital stay and postoperative morbidity were comparable among the three groups and no deaths or related serious adverse events were observed during the study. Conclusion Although caffeine intake after laparoscopic colorectal surgery is safe, its administration was not associated with a shortened time to first bowel movement in contrast to previous studies. Thus, other ingredients of coffee might be responsible for the intestinal stimulatory effect previously described.

Effects of light stroking massage with olive oil on acute pain severity and number of taken non-steroidal anti-inflammatory drugs among outpatients with extremities trauma: A double-blind, placebo-controlled superiority trial

IntroductionCurrently, analgesics are used to alleviate acute pain after trauma; however, these drugs cause some undesirable adverse effects. Hence, there is a need for nonpharmacological methods to reduce trauma-induced pain. This study investigated the effects of massage with olive oil on acute pain severity and number of taken non-steroidal anti-inflammatory drugs (NSAIDs) among trauma patients. MethodsIn this double-blind, placebo-controlled superiority trial, 42 outpatients who suffered from superficial injury in upper or lower extremities were randomly assigned to olive oil and placebo groups. Patients received a 5-min light stroking massage on the trauma site twice a day for nine consecutive days with 10 drops of either olive oil or placebo (liquid paraffin). Also, they received NSAIDs and applied cold and warm compresses on the trauma site. The pain severity (a 0–10 numerical pain rating scale) and the number of NSAIDs were recorded at four points of time, including before the intervention (baseline), and on the third, sixth, and ninth days of intervention. ResultsThere was a significant difference between the study groups in mean ranks of the number of NSAIDs taken on the baseline and third days (P = 0.02, P = 0.009). Considering the number of NSAIDs taken during nine days as a covariate, a significant decrease in the pain severity was found in two groups during the nine days (Ptime< 0.001). However, pain reduction over time was more significant in the olive oil group (Ptime*group = 0.001). Also, mean changes in the pain severity compared to the baseline were significant on the sixth (P = 0.001) and ninth (P = 0.002) days of the intervention in favor of the olive oil group. ConclusionAdministration of light stroking massage with olive oil as a complementary method seems to be potentially effective in reducing the pain severity and use of NSAIDs among patients with trauma to the extremities.

PolyMyalgia Rheumatica treatment with Methotrexate in Optimal Dose in an Early disease phase (PMR MODE): study protocol for a multicenter double-blind placebo controlled trial

BackgroundPolymyalgia rheumatica (PMR) is an inflammatory rheumatic disease affecting people older than 50, resulting in pain and stiffness of the neck, shoulder, and pelvic girdle. To date, glucocorticoids (GC) remain the cornerstone of treatment, but these have several drawbacks. Firstly, a large proportion of patients do not achieve GC-free remission within either the first (over 70%) or second year of treatment (over 50%). Secondly, GC-related adverse events (AE) occur in up to 65% of patients and can be severe.The current EULAR/ACR guidelines for PMR recommend early introduction of methotrexate (MTX) as a GC sparing agent in patients at risk for worse prognosis. However, earlier trials of low to medium quality only studied MTX dosages of 7.5–10 mg/week with no to modest effect. These doses may be suboptimal as MTX is recommended in higher doses (25 mg/week) for other inflammatory rheumatic diseases. The exact role, timing, and dose of MTX in PMR remain unclear, and therefore, our objective is to study the efficacy of MTX 25 mg/week in recently diagnosed PMR patients.MethodsWe set up a double-blind, randomized, placebo-controlled superiority trial (PMR MODE) to assess the efficacy of MTX 25 mg/week versus placebo in a 1:1 ratio in 100 recently diagnosed PMR patients according to the 2012 EULAR/ACR criteria. All patients will receive prednisolone 15 mg/day, tapered to 0 mg over the course of 24 weeks. In case of primary non-response or disease relapse, prednisolone dose will be temporarily increased. Assessments will take place at baseline, 4, 12, 24, 32, and 52 weeks. The primary outcome is the difference in proportion of patients in GC-free remission at week 52.DiscussionNo relapsing PMR patients were chosen, since the possible benefits of MTX may not outweigh the risks at low doses and effect modification may occur. Accelerated tapering was chosen in order to more easily identify a GC-sparing effect if one exists. A composite endpoint of GC-free remission was chosen as a clinically relevant endpoint for both patients and rheumatologist and may reduce second order (treatment) effects.Trial registrationDutch Trial Registration, NL8366. Registered on 10 February 2020

Celecoxib versus placebo as an adjunct to treatment-as-usual in children and youth with obsessive–compulsive disorder: protocol for a single-site randomised quadruple-blind phase II study

BackgroundCyclooxygenase (COX) enzymes oxidise arachidonic acid to prostaglandins, which modulate neuronal function and inflammation in the central nervous system. Consensus guidelines suggest non-steroidal anti-inflammatory drugs as a possible adjunctive approach...

A multi-centre, randomized, double-blind, placebo-controlled clinical trial of the efficacy and safety of chloroquine phosphate, hydroxychloroquine sulphate and lopinavir/ritonavir for the treatment of COVID-19 in Lagos State: study protocol for a randomized controlled trial

BackgroundThe coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that was first identified in Wuhan, Hubei, China, in December 2019. It was recognized as a pandemic by the World Health Organization on 11 March 2020. Outbreak forecasting and mathematical modelling suggest that these numbers will continue to rise. Early identification of effective remedies that can shorten the duration and severity of illness is critical for Lagos State, which is the epi-centre of the disease in Nigeria.MethodsThis is a multi-centre, randomized, double-blind placebo-controlled superiority trial. The study investigates the efficacy of chloroquine phosphate, hydroxychloroquine sulphate and lopinavir/ritonavir added on to standard of care compared to standard of care only in patients with COVID-19 disease. The primary outcome is the clinical status of patients measured using a 7-point ordinal scale at day 15. Research participants and clinicians will be blinded to the allocated intervention. Outcome measures will be directly assessed by clinicians. Statistical analysis will be done by a team blinded to the identity and allocation of research participants. Data analysis will follow intention-to-treat methods, using R software.DiscussionThe current study is of strategic importance for Lagos State in potentially curbing the health, social and economic burden of COVID-19 disease. Should the current study demonstrate that either of the three intervention drugs is more efficacious than standard therapy alone, the State Ministry of Health will develop an evidence-based guideline for the management of COVID-19 in Lagos State. The findings will also be shared nationally and with other states which may lead to a standardized national guideline for the treatment of COVID-19 in Nigeria.Trial registrationPan African Clinical Trials Register PACTR202004801273802. Registered prospectively on April 2, 2020

Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery (UPGRADE): a multicentre, double-blind, randomised, placebo-controlled superiority trial

Rapid weight loss is a major risk factor for the formation of cholesterol gallstones. Consequently, patients with morbid obesity undergoing bariatric surgery frequently develop symptomatic gallstone disease. This trial assessed the efficacy of ursodeoxycholic acid versus placebo for the prevention of symptomatic gallstone disease after bariatric surgery. This multicentre, double-blind, randomised, placebo-controlled superiority trial enrolled patients with an intact gallbladder scheduled for laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy in three hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module to receive 900 mg ursodeoxycholic acid daily for 6 months or matched placebo. Randomisation was stratified by the presence of asymptomatic gallstones at baseline and type of surgery. Patients, clinicians, and study staff were masked to treatment allocation. The primary endpoint was symptomatic gallstone disease within 24 months, assessed in the modified intention-to-treat population (all randomly assigned eligible patients with any post-randomisation measurement). Prespecified subgroup analyses were done based on the stratification groups. Safety was assessed in all patients who took at least one dose of the study drug. This trial is registered with the Netherlands Trial Register, NL5954. Between Jan 11, 2017, and Oct 22, 2018, 985 patients were randomly assigned to receive either ursodeoxycholic acid (n=492) or placebo (n=493). 967 patients were included in the modified intention-to-treat population, of whom 959 had data available for primary endpoint assessment. 189 (20%) patients had asymptomatic gallstones at baseline and 78 (8%) received a sleeve gastrectomy. Symptomatic gallstone disease occurred in 31 (6·5%) of 475 patients in the ursodeoxycholic acid group and in 47 (9·7%) of 484 patients in the placebo group (relative risk 0·67, 95% CI 0·43-1·04, p=0·071). Logistic regression showed a significant interaction between ursodeoxycholic acid and the presence of asymptomatic gallstones at baseline (p=0·046), with an effect of ursodeoxycholic acid in patients without (0·47, 0·27-0·84, p=0·0081), and no effect in patients with asymptomatic gallstones at baseline (1·22, 0·61-2·47, p=0·57). The effect was stronger in patients without gallstones at baseline undergoing RYGB (0·37, 0·20-0·71, p=0·0016), whereas the subgroup of patients undergoing sleeve gastrectomy was too small to draw clear conclusions. Adverse events were rare. In the ursodeoxycholic acid group, diarrhoea occurred in four (0·9%) of 444 patients and skin rash in two (0·5%) patients. In the placebo group, diarrhoea occurred in two (0·4%) of 453 patients and skin rash in two (0·4%) patients. The total number of serious adverse events did not significantly differ between the trial groups (75 [17%] in 444 patients in the ursodeoxycholic acid group and 102 [23%] in 453 patients in the placebo group). The most common serious adverse events were abdominal pain and internal hernia. No serious adverse event was attributed to the study drug. Ursodeoxycholic acid prophylaxis did not significantly reduce the occurrence of symptomatic gallstone disease in all patients after bariatric surgery. In patients without gallstones before RYGB surgery, ursodeoxycholic acid treatment reduced the occurrence of symptomatic gallstone disease compared with placebo. Further research is needed to assess the efficacy of ursodeoxycholic acid after sleeve gastrectomy. The Netherlands Organization for Health Research and Development, Zambon Netherlands BV, Foundation for Clinical Research of the Slotervaart Hospital, the Spaarne Gasthuis Academy, and Amsterdam Gastroenterology Endocrinology Metabolism.

Two Intravenous Injections of Ketamine at 24h-Interval for the Acute Treatment of Severe Suicidal Ideas: A Randomised Double-Blind Placebo-Controlled Superiority Trial

Background: Ketamine is suggested to have rapid-onset anti-suicidal benefits. This must be confirmed in a large sample, alongside a potential moderating effect of comorbid mental disorders. Methods: Double-blind superiority trial comparing ketamine (0•5mg/kg) to placebo, conducted in seven teaching hospitals in France (KETIS). Participants aged 18 and older with current suicidal ideation were electronically randomised and stratified by centre and main diagnosis: bipolar, depressive, or other (non-psychotic) disorders. Two 40-min intravenous injections were administered at baseline and after 24 hours in addition to usual treatment. The primary outcome was the rate of patients in full suicidal remission at Day 3, according to clinician-rated Scale for Suicidal Ideation total score < 3. Analyses were conducted on an intention-to-treat basis. Registered on ClinicalTrials.gov (NCT02299440)(trial closed). Findings: 156 participants were recruited between April 13, 2015 and March 12, 2019 and randomised to placebo (n=83) or ketamine (n=73). More patients reached full remission of suicidal ideas at Day 3 in the ketamine than placebo arm (63•0 vs. 31•6%). However, this effect differed according to diagnoses (treatment: p<0•001; interaction: p=0•02): bipolar (Odds Ratio (OR 95% confidence interval)=14•1 (3•0 – 92•2), p=0•0005), depressive (OR=1•3 (0•3 – 5•2), p=0•6), or other disorders (OR=3•7 (0•9 – 17•3, p=0•07)). Side effects were limited. No manic or psychotic symptom was observed. Moreover, a mediating effect of mental pain was found. At Week 6, the ketamine arm remained superior to placebo for full suicidal remission (69•5 vs. 56•3%). Interpretation: This study confirmed the rapid, safe and persistent benefits of ketamine for acute care in suicidal patients. However, comorbid mental disorders appear to be important moderators. An analgesic effect on mental pain could explain ketamine’s anti-suicidal effects. Clinical Trial Registration Details: This study is listed on www.ClinicalTrials.gov (NCT02299440), and EudraCT: 2014-001324-30 (trial closed). Funding Information: The study was funded by a national public grant (PHRC-N 2013). Declaration of Interests: FJ has no declaration of interests for the last 5 years. PG received during the last 5 years fees for presentations at congresses or participation in scientific boards from Alcediag-Alcen, Angelini, GSK, Janssen, Lundbeck, Otsuka, SAGE and Servier. Wissam El-Hage reports personal fees from EISAI, Janssen, Lundbeck, Otsuka, UCB and Chugai. PC received speaker and consultation fees from Exeltis, Janssen and Pfizer. GV is part of a scientific board for Janssen. RG has received compensation as a member of the scientific advisory board of Janssen, Lundbeck, Roche, SOBI, Takeda. He has served as consultant and/or speaker for Astra Zeneca, Boehringer-Ingelheim, Pierre Fabre, Lilly, Lundbeck, MAPREG, Otsuka, Pileje, SANOFI, Servier, LVMH and received compensation, and he has received research support from Servier. Co-founder and stock shareholder: Regstem. PM has received compensation as consultant and member of a scientific advisory board for Janssen. LS declares fees for advisory board, travel support activities of consultant and lecturer in the last 5 years received from Janssen, Lundbeck and Otsuka. PML declares fees for Advisory board, travel support activities of consultant, lecturer and faculty member in the last 5 years received from Eisai, Janssen, Lundbeck, Otsuka, Sanofi, Teva. MA declares fees from Astra Zeneca and Lundbeck, and has been invited to congresses by Janssen-Cilag, Otsuka, Lundbeck, Servier and Astra Zeneca. CD and PF have no conflicts of interests to declare Ethics Approval Statement: Ethics approval was obtained on July 18, 2014 from the Research Ethics Board “Comite de Protection des Personnes (CPP) Sud Mediterranee III”.All patients gave their informed, written and signed consent before inclusion.

Eplerenone versus placebo for chronic central serous chorioretinopathy: the VICI RCT

Background In chronic central serous chorioretinopathy, fluid accumulates in the subretinal space and causes permanent vision loss in ≈ 30% of patients. There is no definitive treatment. Previous research suggests that the mineralocorticoid receptor antagonist eplerenone is effective but it is not licensed for chronic central serous chorioretinopathy. Objectives The objective was to evaluate whether or not eplerenone was safe and superior to placebo for treating chronic central serous chorioretinopathy. We also aimed to set up a biobank of DNA, serum and plasma samples from treatment-naive participants for future research. Design The trial was a parallel, randomised (1 : 1 ratio), multicentre, double-masked, placebo-controlled superiority trial comparing eplerenone plus usual care with placebo plus usual care. Participants were randomly allocated to eplerenone or placebo using a secure online system that returned a unique number corresponding to a bottle of the investigational medicinal product. Participants, clinical care teams, pharmacists, outcome assessors and the trial management group were masked. Setting The trial took place in 22 NHS hospitals in the UK. Participants Eligible participants were patients aged 18–60 years with treatment-naive chronic central serous chorioretinopathy of at least 4 months’ duration, a best corrected visual acuity score of 54–85 letters and no other conditions affecting visual acuity or contraindications to taking eplerenone or placebo. Interventions The intervention was oral eplerenone (25 mg/day for 1 week, increased to 50 mg/day for up to 12 months). Placebo was a lactose-filled capsule that appeared identical to the overencapsulated eplerenone tablets. To maintain blinding, participants in the placebo group followed the same dose escalation schedule as the eplerenone group. Usual care was included in both groups and was administered at the discretion of clinicians. Main outcome measures The primary outcome was best corrected visual acuity score at 12 months. Secondary outcomes were low-luminance visual acuity, central subfield retinal thickness, change in subretinal fluid thickness, systemic and ocular adverse events, macular atrophy of the retinal pigment epithelium, subfoveal choroidal thickness, choroidal permeability, resolution of subretinal fluid, time to recurrence of subretinal fluid, fundus fluorescein angiography phenotype, incidence of chronic central serous chorioretinopathy in the fellow eye, and patient-reported visual function. Results Between 11 January 2017 and 22 February 2018, 57 participants were randomised to eplerenone and 57 to placebo; 57 and 54 participants, respectively, were included in the analysis of the primary outcome. The modelled mean best corrected visual acuity score at 12 months in the eplerenone and placebo groups was 80.4 letters (standard deviation 4.6 letters) and 79.5 letters (standard deviation 4.5 letters), with an estimated difference between groups of 1.73 letters (95% confidence interval –1.12 to 4.57 letters; p = 0.24). Hyperkalaemia occurred in eight participants in each group (14%). No serious adverse events occurred in the eplerenone group; three unrelated serious adverse events occurred in the placebo group. Limitations Limitations included the inability to prevent co-treatments and discontinuation of the investigational medicinal product in the event of resolution or hyperkalaemia. Conclusions Eplerenone was safe but not superior to placebo in improving best corrected visual acuity in people with chronic central serous chorioretinopathy during 12 months of follow-up. In future work, ophthalmologists should investigate alternative treatments for this condition, which remains complicated to treat. Trial registration Current Controlled Trials ISRCTN92746680. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 2. See the NIHR Journals Library website for further project information.

175. Randomized Double-blind Controlled Trial of Short vs. Standard Course Outpatient Therapy of Community Acquired Pneumonia in Children (SCOUT-CAP)

BackgroundCommunity-acquired pneumonia (CAP) in children is usually treated with 10 days of antibiotics. Shorter antibiotic courses may be beneficial if proven effective, with potentially fewer antibiotic adverse effects and decreased antibiotic exposure.MethodsThis randomized, double-blind, placebo-controlled superiority trial (NCT02891915) compared a strategy of short vs standard course ß-lactam therapy for outpatient CAP in children ages 6–71 months. Children demonstrating clinical improvement by day 3–5 of initial therapy were considered for enrollment. Enrolled children were randomized 1:1 to receive either 5 additional days of the originally prescribed antibiotic (standard) or matching placebo (short). The Desirability of Outcome Ranking (DOOR; PMID: 26113652) was the primary outcome, and was defined by classifying the global experience of children into an ordinal clinical response (OCR) that combined the response to CAP treatment and antibiotic adverse effects 11–15 days after the start of therapy. For those subjects with equivalent OCR, documented days of antibiotic administration was used to further rank the desirability of the outcome with the a priori assumption that shorter antibiotic exposure was more desirable. The OCR was a secondary outcome. The intention to treat population was used to estimate the probability of a more desirable outcome for the strategy of short vs. standard course therapy for both outcomes.Results385 children were enrolled; 380 had complete data for analysis. Baseline characteristics were similar between the two strategies. In both strategies, > 90% of children had an adequate response to CAP treatment and most antibiotic adverse effects were minor (Table). In the OCR analysis, short course therapy had a 48% probability (95% CI: 42%-53%) of a more desirable outcome. In the DOOR analysis, short course therapy was superior to standard therapy with a 69% probability (95% CI: 63%-72%; p< 0.001) of a more desirable outcome. ConclusionAmong children with CAP demonstrating initial clinical improvement with outpatient therapy, both strategies had a similar response to CAP treatment and antibiotic adverse effects, but short course therapy was superior in our a priori defined outcome that incorporated decreased antibiotic exposure.Disclosures Emmanuel B. Walter, MD, MPH, Moderna (Grant/Research Support)Pfizer (Grant/Research Support) Jason Newland, MD, MEd, FPIDS, Merck (Grant/Research Support)Pfizer (Other Financial or Material Support, Industry funded clinical trial) Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Actavis (Grant/Research Support)Advanced Liquid Logics (Grant/Research Support)Affinergy (Consultant, Research Grant or Support)Affinium (Consultant)Allergan (Grant/Research Support)Ampliphi Biosciences (Consultant)Basilea (Consultant, Research Grant or Support)Bayer (Consultant)C3J (Consultant)Cerexa (Consultant, Research Grant or Support)Contrafect (Consultant, Research Grant or Support)Cubist (Grant/Research Support)Debiopharm (Consultant)Destiny (Consultant)Durata (Consultant)Forest (Grant/Research Support)Genentech (Consultant, Research Grant or Support)Integrated Biotherapeutics (Consultant)Janssen (Consultant, Research Grant or Support)Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)Medimmune (Consultant, Research Grant or Support)Merck (Consultant, Research Grant or Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis (Consultant, Research Grant or Support)Pfizer (Grant/Research Support)Regeneron (Consultant, Research Grant or Support)Tetraphase (Consultant)Theravance (Consultant, Research Grant or Support)Trius (Consultant)xBiotech (Consultant) W. Charles Huskins, MD, MSc, ADMA Biologics (Consultant)Pfizer, Inc (Consultant)

Efficacy and safety of cilostazol-nimodipine combined therapy on delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage: a prospective, randomised, double-blinded, placebo-controlled trial protocol

IntroductionDelayed cerebral ischaemia (DCI) due to cerebral vasospasm (cVS) remains the foremost contributor to morbidity and mortality following aneurysmal subarachnoid haemorrhage (aSAH). Past efforts in preventing and treating DCI have...