Convalescent plasma for treatment of COVID-19: study protocol for an open randomised controlled trial in Sweden

IntroductionAlthough there are many studies on the use of convalescent plasma (CP) for treatment of COVID-19, it is not clear (1) which groups of patients may benefit, (2) what dose of plasma to give, or (3) which antibody levels the plasma should contain. Previous phase I/II studies and literature review suggest that CP should only be given to patients with viraemia, that a daily infusion should be given until the patient becomes virus free and that the neutralising antibody titre should preferably be >1:640Methods and analysisAn open randomised controlled trial enrolling patients with COVID-19, who must be SARS-CoV-2 positive in both airway and blood samples and admitted to a study hospital. Block randomisation 2:1 is to either 200 mL CP (preferably titre ≥1/640) daily for up to 10 days (until virus negative in blood) plus standard care or standard care only (control arm). The primary endpoint is mortality by day 28 after study inclusion. Secondary endpoints include mortality by day 60 and doses of plasma needed to clear viraemia. Assuming a reduced mortality of approximately 30% by the CP therapy and 85%–88% survival in the control arm, approximately 600 participants will be enrolled to the CP therapy arm and 300 participants to the control arm.Ethics and disseminationEthical approval has been granted by the Swedish Ethical Review Authority (reference: 2020-06277). Results from this trial will be compiled in a clinical study report, disseminated via journal articles and communicated to stakeholders.Trial registration numberNCT04649879.

Long-term safety and exploratory efficacy of fevipiprant in patients with inadequately controlled asthma: the SPIRIT randomised clinical trial

Background The prostaglandin D2 (PGD2) receptor 2 (DP2 receptor) pathway is an important regulator of the inflammatory cascade in asthma, which can be stimulated by allergic or non-allergic triggers. Fevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the DP2 receptor that inhibits the binding of PGD2 and its metabolites. Methods SPIRIT, a 2-treatment period (52-week, double-blind and optional 104-week single-blind), randomised, placebo-controlled, multicentre, parallel-group study, assessed the long-term safety of fevipiprant (150 mg and 450 mg o.d.) added to standard of care in patients ≥ 12 years with uncontrolled asthma. Stratified block randomisation was used. Patients were randomised in an approximate ratio of 3:3:1 (fevipiprant 150 mg, fevipiprant 450 mg or placebo). Patients were either newly enrolled or had participated in a previous fevipiprant Phase 3 trial. Primary endpoints were: time-to-first treatment emergent adverse event (AE); serious AE; and AE leading to discontinuation from study treatment. Data from both treatment periods were combined for analyses. Data were collected during study site visits. Results In total, 1093 patients were randomised to receive fevipiprant 150 mg, 1085 to fevipiprant 450 mg, and 360 to placebo. Overall, 1184 patients had ≥ 52 weeks’ treatment, while 163 received ≥ 104 weeks’ treatment. Both doses were well tolerated, with a safety profile similar to placebo both in new patients and in those enrolled from previous studies. In exploratory analyses, reduced rates of moderate-to-severe asthma exacerbations, increased time-to-first moderate-to-severe asthma exacerbation and improved FEV1 were observed for both doses of fevipiprant versus placebo; these were without multiplicity adjustment and should be interpreted with caution. SPIRIT was terminated early, on 16 December 2019, by the Sponsor. Conclusions In patients with uncontrolled asthma, the addition of fevipiprant had a favourable long-term safety profile. Trial registration Clinicaltrials.gov, NCT03052517, prospectively registered 23 January 2017, https://clinicaltrials.gov/ct2/show/NCT03052517.

Oral Zinc supplementation in the treatment of sepsis in Nepalese children: A double-blind randomised placebo-controlled trial

Background: Sepsis is one of the most common causes of morbidity and mortality in young children. Zinc supplementation has a preventive effect against diarrhoeal diseases and respiratory infections, but little is known about its effect on the treatment of sepsis. Objectives: To evaluate the benefit of oral Zinc supplementation along with standard antimicrobial therapy in childhood sepsis. Methods: A randomised, double-blind controlled trial was conducted on 164 septic children between 1-15 years of age from 15th April 2017 to 14th April 2018 in a eastern Nepal tertiary care centre. Block randomisation was done with four participants in each block. There were 21 and 20 blocks in the intervention and in the placebo group respectively. Each child received oral zinc (20 mg elemental zinc/day) or a placebo once a day for 14 days. Percentage was calculated for descriptive statistics and Chi-square for inferential statistics with 95% CI and p <0.05 for data analysis using SPSS v.16. Results: Of the participants, 84 (51.21%) received Zinc and 80 (48.79%) received a placebo in adjunct to the standard antimicrobial therapy. Most of the children 76 (46.34%) were under five years and were male 98 (59.75%), and 69 (42.07%) were underweight. Those receiving zinc and placebo had similar improvements at discharge; there was no reduction in the need for higher-order antibiotics or in the length of PICU/ hospital stay. Zinc supplementation in childhood sepsis had no benefit on decreasing mortality or decreasing severity (p >0.05). Conclusion: Zinc supplementation during childhood sepsis does not help in short-term clinical recovery.

Using a BonE BiOPsy (BeBoP) to determine the causative agent in persons with diabetes and foot osteomyelitis: study protocol for a multicentre, randomised controlled trial

Background Diabetic foot osteomyelitis (DFO) poses a major disease burden. It can generally be treated with long-term antibacterial therapy. International guidelines recommend to base antibacterial therapy choices on percutaneous bone biopsy culture, while in practice, therapy is frequently based on (less invasive) ulcer bed cultures. It is currently unknown if treatment outcomes of DFO differ depending on the chosen diagnostic strategy. Methods The BeBoP trial is a multicentre; randomised controlled; physician-, researcher- and subject-blinded; clinical trial comparing two diagnostic strategies in persons with DFO. Culture-directed antibacterial therapy will be based on either percutaneous bone biopsy culture results (intervention group) or ulcer bed biopsy culture results (comparison group). We will enrol 80 subjects with diabetes mellitus (≥ 18 years) and DFO, and we will use block randomisation stratified per centre to randomise them in a 1:1 allocation. The primary outcome is remission of DFO 12 months after enrolment. The secondary outcomes are the time to remission, signs of inflammation or ulceration at the primary location of infection at 6 and 12 months, microbiological and molecular profiles of culture outcomes, surgical interventions including amputation, total antibacterial therapy duration, infection-free survival days, adverse events, quality of life and survival. We will compare the outcomes by intention-to-treat and per-protocol analysis. Discussion We aim to compare clinical remission in persons with DFO treated with antibacterial therapy based on either percutaneous bone biopsy culture results or ulcer bed biopsy culture results. Trial registration Netherlands Trial Register NL 7582. Registered on 05 March 2019

Comparison of Glutues Maximus Activation to Flexion Bias Exercises Along with MET Technique in Subjects with Anterior Rotated Sacroiliac Joint Dysfunction—a Randomised Controlled Trial

Background: Sacroiliac joint dysfunction (SIJD) is the primary source of lowback pain. Main muscles forming the force closure of sacroiliac joint are the biceps femoris and gluteus maximus which increase the stability through massive attachments via sacrotuberous ligament. However, there is a dearth of literature of the importance of activation of gluteus maximus in SIJD. Purpose: To study the effect of gluteus maximus activation on Oswestry Disability Index (ODI), visual analog scale (VAS), and pelvic tilt angle in subjects with anterior rotated sacrolilac joint dysfunction. Settings: The study was conducted in outpatient Physiotherapy Department, Manipal Hospital, Bangalore, India. Participants: Anterior rotated SIJD subjects were recruited in the study. They were divided into two groups (experimental and control groups) by block randomisation. Research Design: This is a randomised control trial. Controlled Treatment: Treatment order was determined by block randomisation. The subjects of both experimental and control group received Muscle Energy Technique (MET) technique on 1st session to correct the anterior rotated SIJD. The experimental group received gluteus maximus activation protocol, whereas the control group received flexion bias exercises. The groups received the treatment of 20 mins per session. There were two supervised sessions per week for four weeks. Main Outcome Measures: The primary outcome measure in the study is Oswestry Disability Index (ODI). The secondary outcome measures included visual analog scale (VAS) and Palpation Meter (PALM). Results: 48 subjects (26 females, 22 males) were randomised into experimental and control groups having anterior rotation SIJD, and average age in groups was 38.83 ± 11.4 years and 34.96 ± 9.5 years, respectively. The within-group analysis showed significant improvements in only ODI outcome of both the groups (p = .001). The between-group analysis in both groups did not show any statistical significant difference in ODI, VAS, or PALM. Conclusion: The flexion bias exercise and the gluteus maximus activation exercises used in this study were equally effective in improving physical function and reduction in pain, and maintaining the normal pelvic angle in subjects with anterior rotated SIJD.

Improving Breastfeeding by Empowering Mothers in Vietnam: A Randomised Controlled Trial of a Mobile App

Breastfeeding provides benefits to the infant and mother; however, the rates of breastfeeding, particularly exclusive breastfeeding, remain below optimal levels in many Asian countries. The aim of this study is to review the benefits of breastfeeding to mothers and infants and current rates of breastfeeding in Vietnam, and to evaluate the effectiveness of a mobile application on exclusive breastfeeding among mothers in Vietnam. A two-arm, parallel triple-blinded randomised controlled trial will be conducted among 1000 mothers in Hanoi City, Vietnam, during 2020–2021. Eligible participants are pregnant women who will seek antenatal care from health facilities at 24–36 weeks of gestation and plan to deliver at two participating hospitals, own a smartphone, and carry a singleton foetus. Permuted-block randomisation method stratified by maternal age, education and parity will be used to ensure an equal number of participants in each group. A smartphone app will be developed to deliver breastfeeding and non-breastfeeding information to the intervention and control group, respectively. Data will be collected at baseline, before hospital discharge, and at 1, 4, and 6 months postpartum. This study envisages demonstrating whether a smartphone-based intervention can be effective at improving breastfeeding in Vietnam. Trials registration: ACTRN12619000531112.

Comparison of video and in-hospital consultations during early in-home care for premature infants and their families: A randomised trial

Introduction Early in-home care is increasingly being used in Scandinavian countries for clinically stable premature infants. Due to challenges with travel and hospital resources, alternative ways to support parents during early in-home care are being considered. The aim of this study was to test whether the proportion of mothers exclusively breastfeeding, parental confidence and mother–infant interaction increased after early in-home care with premature infants, and to compare the outcomes of in-home care involving the use of video communication and a mobile application with those of in-home care involving in-hospital consultations. Methods This study was conducted in four neonatal wards offering premature infant in-home care in Denmark. Premature infants were randomised using 1:1 block randomisation. During early in-home care, families had planned consultations two to three times a week, during which they received support from nurses: the intervention group had video consultations, while the control group had in-hospital consultations. Results The proportion of exclusively breastfeeding mothers at discharge was 66.7% in the intervention group vs 66% in the control group and decreased to 49.4% vs 55%, respectively, 1 month after discharge. No significant improvements were found in the intervention group compared with the control group. In the intervention group, some video consultations were changed to telephone consultations due to problems with the video function, or to in-hospital consultations due to infants’ requirement for medical services. No significant differences in secondary outcomes were observed. Discussion The study showed similar breastfeeding proportions at discharge. No unfavourable effects of video consultation compared with in-hospital consultation were found, indicating that video consultation could be a viable option and an important supplement during early in-home care. Trial registration ClinicalTrials.gov ID: NCT02581800.

Effects of a kindergarten intervention on vegetables served and staff’s food-related practices: results of a cluster randomised controlled trial – the BRA study

Objective:The aim of the current study was to evaluate the effect on frequency, variety and amount of vegetables served and staff’s food-related practices in the multicomponent BRA intervention.Design:Cluster randomised controlled trial, conducted between Spring 2015 and Spring 2016. For allocation of the kindergartens, a stratified block randomisation was used. Data were collected in three ways: (i) a questionnaire for pedagogical leaders assessing the variety and frequency of vegetables served, including staff’s food-related practices assumed to be related to vegetable intake; (ii) a questionnaire for kindergarten assistants assessing staff’s food-related practices; (iii) a 5-d weighted vegetable diary assessing amount of vegetables served in a department.Setting:The target group for this study was public and private kindergartens in the counties of Vestfold and Buskerud, Norway.Participants:A total of seventy-three kindergartens participated.Results:At follow-up I, the amount of vegetables served increased by approximately 20 g per person per day (P = 0·002), and the variety in served vegetables increased by one-and-a-half kind per month (P = 0·014) in the intervention group compared to the control group. No effects on the frequency of vegetables served or on staff’s food-related practices were found.Conclusions:The BRA intervention was successful in increasing the amount and variety of vegetables served within intervention kindergartens. Further research is needed to understand the mechanisms that can affect the staff’s food-related practices.

Comparison of a Combination of Caudal Levobupivacaine with Fentanyl and Levobupivacaine Alone for Alleviating Postoperative Pain During Infraumbilical Procedures in Children Under 3 Years

Background: To compare the post-operative analgesic efficacy of caudal blockade using levobupivacaine alone and a combination of fentanyl with levobupivacaine in children under 3 years undergoing infraumbilical surgeries. Combination of levobupivacaine with fentanyl and levobupivacaine alone in children for caudal block was never studied before. Hence there was a need for the study. Methods: After approval from Institutional Ethical Committee, Kasturba Medical College, Mangaluru, 60 patients of age group 0-3 years, either sex of ASA physical status 1 and 2 undergoing infraumbilical surgeries were chosen after written parental consent and were randomised into 2 groups of 30 each L and LF using computer generated block randomisation to receive caudal blocks. Post operatively assessed for pain using CHIPPS scale at 2, 4, 6, 12 and 24 hours and compared in both groups. Results: Out of 60 patients, 30 in each group [L and LF], CHIPPS scores at 2, 4, 6, 12 and 24 hours post-operatively exhibited a p-value of 0.545, 0.492, 0.626, 0.166, and 0.329 respectively [not significant]. Mean duration of analgesia was 14.60 in Group L & 17.67 in Group LF with a t test p value of 0.119 [not significant]. Conclusion: Combination of fentanyl with levobupivacaine when compared to levobupivacaine alone for caudal block was equianalgesic in children less than 3 years undergoing infra umbilical procedures.

Merged block randomisation: A novel randomisation procedure for small clinical trials

Background/Aims: Randomisation in small clinical trials is a delicate matter, due to the tension between the conflicting aims of balanced groups and unpredictable allocations. The commonly used method of permuted block randomisation has been heavily criticised for its high predictability. This article introduces merged block randomisation, a novel and conceptually simple restricted randomisation design for small clinical trials (less than 100 patients per stratum). Merged block randomisation is a simple procedure that can be carried out without need for a computer. Merged block randomisation is not restricted to 1:1 randomisation, but is readily applied to unequal target allocations and to more than two treatment groups. Methods: The position of merged block randomisation on the spectrum of balance and predictability is investigated in a simulation study, in two common situations: a single-centre study and a multicentre study (with sampling stratified per centre). Methods included for comparison were permuted block randomisation, Efron’s biased coin design, the maximal procedure, the block urn design and the big stick design. Results: Compared to permuted block randomisation with blocks of size 4, merged block randomisation has the same maximum tolerated imbalance and is thus as impervious to chronological bias, with the added benefit of being less predictable. Each method in the study takes a different position on the balance/determinism spectrum, and none was uniformly best. Merged block randomisation was either less predictable or more balanced than the other methods, in all simulation settings. Conclusion: Merged block randomisation is a versatile restricted randomisation method that outperforms permuted block randomisation and is a good choice for small clinical trials where imbalance is a main concern, especially in multicentre trials where the number of patients per centre may be small.