The RING study: A Randomized Controlled Trial of GCSF-stimulated Granulocytes in Granulocytopenic Patients

Bacterial and fungal infections continue to be a major clinical problem in patients with prolonged severe neutropenia due to hematopoietic stem cell transplantation or aggressive chemotherapy. Although early controlled trials suggested that granulocyte transfusions were modestly effective in this setting, the doses of granulocytes provided in these studies were considered to be inadequate. Renewed interest in this therapy came with the possibility of greatly increasing the dose transfused by administering granulocyte colony-stimulating factor (G-CSF) ± dexamethasone to normal granulocyte donors. Subsequent studies showed that three to four times as many granulocytes could be collected from such donors, that these cells circulated in neutropenic recipients, and that the cells appeared to function normally both in vitro and in vivo. The evidence for clinical efficacy of this high-dose therapy has been inconclusive. The RING study is a recently completed randomized controlled study examining the efficacy of high-dose granulocyte transfusion therapy, carried out as part of the NHLBI Transfusion Medicine/Hemostasis Clinical Trials Network. Fourteen clinical sites participated. Subjects eligible for the study were those with neutropenia (ANC<500) and proven/probable/presumed bacterial or fungal infection. Subjects were randomized to receive either: 1) standard antimicrobial therapy; or 2) standard antimicrobial therapy plus daily granulocyte transfusions from normal donors stimulated with G-CSF (450µg) and dexamethasone (8mg). The primary endpoint was a composite one: survival plus a microbial response, both evaluated 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Desired sample size was 236 subjects, designed to have 80% power to detect a 20% difference in success rates between the treatment and control groups. One hundred and fourteen subjects were enrolled. Subjects in both arms were well matched in terms of demographics, underlying disease, types and sites of infection, and severity of illness. Of the 56 subjects randomized to the granulocyte arm, 51 received at least one transfusion. Among these 51 subjects, the median number of transfusions was five (quartiles 3 and 9) given over a median of six days (quartiles 4 and 11). The median number of granulocytes administered per transfusion was 54.9x109 (quartiles 26.1x109, 72.5x109). Among subjects with sufficient data to determine the primary outcome, success rates were 42% (20/48) and 43% (21/49) for the granulocyte and control groups, respectively (p> 0.99) on Intention to Treat analysis, and 49% (17/35) and 41% (16/39), respectively, for subjects who adhered to their assigned treatments (Per Protocol analysis; p=0.64). Overall, patient infections were 36% invasive fungal, 27% invasive bacterial, 11% fungemia, and 26% bacteremia. Differences in primary endpoint success rates for granulocyte and control arms were not statistically significantly different for any infection type whether analyzed by Intention to Treat or Per Protocol. Because of the low accrual, the power of this study to detect a 20% difference in the overall success rates was reduced to approximately 40%; it is thus possible that a true effect was missed, particularly if the effect is limited to certain subject subsets. Disclosures Off Label Use: In the study being discussed, G-CSF is administered to normal blood donors. This is an off-label use of G-CSF. .

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A Randomized Controlled Trial on the Efficacy of High-Dose Granulocyte Transfusion Therapy in Neutropenic Patients with Infection

Blood ◽

10.1182/blood.v124.21.597.597 ◽

2014 ◽

Vol 124 (21) ◽

pp. 597-597 ◽

Cited By ~ 2

Author(s):

Thomas H. Price ◽

Jeffrey McCullough ◽

Paul Ness ◽

Ronald G. Strauss ◽

Shelley M. Pulkrabek ◽

...

Keyword(s):

Primary Outcome ◽

Controlled Trial ◽

Median Number ◽

High Dose ◽

Success Rates ◽

Granulocyte Transfusion ◽

Transfusion Therapy ◽

Microbial Response ◽

Significant Difference ◽

And Control

Abstract Bacterial and fungal infections continue to be a major problem in patients with prolonged severe neutropenia. Early controlled trials suggested that granulocyte transfusions were modestly effective in this setting, but the doses provided were later considered inadequate. Recent studies have shown that the dose can be increased substantially by administering G-CSF ± dexamethasone to granulocyte donors. Although these cells circulate in neutropenic recipients and appear to function normally, the evidence for clinical efficacy has been inconclusive. We report here the result of the RING study, a recently completed randomized controlled trial on the efficacy of high-dose granulocyte transfusion therapy, carried out as part of the NHLBI Transfusion Medicine/Hemostasis Clinical Trials Network. Fourteen clinical sites participated. Eligible subjects were those with neutropenia (ANC<500) and proven/probable/presumed bacterial or fungal infection. Subjects were randomized to receive either 1) standard antimicrobial therapy or 2) standard antimicrobial therapy plus daily granulocyte transfusions from normal donors stimulated with G-CSF (450µg) and dexamethasone (8mg). The primary end point was a composite one; survival plus a microbial response, both evaluated 42 days after randomization. Microbial response was determined by a blinded adjudication panel. The target sample size was 236 subjects, designed to provide 80% power to detect a 20% difference in success rates between treatment and control groups; however, only 114 subjects could be enrolled. Patient infections were 36% invasive fungal, 27% invasive bacterial, 11% fungemia, and 26% bacteremia. Subjects in both arms were well matched in terms of demographics, underlying disease, types and sites of infection, and severity of illness. Fifty six subjects were randomized to the granulocyte arm; 51 received at least one transfusion; the mean time from eligibility to the first transfusion was 2.3 +/- 1.2 days. Among these 51 subjects, the median number of transfusions was 5 (quartiles 3 and 9), given over a median of 6 days (quartiles 4 and 11). The median number of granulocytes administered per transfusion was 54.9 x109 (quartiles 26.1 x109, 72.5 x109). Fourteen percent of these patients had > Grade 3 hypoxemia develop during or within six hours after a granulocyte transfusion, requiring ventilation in one patient (2%). No deaths were attributed to adverse effects associated with the transfusions. Among subjects with sufficient data to determine the primary outcome, success rates were 42% (20/48) and 43% (21/49) for the granulocyte and control groups, respectively (p> 0.99) on Intention to Treat (ITT) analysis, and 49% (17/35) and 41% (16/39), respectively, for subjects who adhered to their assigned treatments (Per Protocol (PP) analysis)(p=0.64). There was also no significant difference between treatment groups in a model of the primary outcome that adjusted for baseline prognostic factors (e.g. ventilator use, high Zubrod score). Differences in primary end point success rates for granulocyte and control arms did not differ significantly for any infection type whether analyzed by ITT or PP. Outcomes for patients who received the first transfusion within 2 days of eligibility were similar to outcomes for patients who received the first transfusion later. For patients who received at least three granulocyte transfusions, those who received an average dose per transfusion of >50x109 granulocytes had a higher success rate (57.7%)(n=26) than those receiving <5x109 cells per transfusion (11.1%)(n=9)(p = 0.04); while supporting the hypothesis that dose is critical to the outcome, this result needs be interpreted with caution because of the low numbers and poor outcome of the low dose group. There was no significant difference between the granulocyte and control arms on overall survival to either 42 or 90 days after randomization. Because of incomplete patient enrollment, the power of this study to detect a 20% difference in overall success rates was reduced to approximately 40%. Thus it is possible that a true convincing favorable effect was missed, particularly, as suggested, in the subset of patients who received daily transfusions containing at least 50x109 granulocytes per transfusion. Disclosures Off Label Use: In the study being discussed, G-CSF is administered to normal blood donors. This is an off-label use of G-CSF. McCullough:Fresenius/Kabe: Membership on an entity's Board of Directors or advisory committees. Ness:Terumo BCT: Consultancy.

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Protocol violations in López-Medina et al.: 38 switched ivermectin (IVM) and placebo doses, failure of blinding, widespread IVM sales OTC in Cali, and nearly identical AEs for the IVM and control groups

10.31219/osf.io/u7ewz ◽

2021 ◽

Author(s):

David Scheim ◽

Jennifer A. Hibberd ◽

Juan Chamie-Quintero

Keyword(s):

Randomized Controlled Trial ◽

Adverse Events ◽

Controlled Trial ◽

Control Group ◽

High Dose ◽

Control Groups ◽

Over The Counter ◽

Randomized Controlled ◽

Widespread Availability ◽

And Control

A randomized controlled trial for treatment of mild cases of COVID-19 conducted in Cali, Colombia reported no statistically significant differences in outcomes for its ivermectin (IVM) and placebo arms. A striking anomaly, however, was that certain adverse events (AEs) that are distinctive for the study’s high-dose IVM use occurred at nearly identical rates in its IVM and placebo arms. The backdrop for these indicators of IVM use in study controls was widespread sales of IVM for COVID-19 in the Cali area during the study period, with 1.6 IVM doses sold over the counter for each case of COVID-19. The study compounded these risks of contamination of the control arm with critical errors in blinding and segregation of IVM v. placebo doses. A labeling error substituted IVM for placebo doses of 38 patients. Also, 5% dextrose solution was used for several weeks as a placebo, easily distinguishable from bitter tasting IVM. Given widespread availability and sales of IVM in Cali, lapses in segregation and blinding of IVM and control doses, and IVM-characteristic AEs in controls, the integrity of the study’s control arm was violated. Some useful information can nevertheless be salvaged from outcomes of this study’s IVM treatment arm, which had 0 deaths and generally mild symptoms, with AEs typical for high-dose IVM (replicated in the control group) that were generally mild and transient.

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Remdesivir and Hydroxychloroquine: A Compassionate Use in Covid-19

Current Drug Targets ◽

10.2174/1389450121999201228212842 ◽

2020 ◽

Vol 21 ◽

Author(s):

Amritpal Kaur ◽

Gaurav Chaudhary ◽

Pargat Singh ◽

Sandeep Arora ◽

Rajwinder Kaur

Keyword(s):

Literature Search ◽

Review Paper ◽

Off Label Use ◽

Compassionate Use ◽

Off Label ◽

Parenteral Route ◽

Randomized Controlled ◽

Novel Coronavirus ◽

Microsoft Office ◽

Antiparasitic Agents

Objective:: Early in December 2019, a mass of sufferers with Novel Coronavirus Pneumonia (SAS-CoV-19) in Wuhan (China) roused worldwide concern. Hardly any drugs showed the light of hope concerning the depletion in the period of treatment and virological suppression is troubled. Furthermore, numerous sufferers have undergone off-label use or compassionate use treatments as well as antiretroviral, antiparasitic agents, anti-inflammatory compounds, and convales-cent plasma in either oral/parenteral route. This study aims to compile and analyze the efficient value of Remdesivir and Hydroxychloroquine and give an insight to their drug profile in the treatment and management of COVID-19 patients. Method:: The literature search from PubMed, Crossref, Springer, Bentham Sciences, Google Scholar, DOAJ, ScienceDirect, and MEDLINE by using keywords like COVID-19, SAS-COV-2, Remdesivir, and hydroxychloroquine was done and ap-propriate peer-reviewed review articles, as well as research articles, were included and compiled in this review paper. The figures were prepared by using ChemOffice 2016 (ChemDraw Professional 2016) and Microsoft Office. Results:: The results of this study indicate that remdesivir in 5/10 studies from collected literature show a reduction in time of recovery and 5/10 shows no variance and having limitations. However, 6/12 shows an increase in the survival/reduction in time of recovery and 6/12 shows no effect or has limitations in the case of hydroxychloroquine. Conclusion:: There is a need to assess more pharmacokinetics and randomized controlled trials (RCT) for both remdesivir and hydroxychloroquine. Furthermore, studies should be conducted in different combinations along with hydroxychloro-quine and remdesivir to get efficient results.

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Immersive Virtual Reality Improves Labor and Delivery Experience for Women: A Randomized Controlled Trial

10.21203/rs.3.rs-898920/v1 ◽

2021 ◽

Author(s):

Elif Gizem Carus ◽

Nazli Albayrak ◽

Selen Gur Ozmen ◽

Halit Mert Bildirici

Keyword(s):

Virtual Reality ◽

Patient Satisfaction ◽

Rating Scale ◽

Secondary Outcome ◽

Immersive Virtual Reality ◽

Labor And Delivery ◽

Control Groups ◽

Randomized Controlled ◽

Pain Scores ◽

And Control

Abstract Objective: To evaluate the effectiveness of immersive Virtual Reality (VR) in laboring women on patient satisfaction as a distractive tool and pain relief.Methods: Randomized, controlled clinical trial with 42 laboring women allocated to VR intervention and control groups. Among the VR group, patient satisfaction with the use of VR was assessed by a Virtual Reality Satisfaction Survey and questioning whether they would choose VR in future labor. As a primary outcome patient satisfaction scores regarding the overall labor and delivery experience were compared between the two groups. A secondary outcome was pain assessed by a visual pain rating scale in the early and active phases of labor in both groups. Psychometric information was also collected from participants in each group using Beck Anxiety Inventory and Beck Depression Inventory. Results: We observed a high level of patient satisfaction with the use of immersive VR during labor. The survey revealed a mean satisfaction score of 89.6 ± 10.8 out of a maximum of 100. 20 out of 21 (95%) women in the VR group stated that they would like to use VR again in future labor. VR improved pain scores in early labor and contributed positively to overall labor and delivery experience. The mean pain score pre-VR was 2.6±1.2 compared to 2.0±1.3, post-VR, respectively (p<0.01). Anxiety and depression scores were similar in the intervention and control groups (p=0.103, p=0.13, respectively). Conclusion: Immersive VR application during labor was feasible and associated with higher patient satisfaction based on our study. VR also improved pain scores in early labor before epidural placement. Immersive VR may find a place as an adjunct in Labor and Delivery Units to improve the lengthy labor experience for women. Larger studies are needed to confirm these observations. Trial Registration: ClinicalTrials.gov: NCT05032456 / 02/09/2021https://clinicaltrials.gov/ct2/show/NCT05032456

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High-dose enoxaparin in the treatment of abdominal angiostrongyliasis in Swiss mice

Journal of Helminthology ◽

10.1017/s0022149x17000852 ◽

2017 ◽

Vol 92 (6) ◽

pp. 662-667 ◽

Cited By ~ 2

Author(s):

A.S.S. Sandri ◽

R. Rodriguez ◽

M.M. Costa ◽

S.M. Porto ◽

D. Schwingel ◽

...

Keyword(s):

Survival Rates ◽

Mesenteric Arteries ◽

High Dose ◽

Control Groups ◽

Intestinal Infarction ◽

Intestinal Lesions ◽

Group 2 ◽

High Doses ◽

And Control ◽

Group 1

AbstractAbdominal angiostrongyliasis (AA) is caused by Angiostrongylus costaricensis, which inhabits mesenteric arteries. There is no drug treatment for AA, and since intestinal infarction due to thrombi is one of the main complications of the disease, the use of anticoagulants may be a treatment option. Thus, we aimed to assess the effect of high doses of enoxaparin on the prevention of ischaemic intestinal lesions and on the survival of mice infected with A. costaricensis. Twenty-four mice were infected with L3 of A. costaricensis and divided equally into two groups: Group 1, control treated with placebo, and Group 2, treated daily with enoxaparin (2.5 mg/kg) for 50 days. All mice were subjected to necropsy and histological analysis. The results from gross and microscopic assessments showed no variation in the prevalence of lesions between the groups. An analysis was also performed among survivors and non-survivors, showing that animals that died often presented lesions, such as granulation tissue in the serosa, and intestinal infarction and adhesion. The mortality rate did not vary between the enoxaparin-treated and control groups. Thus, we showed that high doses of enoxaparin have no protective effect against AA, as the survival rates and lesions of mice did not vary between the treated and control groups. Considering that the use of prophylactic doses was also shown to be ineffective in a previous study, we do not recommend the use of enoxaparin for AA treatment.

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The Effectiveness of Auditory Stimuli from Murottal Quran to Improve Comfort and Weight in Low Birth Weight Infants: Randomized Controlled Trial

Jurnal NERS ◽

10.20473/jn.v13i2.14823 ◽

2019 ◽

Vol 14 (1) ◽

pp. 111

Author(s):

Desriati Devi ◽

Yeni Rustina ◽

Defi Efendi

Keyword(s):

Randomized Controlled Trial ◽

Birth Weight ◽

Low Birth Weight ◽

Controlled Trial ◽

Auditory Stimuli ◽

Control Groups ◽

Low Birth Weight Infants ◽

Randomized Controlled ◽

Significant Difference ◽

And Control

Introduction: Low birth weight (LBW) infants who have been hospitalized are exposed to various conditions that provoke discomfort, which could trigger a stress response and growth disorders. This study aimed to identify the effects of auditory stimuli from Murottal Quran when it comes to the comfort and weight of LBW infants.Methods: This study used a clinical randomized controlled trial design involving 52 low birth weight infants. The infants were randomly assigned to either the intervention group (n=26) or the control (n=26). The intervention of Murottal Quran was given using a speaker 4 times a day for 20 minutes every 3 hours. This intervention was conducted for three days.Results: The results of this study show that there is a significant difference in the comfort of low birth weight infants after Murottal Qur’an on the first, second, and third days between the intervention and control groups (p=0.014; <0.001; <0.001). There was no significant difference in the weight between the intervention and control groups in the first, second, and third days (p=0.481; 0.481; 0.464).Conclusion: The auditory stimuli of Murottal Quran can help to improve the comfort level of low birth weight infants during hospitalization. It can therefore be used as a supportive therapy to facilitate low birth weight infant and premature infant development.

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The Effectiveness of Tocilizumab in the Treatment of COVID-19 in Adults: A Meta-Analysis of Randomized Controlled Trials.

10.21203/rs.3.rs-551091/v1 ◽

2021 ◽

Author(s):

Chun Chen ◽

ZeMei Zhou ◽

Jing Zhang

Keyword(s):

Randomized Controlled Trials ◽

Hospital Discharge ◽

Meta Analysis ◽

Controlled Trials ◽

Cochrane Central Register ◽

Composite Outcome ◽

Control Groups ◽

Randomized Controlled ◽

Serious Infection ◽

And Control

Abstract Background: Since December 2019, COVID-19 has spread to the world which leads to a global health threat. We aimed to investigate the effectiveness of tocilizumab on COVID-19 patients.Methods: We systematically searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and WHO international Clinical Trials Registry Platform (ICTRP) from their inception to March 10, 2021 for randomized controlled trials (RCTs) on tocilizumab supplementation in adults with COVID-19 disease. The primary outcomes were mortality at 28-30 day and 60-day, incidence of mechanical ventilation (MV), composite outcome of death or MV, time to hospital discharge, and intensive care unit (ICU) admissions. A random-effects meta-analysis model was used to pool studies. Results: Eleven studies with a total of 6,579 patients were included in our meta-analysis, of which 3,406 and 3,173 were respectively assigned to the tocilizumab and control groups. Tocilizumab could significantly reduce 28-30 day mortality (RR = 0.89, 95% CI 0.80-0.99, P = 0.04), incidence of MV (RR= 0.79, 95% CI 0.71-0.89, P = 0.0001), composition outcome of MV or death (RR = 0.81, 95% CI 0.72-0.90, P = 0.0002), time to hospital discharge (HR = 1.30, 95% CI 1.16-1.45, P ＜ 0.00001 ), ICU admissions (RR = 0.64, 95% CI 0.47-0.88, P = 0.006), serious infection (RR = 0.61, 95% CI 0.40-0.94, P = 0.02) and events of serious adverse advents (RR = 0.64, 95% CI 0.47-0.86, P = 0.004). There was no significant difference between tocilizumab and control groups in 60-day mortality and adverse events (AEs).Conclusions: Tocilizumab could reduce the short-term mortality, incidence of MV, composite outcome of death or MV, ICU admissions, serious infection and events of serious adverse advents, and shorten the time to hospital discharge in hospitalized patients with COVID-19. The optimal effective dose needs to be confirmed by further studies.

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A randomized controlled trial of combination of peppermint, lavender, and turmeric oil for antipruritic agent in pregnant women

Medical Journal of Indonesia ◽

10.13181/mji.oa.204467 ◽

2021 ◽

Vol 30 (1) ◽

pp. 39-44

Author(s):

Fransisca Retno Asih ◽

Farid Husin ◽

Oki Suwarsa ◽

Irda Fidrianny ◽

Dany Hilmanto

Keyword(s):

Pregnant Women ◽

Controlled Trial ◽

Control Groups ◽

Analog Scale ◽

Chi Square ◽

Herbal Products ◽

Randomized Controlled ◽

Level I ◽

And Control ◽

Single Blind

BACKGROUND Pruritus is the most common dermatological complaint that occurs during pregnancy, which is around 14–20%. No research related to herbal products to reduce some of the characteristics of pruritus at once has been conducted. This study aimed to assess the effect of blending oil to reduce pruritus based on visual analog scale (VAS). METHODS This was a single-blind, randomized clinical trial that included 57 pregnant women who were at 25–38 weeks of gestation, had a pruritus during pregnancy, a single pregnancy, a level I and II pruritus and a moderate to severe pruritus based on VAS. Pruritus scores were measured using VAS in both the treatment and control groups. The treatment and control groups applied blending oil and placebo, respectively, twice a day after bathing for 2 weeks. Mann–Whitney U, paired t, and chi-square tests were used for the analysis. RESULTS Pruritus reduction in pregnant women who received blending oil was higher than those using placebo (61.08% versus 12.41%, p<0.05). 83% of subjects using blending oils had a reduction of pruritus by >25 mm. Pregnant women who used placebo had a six times greater risk of experiencing pruritus than those who used blending oil (RR = 5.8, 95% CI = 2.613–12.874). CONCLUSIONS Blending oil can be used topically to treat a pruritus in pregnant women.

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Management of Chronic Fistula Using the Cardiac Septal Defect Occluder

10.37179/rijgh.000001 ◽

2021 ◽

Vol 01 (01) ◽

pp. 001-002

Author(s):

Guilherme Henrique Peixoto de Oliveira

Keyword(s):

Endoscopic Treatment ◽

Septal Defect ◽

Critical Role ◽

Therapeutic Endoscopy ◽

Treatment Modalities ◽

Success Rates ◽

Off Label Use ◽

Chronic Fistula ◽

Off Label ◽

Variable Success

Therapeutic endoscopy plays a critical role in the management of gastrointestinal (GI) fistulas. Innovative endoscopic approaches have revolutionized the treatment of GI fistulas; however, current endoscopic treatment modalities require multiple sessions and are associated with highly variable success rates and safety profi les. Due to these currently limitations, the off -label use of cardiac septal defect occluders (CSDOs) has emerged as a promising device to treatment GI fi stulas, with early studies suggesting it to be a technically feasible, effective, and safe treatment. Therefore, we believe CSDO devices may be a preferred option for the management of refractory GI fistulas.

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Auditory and Visual Executive Functions in Children and Response to Methylphenidate: A Randomized Controlled Trial

Journal of Attention Disorders ◽

10.1177/1087054717700978 ◽

2017 ◽

Vol 24 (2) ◽

pp. 235-245

Author(s):

Yaffa Hadar ◽

Shraga Hocherman ◽

Oren Lamm ◽

Emanuel Tirosh

Keyword(s):

Executive Functions ◽

Visual Cues ◽

Controlled Trial ◽

Crossover Design ◽

Control Groups ◽

Children With Adhd ◽

Randomized Controlled ◽

The Difference ◽

Visually Based ◽

And Control

Objectives: The aim of the study was to assess auditory and visually based executive functions (EFs) and the effect of methylphenidate (MPH) in children with ADHD. Methods: Thirty-six boys between the ages of 8.3 and 9.7 years with ADHD and 36 matched controls were included. The study group was randomized into MPH and placebo for 7 days each in a crossover design. A Cued Choice Reaction Time (CCRT) test that included incongruent cuing was administered at baseline and following 1 and 2 weeks. Results: The difference between the study and control groups was more evident with visual cues and incongruent cuing. Increased gains by children with predominantly hyperactive–impulsive\combined (HI\C) type of ADHD were observed under MPH. Conclusions: The differences between children with ADHD and typical children are more pronounce under incongruent auditory cuing . The gains attributable to MPH are more specific to tasks involving auditory and visual EFs and in children with HI\C type ADHDs.

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