Hepcidin-guided screen-and-treat interventions for young children with iron-deficiency anaemia in The Gambia: an individually randomised, three-arm, double-blind, controlled, proof-of-concept, non-inferiority trial.
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SUBMITTER: Wegmuller R
PROVIDER: S-EPMC9764454 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Hepcidin-guided screen-and-treat interventions for young children with iron-deficiency anaemia in The Gambia: an individually randomised, three-arm, double-blind, controlled, proof-of-concept, non-inferiority trial.
Wegmüller Rita R Bah Amat A Kendall Lindsay L Goheen Morgan M MM Sanyang Saikou S Danso Ebrima E Sise Ebrima A EA Jallow Amadou A Verhoef Hans H Jallow Momodou W MW Wathuo Miriam M Armitage Andrew E AE Drakesmith Hal H Pasricha Sant-Rayn SR Cross James H JH Cerami Carla C Prentice Andrew M AM
The Lancet. Global health 20230101 1
<h4>Background</h4>Iron deficiency is the most prevalent nutritional disorder worldwide. Iron supplementation has modest efficacy, causes gastrointestinal side-effects that limit compliance, and has been associated with serious adverse outcomes in children across low-income settings. We aimed to compare two hepcidin-guided screen-and-treat regimens designed to reduce overall iron dosage by targeting its administration to periods when children were safe and ready to receive iron supplementation, ...[more]
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Project description:BackgroundWHO recommends daily iron supplementation for pregnant women, but adherence is poor because of side-effects, effectiveness is low, and there are concerns about possible harm. The iron-regulatory hormone hepcidin can signal when an individual is ready-and-safe to receive iron. We tested whether a hepcidin-guided screen-and-treat approach to combat iron-deficiency anaemia could achieve equivalent efficacy to universal administration, but with lower exposure to iron.MethodsWe did a three-arm, randomised, double-blind, non-inferiority trial in 19 rural communities in the Jarra West and Kiang East districts of The Gambia. Eligible participants were pregnant women aged 18-45 years at between 14 weeks and 22 weeks of gestation. We randomly allocated women to either WHO's recommended regimen (ie, a daily UN University, UNICEF, and WHO international multiple-micronutrient preparation [UNIMMAP] containing 60 mg iron), a 60 mg screen-and-treat approach (ie, daily UNIMMAP containing 60 mg iron for 7 days if weekly hepcidin was <2·5 μg/L or UNIMMAP without iron if hepcidin was ≥2·5 μg/L), or a 30 mg screen-and-treat approach (ie, daily UNIMMAP containing 30 mg iron for 7 days if weekly hepcidin was <2·5 μg/L or UNIMMAP without iron if hepcidin was ≥2·5 μg/L). We used a block design stratified by amount of haemoglobin at enrolment (above and below the median amount of haemoglobin on every enrolment day) and stage of gestation (14-18 weeks vs 19-22 weeks). Participants and investigators were unaware of the random allocation. The primary outcome was the amount of haemoglobin at day 84 and was measured as the difference in haemoglobin in each screen-and-treat group compared with WHO's recommended regimen; the non-inferiority margin was set at -5·0 g/L. The primary outcome was assessed in the per-protocol population, which comprised all women who completed the study. This trial is registered with the ISRCTN registry, number ISRCTN21955180.FindingsBetween June 16, 2014, and March 3, 2016, 498 participants were randomised, of whom 167 were allocated to WHO's recommended regimen, 166 were allocated to the 60 mg per day screen-and-treat approach, and 165 were allocated to the 30 mg per day screen-and-treat approach. 78 participants were withdrawn or lost to follow-up during the study; thus, the per-protocol population comprised 140 women assigned to WHO's recommended regimen, 133 allocated to the 60 mg screen-and-treat approach, and 147 allocated to the 30 mg screen-and-treat approach. The screen-and-treat approaches did not exceed the non-inferiority margin. Compared with WHO's recommended regimen, the difference in the amount of haemoglobin at day 84 was -2·2 g/L (95% CI -4·6 to 0·1) with the 60 mg screen-and-treat approach and -2·7 g/L (-5·0 to -0·5) with the 30 mg screen-and-treat approach. Adherence, reported side-effects, and adverse events were similar between the three groups. The most frequent side-effect was stomachache, which was similar in the 60 mg screen-and-treat group (82 cases per 1906 person-weeks) and with WHO's recommended regimen (81 cases per 1974 person-weeks; effect 1·0, 95% CI 0·7 to 1·6); in the 30 mg screen-and-treat group the frequency of stomachache was slightly lower than with WHO's recommended regimen (58 cases per 2009 person-weeks; effect 0·7, 95% CI 0·5 to 1·1). No participants died during the study.InterpretationThe hepcidin-guided screen-and-treat approaches had no advantages over WHO's recommended regimen in terms of adherence, side-effects, or safety outcomes. Our results suggest that the current WHO policy for iron administration to pregnant women should remain unchanged while more effective approaches continue to be sought.FundingBill & Melinda Gates Foundation and the UK Medical Research Council.
| S-EPMC7109523 | biostudies-literature
Project description:BackgroundMechanical labour induction with a transcervical balloon is as effective as pharmacological methods, with fewer adverse effects. Its use has been limited to labour induction with an unfavourable cervix able to retain the balloon. We have developed an innovative approach using 2-3 balloons side-by-side to extend the benefits of mechanical labour induction/augmentation with a favourable cervix without having to resort to amniotomy or uterotonics.ObjectivesTo assess the effectiveness of side-by-side balloons for extended labour induction/augmentation.MethodsWe conducted a single arm proof of concept trial at Princess Marina Hospital (PMH) in Gaborone, Botswana. Participants were assessed as unsuitable for single balloon labour induction based on a modified Bishop cervical score of 7 or more. Three Foley catheters taped symmetrically side by side were passed through the cervix and inflated with 60mls each. Traction was applied with a weight of 250mls water suspended over the bed-end. The use of uterotonics, time from induction to birth, mode of birth, Apgar scores and adverse maternal and neonatal outcomes were recorded. Participants' satisfaction with the method of labour induction was assessed using a descriptive scale.ResultsWe enrolled 20 participants of whom two were nulliparous. Indications for labour induction were mainly late term (70%) and hypertensive disorders of pregnancy (25%). The mean cervical score was 7.2. Overall, 17 (85%) of the participants achieved a vaginal birth, of whom 5 required oxytocin for labour augmentation. Four of these had requested removal of the balloons, one due to discomfort and three felt the process was taking too long. Three participants underwent caesarean birth. The mean time from initiation of labour induction to vaginal birth was 16 h (standard deviation (SD) 8.4) and 20 h for caesarean birth (SD 10.5). There were no 5-minute Apgar scores below 7 nor neonatal admissions. One baby required brief resuscitation. There were no adverse maternal outcomes.ConclusionThis proof-of-concept study suggests that use of side-by-side balloons in participants with favourable cervix is effective in achieving vaginal birth in most participants without uterotonics or amniotomy. There were no adverse outcomes, though the study was too small to exclude the possibility of rare adverse outcomes. This offers a novel option for labour induction/augmentation, particularly where uterotonics or amniotomy are best avoided such as prior caesarean birth, vertical infection transmission risk and in settings with limited capacity for fetal surveillance. The results clearly justify larger randomized trials to evaluate this novel approach with greater precision. On the basis of the current study we are developing a purpose-designed balloon for extended balloon labour induction.
| S-EPMC10462842 | biostudies-literature
Project description:IntroductionAlternative drugs and diagnostics are needed for the treatment and control of schistosomiasis. The exclusive use of praziquantel (PZQ) in mass drug administration programmes may result in the emergence of drug resistance. PZQ has little activity against Schistosoma larvae, thus reinfection remains a problem in high-risk communities. Furthermore, the insufficient sensitivity of conventional microscopy hinders therapeutic response assessment. Evaluation of artesunate-mefloquine (AM) as a Novel Alternative Treatment for Schistosomiasis in African Children (SchistoSAM) aims to evaluate the safety and efficacy of the antimalarial combination artesunate-mefloquine, re-purposed for the treatment of schistosomiasis, and to assess the performance of highly sensitive novel antigen-based and DNA-based assays as tools for monitoring treatment response.Methods and analysisThe SchistoSAM study is an open-label, two-arm, individually randomised controlled non-inferiority trial, with a follow-up of 48 weeks. Primary school-aged children from the Richard Toll district in northern Senegal, an area endemic for Schistosoma mansoni and Schistosoma haematobium, are allocated to the AM intervention arm (3-day courses at 6-week intervals) or the PZQ control arm (single dose of 40 mg/kg). The trial's primary endpoints are the efficacy (cure rate (CR), assessed by microscopy) and safety (frequency and pattern of drug-related adverse events) of one AM course versus PZQ at 4 weeks after treatment. Secondary endpoints include (1) cumulative CR, egg reduction rate and safety after each additional course of AM, and at weeks 24 and 48, (2) prevalence and severity of schistosomiasis-related morbidity and (3) malaria prevalence, incidence and morbidity, both after 24 and 48 weeks. CRs and intensity reduction rates are also assessed by antigen-based and DNA-based diagnostic assays, for which performance for treatment monitoring is evaluated.Ethics and disseminationEthics approval was obtained both in Belgium and Senegal. Oral assent from the children and signed informed consent from their legal representatives was obtained, prior to enrolment. The results will be disseminated in peer-reviewed journals and at international conferences.Trial registration numberNCT03893097; pre-results.
| S-EPMC8231067 | biostudies-literature
Project description:Brain arteriovenous malformations (bAVMs) are relatively rare, although their potential for secondary intracranial haemorrhage (ICH) makes their diagnosis and management essential to the community. Currently, invasive therapies (surgical resection, stereotactic radiosurgery and endovascular embolisation) are the only interventions that offer a reduction in ICH risk. There is no designated medical therapy for bAVM, although there is growing animal and human evidence supporting a role for bevacizumab to reduce the size of AVMs. In this single-arm pilot study, two patients with large bAVMs (deemed unresectable by an interdisciplinary team) received bevacizumab 5 mg/kg every 2 weeks for 12 weeks. Due to limitations of external funding, the intended sample size of 10 participants was not reached. Primary outcome measure was change in bAVM volume from baseline at 26 and 52 weeks. No change in bAVM volume was observed 26 or 52 weeks after bevacizumab treatment. No clinically important adverse events were observed during the 52-week study period. There were no observed instances of ICH. Sera vascular endothelial growth factor levels were reduced at 26 weeks and returned to baseline at 52 weeks. This pilot study is the first to test bevacizumab for patients with bAVMs. Bevacizumab therapy was well tolerated in both subjects. No radiographic changes were observed over the 52-week study period. Subsequent larger clinical trials are in order to assess for dose-dependent efficacy and rarer adverse drug effects. Trial registration number: NCT02314377.
| S-EPMC8204171 | biostudies-literature
Project description:PurposeThe aim of the present study was to describe the profiles of a sample of young cannabis users not seeking care, for use in general practice in France.MethodsIn this cross-sectional study, baseline data were used from a previous clinical randomized trial, in which a brief intervention was tested. The participants were 262 cannabis users aged 15 to 25 years who smoked at least one joint per month. Assessment was undertaken both by the GP and via an anonymous self-reporting questionnaire. All statistical analyses were performed using Stata software and R. We used multiple correspondence analysis to determine the profiles of users.ResultsAmong the 262 patients, 46.2% were daily users (more than 30 joints per month), 25.6% were regular users (from 10 to 29 joints per month), and 28.2% were recent users (fewer than 10 joints per month). The higher the frequency of use, the greater the incidence of unaccompanied use, daily use and week use (p from <0.001 to 0.01). The motivations of daily users were mostly self-treatment and habit (p <0.05). The cannabis abuse screening trial score revealed risky use for 87.5% of daily users and 34.4% for recent users. Factorial analysis identified 5 profiles according to age, risk, and motive for use. The reasons for consultation were equally distributed among users regardless of their level of use or their profile (p > 0.05).ConclusionsThe results provide support for the practice of asking young patients systematically about their cannabis use, allowing GPs to identify users who require medical care. GPs should consider the differences between participants according to their profile in order to determine the appropriate type of care.Trial registrationClinicaltrials.gov NCT01433692.
| S-EPMC6886842 | biostudies-literature
Project description:Three-arm non-inferiority (NI) trial including the experimental treatment, an active reference treatment, and a placebo where the outcome of interest is binary are considered. While the risk difference (RD) is the most common and well explored functional form for testing efficacy (or effectiveness), however, recent FDA guideline suggested measures such as relative risk (RR), odds ratio (OR), number needed to treat (NNT) among others, on the basis of which NI can be claimed for binary outcome. Albeit, developing test based on these different functions of binary outcome are challenging. This is because the construction and interpretation of NI margin for such functions are non-trivial extensions of RD based approach. A Frequentist test based on traditional fraction margin approach for RR, OR and NNT are proposed first. Furthermore a conditional testing approach is developed by incorporating assay sensitivity (AS) condition directly into NI testing. A detailed discussion of sample size/power calculation are also put forward which could be readily used while designing such trials in practice. A clinical trial data is reanalyzed to demonstrate the presented approach.
| S-EPMC6867690 | biostudies-literature
Project description:BackgroundAmygdala activity dysregulation plays a central role in post-traumatic stress disorder (PTSD). Hence learning to self-regulate one's amygdala activity may facilitate recovery. PTSD is further characterized by abnormal contextual processing related to the traumatic memory. Therefore, provoking the personal traumatic narrative while training amygdala down-regulation could enhance clinical efficacy. We report the results of a randomized controlled trial (NCT02544971) of a novel self-neuromodulation procedure (i.e. NeuroFeedback) for PTSD, aimed at down-regulating limbic activity while receiving feedback from an auditory script of a personal traumatic narrative. To scale-up applicability, neural activity was probed by an fMRI-informed EEG model of amygdala activity, termed Amygdala Electrical Finger-Print (AmygEFP).MethodsFifty-nine adults meeting DSM-5 criteria for PTSD were randomized between three groups: Trauma-script feedback interface (Trauma-NF) or Neutral feedback interface (Neutral-NF), and a control group of No-NF (to control for spontaneous recovery). Before and immediately after 15 NF training sessions patients were blindly assessed for PTSD symptoms and underwent one session of amygdala fMRI-NF for transferability testing. Follow-up clinical assessment was performed at 3- and 6-months following NF treatment.ResultsPatients in both NF groups learned to volitionally down-regulate AmygEFP signal and demonstrated a greater reduction in PTSD symptoms and improved down-regulation of the amygdala during fMRI-NF, compared to the No-NF group. The Trauma-NF group presented the largest immediate clinical improvement.ConclusionsThis proof-of-concept study indicates the feasibility of the AmygEFP-NF process-driven as a scalable intervention for PTSD and illustrates its clinical potential. Further investigation is warranted to elucidate the contribution of AmygEFP-NF beyond exposure and placebo effects.
| S-EPMC8551212 | biostudies-literature
Project description:We report results of a randomized controlled trial to compare 'HPV screen and treat' (Arm 1) and 'HPV screen, triage and treat' (Arm 2) in women living with HIV (WLHIV), using visual inspection with acetic acid (VIA) as the triaging test. Treatment was offered to all HPV-positive women in Arm 1 and to VIA-positive women in Arm 2 with either thermal ablation or large loop excision. All women underwent a repeat HPV test one year after randomization. The primary outcome was non-inferiority of HPV clearance of Arm 2 at one-year follow up when compared to Arm 1. Of 544 HPV-positive consenting WLHIV, 433 were randomised in a 1:1 ratio to trial arms. At baseline, CIN 2/3 lesions were detected in 16.7% and 13.3% women in Arm 1 and Arm 2 respectively. HPV clearance was observed in 56.6% (95%CI 48.9-64.1) women in Arm 1 and 41.4% (95%CI 34.3-48.7) women in Arm 2 at follow-up in the intention-to-treat population (P = 0.004). 'HPV screen, VIA triage and treat' strategy was non-inferior to the 'screen and treat' strategy as the lower bound of the 95% confidence interval from the regression model was greater than 0.49 in both intention-to-treat analysis (RR 0.73, 95%CI 0.59-0.91) and per-protocol analysis (RR 0.74, 95%CI 0.60-0.93) according to the pre-specified analysis plan. Clinical trial registration: CTRI/2020/02/023349.
| S-EPMC11846853 | biostudies-literature
Project description:The aim of this study was to assess the acceptability and feasibility of offering risk-based breast cancer screening and its integration into regular clinical practice. A single-arm proof-of-concept trial was conducted with a sample of 387 women aged 40-50 years residing in the city of Lleida (Spain). The study intervention consisted of breast cancer risk estimation, risk communication and screening recommendations, and a follow-up. A polygenic risk score with 83 single nucleotide polymorphisms was used to update the Breast Cancer Surveillance Consortium risk model and estimate the 5-year absolute risk of breast cancer. The women expressed a positive attitude towards varying the frequency of breast screening according to individual risk and, especially, more frequently inviting women at higher-than-average risk. A lower intensity screening for women at lower risk was not as welcome, although half of the participants would accept it. Knowledge of the benefits and harms of breast screening was low, especially with regard to false positives and overdiagnosis. The women expressed a high understanding of individual risk and screening recommendations. The participants' intention to participate in risk-based screening and satisfaction at 1-year were very high.
| S-EPMC9407798 | biostudies-literature
Project description:BackgroundThere is strong rationale for interference with T cell co-stimulation in IgG4-related disease (IgG4-RD), but the literature to evaluate this is limited to a single case report.MethodsWe conducted a ten-subject proof-of-concept trial of abatacept in active IgG4-RD. All subjects met the ACR/EULAR Classification Criteria for IgG4-RD. Subjects received subcutaneous abatacept 125 mg weekly for 24 weeks. Concurrent glucocorticoid treatment was permitted but if used had to be discontinued by week four. The primary endpoint, complete remission at 24 weeks, was defined as an IgG4-RD Responder Index score of 0. Peripheral blood mononuclear cells were collected at baseline, four weeks, and 12 weeks. B and T cell subsets were quantified using a 25-parameter flow cytometry panel.FindingsThe subjects' median age was 68 years; seven subjects were male and nine were Caucasian. Baseline organ involvement was diverse with a median of 5 organs affected at the time of enrollment. The median serum IgG4 concentration was 597 mg/dL (IQR 304-913 mg/dL). Three subjects received concomitant prednisone at baseline. Six subjects (60%) had a disease response by week 12, five of whom maintained this response at week 24. Abatacept was stopped in the remaining five subjects (50%) due to flare (N = 1) or lack of response by week 12 (N = 4). Three subjects (30%) achieved the primary endpoint.Baseline proportions of unswitched memory B cells predicted responsiveness to abatacept. Reductions in serum IgE, circulating plasmablasts, and activated type 2 T follicular helper (TFH2) cells correlated with response to treatment. One adverse event (grade two thrombocytopenia) was attributed to abatacept.InterpretationAbatacept was associated with variable treatment responses in IgG4-RD. Half of the subjects achieved sustained treatment responses to abatacept alone, without glucocorticoids. Correlates of clinical response included reductions in serum IgE, circulating plasmablasts, and activated TFH2 cells. Response to abatacept was predicted by higher proportions of unswitched memory B cells at baseline.
| S-EPMC9004478 | biostudies-literature