External Control Group Research Articles

SA6 The Utility of “Single Exposure” Versus Causal Architecture Approaches in Real-World Research

Over recent decades, epidemiologic methodology has evolved substantially to encompass a gamut of techniques for focalizing on the most unbiased effect estimate of a single exposure (e.g., a treatment effect). By contrast, less attention has been paid to the refinement of study designs and analytic techniques intended to encompass the underlying milieu of co-occurring clinical, environmental, and social determinants that interactively influence disease risk or outcomes. Single exposure approaches (i.e., the “potential outcomes framework”) have been criticized as being reductionist and have long been debated in the broader epidemiologic community, despite the utility of this approach in optimizing internal validity. Further, the gap between clinical trial efficacy and real-world (RW) effectiveness remains a concern for both regulatory entities and payers, though this gap may be partly attributable to varying prevalences of important effect modifiers between trial and RW patient populations. This conceptual paper will expand upon the existing conceptual paradigms by applying them to RW research and delineating key considerations related to assessing whether a single exposure or causal architecture approach would be fit-for-purpose based on the overarching research question. Drawing upon examples from RW research types, such as use of external control groups, comparative effectiveness, and prediction of likely responders to treatment, the strengths and weaknesses of each approach will be demonstrated using case studies related to regulatory and/or payer decision-making. Methodologic recommendations will be provided. Ultimately, both single exposure and causal architecture approaches to study design and analysis have a place in pharmacoepidemiology and real-world research. A careful examination of when each approach is fit-for-purpose can lead to the application of innovative strategies to the design and conduct of RW studies.

Diagnostic Accuracy of Ocular Ultrasonography in Identifying Raised Intracranial Pressure among Pediatric Population

Introduction: Role of CT scan, MRI, ophthalmoscopy, direct monitoring by a transducer probe in identifying raised intracranial pressure (ICP) in emergency department is limited. There are few studies correlating elevated optic nerve sheath diameter (ONSD) measured by point of care ultrasound (POCUS) with raised ICP in pediatrics emergencies. We studied the diagnostic accuracy of ONSD, crescent sign, and optic disc elevation in identifying increased ICP in pediatrics. Methods: Prospective observational study was done between April 2018 and August 2019 after ethics approval. Out of 125 subjects, 40 patients without clinical features of raised ICP were recruited as external controls and 85 with clinical features of raised ICP as study subjects. Their demographic profile, clinical examination, and ocular ultrasound findings were noted. This was followed by CT scan. Out of 85 patients, 43 had raised ICP (cases) and 42 had normal ICP (disease controls). Diagnostic accuracy of ONSD in identifying raised ICP was evaluated using STATA. Results: The mean ONSD in case group was 5.5 ± 0.6 mm, 4.9 ± 0.5 mm in disease control group and external control group was 4.8 ± 0.3 mm. Cut-off of ONSD for raised ICP at ≥4.5 mm had a sensitivity and specificity of 97.67% and 10.98%, while ≥5.0 mm showed a sensitivity and specificity of 86.05% and 71.95%. Crescent sign and optic disc elevation had good correlation with increased ICP. Conclusion: ONSD ≥5 mm by POCUS identified raised ICP in pediatric population. Crescent sign and optic disc elevation may function as additional POCUS signs in identifying raised ICP.

Nasal spray of an IgM-like ACE2 fusion protein HH-120 accelerates SARS-CoV-2 clearance: A single-center propensity score-matched cohort study.

HH-120, a recently developed IgM-like ACE2 fusion protein with broad-spectrum neutralizing activity against all ACE2-utilizing coronaviruses, has been developed as a nasal spray for use as an early treatment agent to reduce disease progression and airborne transmission. The objective of this study was to evaluate the safety and efficacy of the HH-120 nasal spray in SARS-CoV-2-infected subjects. Eligible symptomatic or asymptomatic SARS-CoV-2-infected participants were enrolled in a single-arm trial to receive the HH-120 nasal spray for no longer than 6 days or until viral clearance at a single hospital between August 3 and October 7, 2022. An external control was built from real-world data of SARS-CoV-2-infected subjects contemporaneously hospitalized in the same hospital using a propensity score matching (PSM) method. After PSM, 65 participants in the HH-120 group and 103 subjects with comparable baseline characteristics in the external control group were identified. The viral clearance time was significantly shorter in participants receiving the HH-120 nasal spray than that in subjects of the control group (median 8 days vs. 10 days, p < 0.001); the difference was more prominent in those subgroup subjects with higher baseline viral load (median 7.5 days vs. 10.5 days, p < 0.001). The incidence of treatment-emergent adverse eventsand treatment-related adverse eventsof HH-120 group were 35.1% (27/77) and 3.9% (3/77), respectively. All the adverse events observed were mild, being of CTCAE grade 1 or 2, and transient. The HH-120 nasal spray showed a favorable safety profile and promising antiviral efficacy in SARS-CoV-2-infected subjects. The results from this study warrant further assessment of the efficacy and safety of the HH-120 nasal spray in large-scale randomized controlled clinical trials.

Evaluating the Effect of Sodium Phenylbutyrate and Taurursodiol on Survival Outcomes in Amyotrophic Lateral Sclerosis Using a Propensity Score–Matched Cohort From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database (S33.005)

Evaluating the Effect of Sodium Phenylbutyrate and Taurursodiol on Survival Outcomes in Amyotrophic Lateral Sclerosis Using a Propensity Score–Matched Cohort From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database (S33.005)

Long-term survival benefits of intrathecal autologous bone marrow-derived mesenchymal stem cells (Neuronata-R®: lenzumestrocel) treatment in ALS: Propensity-score-matched control, surveillance study.

Neuronata-R® (lenzumestrocel) is an autologous bone marrow-derived mesenchymal stem cell (BM-MSC) product, which was conditionally approved by the Korean Ministry of Food and Drug Safety (KMFDS, Republic of Korea) in 2013 for the treatment of amyotrophic lateral sclerosis (ALS). In the present study, we aimed to investigate the long-term survival benefits of treatment with intrathecal lenzumestrocel. A total of 157 participants who received lenzumestrocel and whose symptom duration was less than 2 years were included in the analysis (BM-MSC group). The survival data of placebo participants from the Pooled-Resource Open-Access ALS Clinical Trials (PROACT) database were used as the external control, and propensity score matching (PSM) was used to reduce confounding biases in baseline characteristics. Adverse events were recorded during the entire follow-up period after the first treatment. Survival probability was significantly higher in the BM-MSC group compared to the external control group from the PROACT database (log-rank, p < 0.001). Multivariate Cox proportional hazard analysis showed a significantly lower hazard ratio for death in the BM-MSC group and indicated that multiple injections were more effective. Additionally, there were no serious adverse drug reactions found during the safety assessment, lasting a year after the first administration. The results of the present study showed that lenzumestrocel treatment had a long-term survival benefit in real-world ALS patients.

Comparative effectiveness of mobocertinib and standard of care in patients with NSCLC with EGFR exon 20 insertion mutations: An indirect comparison

IntroductionMobocertinib is a novel, first-in-class, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to selectively target in-frame EGFR exon 20 insertions (ex20ins). Comparative effectiveness data for mobocertinib versus real-world treatments are lacking in this rare population. This study compared data for mobocertinib reported in a Phase I/II single-arm clinical trial with an external control group consisting of patients who received available treatment in the real-world setting in the United States (US). Materials and MethodsThe mobocertinib group included platinum-pretreated patients with advanced EGFR ex20ins non-small cell lung cancer (NSCLC) receiving mobocertinib 160 mg QD in an ongoing, single-arm, phase 1/2 clinical trial (NCT02716116; n = 114). The real-world data (RWD) group included platinum-pretreated patients with advanced EGFR ex20ins-mutant NSCLC from the Flatiron Health database (n = 50). Inverse probability treatment weighting based on the propensity score method controlled for potential confounding between groups. Confirmed overall response rate (cORR), progression-free survival (PFS), and overall survival (OS) were compared between groups. ResultsAfter weighting, baseline characteristics were balanced. Patients in the RWD group received EGFR TKI (20 %), immuno-oncology therapy (40 %), or any regimens containing chemotherapy (40 %) in the second- or later-line setting. In the mobocertinib and RWD groups, respectively, cORR was 35.1 % and 11.9 % (odds ratio: 3.75 [95 % confidence interval (CI): 2.05, 6.89]); median PFS was 7.3 and 3.3 months (hazard ratio [HR]: 0.57 [95 % CI: 0.36, 0.90]); and median OS was 24.0 and 12.4 months (HR: 0.53 [95 % CI: 0.33, 0.83]) after weighting. DiscussionMobocertinib showed substantially improved outcomes versus an external control group using available therapies in platinum-pretreated patients with EGFR ex20ins-mutant NSCLC. In the absence of comparative evidence from randomized trials, these findings help elucidate potential benefits of mobocertinib in this rare population.

Utility of BAP1, p16, and Methylthio-Adenosine Phosphorylase Immunohistochemistry in Cytological and Histological Samples of Pleural Mesotheliomas

Introduction: In most cases, the diagnostic workup of pleural mesotheliomas (MPMs) starts with cytological examination of pleural effusion, but histology is needed to confirm the diagnosis. The introduction of BAP1 and methylthio-adenosine phosphorylase (MTAP) immunohistochemistry has become a powerful tool to confirm the malignant nature of mesothelial proliferations also in cytological specimens. The objective of this study was to determine the concordance of BAP1, MTAP, and p16 expression between cytological and histological samples of patients with MPM. Methods: Immunohistochemistry of BAP1, MTAP, and p16 was performed on cytological samples and compared with the corresponding histological specimen of 25 patients with MPM. Inflammatory and stromal cells served as positive internal control for all three markers. In addition, samples of 11 patients with reactive mesothelial proliferations served as an external control group. Results: Loss of BAP1, MTAP, and p16 expression was found in 68%, 72%, and 92% of MPM, respectively. Loss of MTAP was associated with loss of p16 expression in all cases. Concordance of BAP1 between cytological and corresponding histological samples was 100% (kappa coefficient 1; p = 0.008). For MTAP and p16, kappa coefficient was 0.9 (p = 0.01) and 0.8 (p = 0.7788), respectively. Conclusions: Concordant BAP1, MTAP, and p16 expression is found between cytological and corresponding histological samples, indicating that a reliable diagnosis of MPM can be made on cytology only. Of the three markers, BAP1 and MTAP are most reliable in distinguishing malignant from reactive mesothelial proliferations.

Quadrant laser photocoagulation trial to ameliorate choroidal congestion in central serous chorioretinopathy.

To investigate the efficacy and safety of quadrant laser photocoagulation to ameliorate the choroidal congestion in central serous choroidopathy (CSC). Historically controlled study. We prospectively studied 20 eyes with acute CSC in the quadrant laser group, in which laser photocoagulation was applied to the macular leakage point(s) as well as the quadrant of the fundus showing vortex vein dilatation. Central choroidal thickness (CCT), vertical diameter of dilated vortex vein, resolution rate of serous retinal detachment (SRD), and visual field were evaluated post-treatment. We also compared the results with those of 18 retrospectively analyzed eyes with acute CSC in an external control group, in which laser photocoagulation had been applied only to the macular leakage point(s). In the quadrant laser group, 2 eyes were excluded from data analysis due to choroidal neovascularization (CNV). CCT was significantly reduced in both groups, but more significantly in the quadrant laser group. The vertical diameter of the dilated vortex vein was significantly decreased only in the quadrant laser group. The resolution rate of SRD was similar in the two groups. In the quadrant laser group, 8 eyes (44.4%) showed mild deterioration of the visual field, consistent with the area subjected to quadrant laser photocoagulation. Quadrant laser photocoagulation can have limited efficacy for ameliorating vortex vein congestion in CSC. When laser photocoagulation to the macular area is combined with quadrant laser photocoagulation, attention must be paid to the possible development of CNV and visual field deterioration.

NEUROPHYSIOLOGICAL BASIS OF THE COMBINED EFFECTS OF ACUTE STRESS AND LOW DOSES OF IONIZING RADIATION ON HUMAN BRAIN.

to study the clinical and neurophysiological features in the Chornobyl clean-up workers with a verified chronic cerebrovascular disease/cerebral small vessels disease (SVD) exposed to low doses of ionizing radiation (IR), employees of the Chornobyl Nuclear Power Plant (SSE ChNPP), who were exposed to the stress factor of a full-scale war as a result of being held captive by the Russian military at their workplaces, and individuals of the non-irradiated comparison group.Design, object and methods. A cross-sectional clinical study with parallel external control groups. We studied and carried out an expert statistical analysis of the clinical and neurophysiological characteristics of 62 male subjects, from which three examination groups were formed: 1) a randomized sample from the Clinical Epidemiological Register (CER) of the State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine» (NRCRM) of 22 Chornobyl clean-up workers ('Chornobyl liquidators') in 1986-1990,examined during 2020-2021, aged 50-68 years at the time of examination (M ± SD: (58.1 ± 5.2) years) with a documented external radiation dose of 0.03-2.30 Sv; 2) 24 SSE ChNPP employees exposed to the stress factor impact of a full-scale war as a result of being held captive by the Russian military at their workplaces. The average age of the examined was (54.5 ± 5.8) years (range 46-71 years). 3) Comparison group - 16 non-exposed men with verified chronic cerebrovascular disease/cerebral small vessels disease (SVD). The average age of the examined was (57.8 ± 5.6) years (range 50-70 years). Neurophysiological studies confirm the presence of the pronounced dysfunction of the cortico-limbic system of the left dominant hemisphere of the brain with special involvement of the hippocampus in the Chornobyl clean-up workers. In the SSE ChNPP group, for the first time, the disorders of cerebral neurodynamics were detected in the form of functional hypofrontality and hyperfunction of the cortico-limbic system with lateralization to the right hemisphere. Today there exists a long-term thorough methodological and evidence base for a possible neurophysiological diagnosis and differential diagnosis of the combined cerebral effects of IR and psycho-emotional stress associated with the conditions of military conflicts. Neurophysiological technologies can be used in the objective professional and qualification selection of employees in a number of professions that require quick and responsible decision-making. Employees of SSE ChNPP need further medical and psychological support due to an increased risk of developing mental health disorders.

Using an external control to contextualize efficacy data from patients with prodromal and mild Alzheimer’s disease treated with gantenerumab in SCarlet RoAD and Marguerite RoAD open‐label extension studies

AbstractBackgroundGantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Abeta), is a potential disease‐modifying treatment for early (prodromal‐to‐mild) Alzheimer’s disease (AD). SCarlet RoAD (SR) (NCT01224106) and Marguerite RoAD (MR) (NCT02051608) were two Phase III trials with open‐label extensions (OLEs), during which participants were treated with up to 1,200 mg/month of subcutaneous gantenerumab for up to 5 years. Substantial Abeta removal was confirmed without new or unexpected safety findings. This work aims to evaluate the gantenerumab treatment effect during the SR and MR uncontrolled OLE studies by using an external control group based on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.MethodParticipants from the ADNI studies were weighted using the inverse probability of treatment weighting method1 to make their demographics and baseline characteristics more comparable to the patients in the OLE stages of the pooled SR and MR studies. In the weighted sample, the treatment effects of gantenerumab, per change from the OLE Baseline in Clinical Dementia Rating – Sum of Boxes (CDR‐SB), Alzheimer’s Disease Assessment Scale – Cognitive subscale 13 (ADAS‐Cog13), and Mini‐Mental State Exam (MMSE) at Weeks 104 and 156 were investigated by a mixed‐effect model of repeated measure.ResultsApplying inclusion and exclusion criteria from the ongoing GRADUATE gantenerumab trials (NCT03444870, NCT03443973) to the SR and MR OLE cohorts, 164 participants from the SR and MR OLE studies and 1,218 participants from ADNI were selected. After weighting, the demographics and baseline characteristics were comparable between the two populations. A comparison of relative reductions between the pooled participants in SR and MR OLE studies and weighted ADNI participants can be found in Table 1.ConclusionsWhen comparing participants in the SR and MR OLE studies to a matched ADNI control group, a slower progression was observed with gantenerumab treatment. Specifically, gantenerumab showed effects on slowing cognitive decline in the SR and MR OLE studies compared with weighted ADNI participants on the CDR‐SB and ADAS‐Cog13 scales, although with a smaller effect on MMSE. The efficacy and safety of gantenerumab in early AD participants will be assessed in the two ongoing Phase III GRADUATE trials.1. Austin PC &amp; Stuart EA, 2015; Stat Med. 34:28

Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation.

Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P < 0.01) with a maximal follow-up of 3.9years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48months after vision loss (89.6% versus 48.1%; P < 0.01) and at last observation (76.1% versus 44.4%; P < 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was -0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P < 0.0001). Treatment effect was consistent across all phase3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection. The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection. NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY).

The Troublesome Ticks Research Protocol: Developing a Comprehensive, Multidiscipline Research Plan for Investigating Human Tick-Associated Disease in Australia.

In Australia, there is a paucity of data about the extent and impact of zoonotic tick-related illnesses. Even less is understood about a multifaceted illness referred to as Debilitating Symptom Complexes Attributed to Ticks (DSCATT). Here, we describe a research plan for investigating the aetiology, pathophysiology, and clinical outcomes of human tick-associated disease in Australia. Our approach focuses on the transmission of potential pathogens and the immunological responses of the patient after a tick bite. The protocol is strengthened by prospective data collection, the recruitment of two external matched control groups, and sophisticated integrative data analysis which, collectively, will allow the robust demonstration of associations between a tick bite and the development of clinical and pathological abnormalities. Various laboratory analyses are performed including metagenomics to investigate the potential transmission of bacteria, protozoa and/or viruses during tick bite. In addition, multi-omics technology is applied to investigate links between host immune responses and potential infectious and non-infectious disease causations. Psychometric profiling is also used to investigate whether psychological attributes influence symptom development. This research will fill important knowledge gaps about tick-borne diseases. Ultimately, we hope the results will promote improved diagnostic outcomes, and inform the safe management and treatment of patients bitten by ticks in Australia.

Trajectory for the Regulatory Approval of a Combination of Pertuzumab Plus Trastuzumab for Pre-treated HER2-positive Metastatic Colorectal Cancer Using Real-world Data

Utilizing real-world data (RWD) for effective clinical implementation is becoming more and more appealing as the cost of drug development rises, especially for patients with rare diseases and rare molecular subtypes for whom conducting randomized controlled trials is challenging. If a regulatory approval methodology based on RWD as an external control group can be established, drug development for rarer fractions can be accelerated by lowering costs and time, as well as reducing physical and emotional burdens on both patients and healthcare professionals. Since 2017, we have been prospectively collecting the clinical data of standard therapies in patients with rare molecular fractions under the SCRUM-Japan Registry platform, which is a qualified registry utilized as external control data for regulatory submission. Based on the results of the phase II TRIUMPH study (UMIN000027887) and the extracted data from the SCRUM-Japan Registry, the pharmaceutical company submitted an application for pertuzumab and trastuzumab in patients with HER2-positive metastatic colorectal cancer in April 2021. Pertuzumab and trastuzumab were approved as expanded indications on March 28, 2022, as 6 cases out of 14 extracted from the SCRUM-Japan Registry were classified and utilized as “evaluation material” under the review process of the Pharmaceuticals and Medical Devices Agency (PMDA). Through the TRIUMPH study and the SCRUM-Japan Registry, we have paved the way for regulatory approval of RWD in Japan. In future, we must define the steps for constructing regulatory-grade registries and the method/process for utilizing RWD by accumulating case experiences.

External control during RWD/RWE research: a methodological approach

At the moment, randomized controlled trials (RCTs) are the gold standard for providing evidence of the effectiveness and safety of medicines. If it is impossible to randomize and create an internal control group, alternative methods of collecting evidence are used, for example, the use of so-called external control groups created, among other things, based on real world data (RWD). The increase in the number of studies using RWD and external control is clearly visible in oncology, where there are problems with randomization classically. Meanwhile, this trend is of concern and requires a better understanding of the acceptability of using external control groups and validation of RWD.

Interventions to improve water, sanitation, and hygiene for preventing soil-transmitted helminth infection.

BackgroundIt is estimated that 1.5 billion people are infected with soil‐transmitted helminths (STHs) worldwide. Re‐infection occurs rapidly following deworming, and interruption of transmission is unlikely without complementary control efforts such as improvements in water, sanitation, and hygiene (WASH) access and behaviours.ObjectivesTo assess the effectiveness of WASH interventions to prevent STH infection.Search methodsWe used standard, extensive Cochrane search methods. The latest search date was 19 October 2021.Selection criteriaWe included interventions to improve WASH access or practices in communities where STHs are endemic. We included randomized controlled trials (RCTs), as well as trials with an external control group where participants (or clusters) were allocated to different interventions using a non‐random method (non‐RCTs). We did not include observational study designs. Our primary outcome was prevalence of any STH infection. Prevalence of individual worms was a secondary outcome, including for Ascaris lumbricoides, Trichuris trichiura, hookworm (Ancylostoma duodenale or Necator americanus), or Strongyloides stercoralis. Intensity of infection, measured as a count of eggs per gram of faeces for each species, was another secondary outcome.Data collection and analysisTwo review authors independently reviewed titles and abstracts and full‐text records for eligibility, performed data extraction, and assessed risk of bias using the Cochrane risk of bias assessment tool for RCTs and the EPOC tool for non‐RCTs. We used a random‐effects meta‐analysis to pool study estimates. We used Moran’s I² statistic to assess heterogeneity and conducted subgroup analyses to explore sources of heterogeneity. We assessed the certainty of the evidence using the GRADE approach.Main resultsWe included 32 studies (16 RCTs and 16 non‐RCTs) involving a total of 52,944 participants in the review. Twenty‐two studies (14 RCTs (16 estimates) and eight non‐RCTs (11 estimates)) reported on our primary outcome, prevalence of infection with at least one STH species. Twenty‐one studies reported on the prevalence of A lumbricoides (12 RCTs and 9 non‐RCTs); 17 on the prevalence of T trichiura (9 RCTs and 8 non‐RCTs); 18 on the prevalence of hookworm (10 RCTs and 8 non‐RCTs); and one on the prevalence of S stercoralis (1 non‐RCT). Sixteen studies measured the intensity of infection for an individual STH type. Ten RCTs and five non‐RCTs reported on the intensity of infection of A lumbricoides; eight RCTs and five non‐RCTs measured the intensity of infection of T trichiura; and eight RCTs and five non‐RCTs measured the intensity of hookworm infection. No studies reported on the intensity of infection of S stercoralis.The overall pooled effect estimates showed that the WASH interventions under study may result in a slight reduction of any STH infection, with an odds ratio (OR) of 0.86 amongst RCTs (95% confidence interval (CI) 0.74 to 1.01; moderate‐certainty evidence) and an OR of 0.71 amongst non‐RCTs (95% CI 0.54 to 0.94; low‐certainty evidence). All six of the meta‐analyses assessing individual worm infection amongst both RCTs and non‐RCTs had pooled estimates in the preventive direction, although all CIs encapsulated the null, leaving the possibility of the null or even harmful effects; the certainty of the evidence ranged from very low to moderate. Individual studies assessing intensity of infection showed mixed evidence supporting WASH. Subgroup analyses focusing on narrow specific subsets of water, sanitation, and hygiene interventions did very little to elucidate which interventions might be better than others. Data on intensity of infection (e.g. faecal egg count) were reported in a variety of ways across studies, precluding the pooling of results for this outcome.We did not find any studies reporting adverse events resulting from the WASH interventions under study or from mass drug administration (MDA).Authors' conclusionsWhilst the available evidence suggests that the WASH interventions under study may slightly protect against STH infection, WASH also serves as a broad preventive measure for many other diseases that have a faecal oral transmission route of transmission. As many of the studies were done in addition to MDA/deworming (i.e. MDA was ongoing in both the intervention and control arm), our data support WHO recommendations for implementation of improvements to basic sanitation and adequate access to safe water alongside MDA. The biological plausibility for improved access to WASH to interrupt transmission of STHs is clear, but WASH interventions as currently delivered have shown impacts that were lower than expected. There is a need for more rigorous and targeted implementation research and process evaluations in order that future WASH interventions can better provide benefit to users. Inconsistent reporting of the intensity of infection underscores the need to define the minimal, standard data that should be collected globally on STHs to enable pooled analyses and comparisons.

Length of initial prescription at hospital discharge and long-term medication adherence for elderly, post-myocardial infarction patients: a population-based interrupted time series study

BackgroundPreliminary evidence suggests that providing longer duration prescriptions at discharge may improve long-term adherence to secondary preventative cardiac medications among post-myocardial infarction (MI) patients. We implemented and assessed the effects of two hospital-based interventions—(1) standardized prolonged discharge prescription forms (90-day supply with 3 repeats for recommended cardiac medications) plus education and (2) education only—on long-term cardiac medication adherence among elderly patients post-MI.MethodsWe conducted an interrupted time series study of all post-MI patients aged 65–104 years in Ontario, Canada, discharged from hospital between September 2015 and August 2018 with ≥ 1 dispensation(s) for a statin, beta blocker, angiotensin system inhibitor, and/or secondary antiplatelet within 7 days post-discharge. The standardized prolonged discharge prescription forms plus education and education-only interventions were implemented at 2 (1,414 patients) and 4 (926 patients) non-randomly selected hospitals in September 2017 for 12 months, with all other Ontario hospitals (n = 143; 18,556 patients) comprising an external control group. The primary outcome, long-term cardiac medication adherence, was defined at the patient-level as an average proportion of days covered (over 1-year post-discharge) ≥ 80% across cardiac medication classes dispensed at their index fill. Primary outcome data were aggregated within hospital groups (intervention 1, 2, or control) to monthly proportions and independently analyzed using segmented regression to evaluate intervention effects. A process evaluation was conducted to assess intervention fidelity.ResultsAt 12 months post-implementation, there was no statistically significant effect on long-term cardiac medication adherence for either intervention—standardized prolonged discharge prescription forms plus education (5.4%; 95% CI − 6.4%, 17.2%) or education only (1.0%; 95% CI − 28.6%, 30.6%)—over and above the counterfactual trend; similarly, no change was observed in the control group (− 0.3%; 95% CI − 3.6%, 3.1%). During the intervention period, only 10.8% of patients in the intervention groups received ≥ 90 days, on average, for cardiac medications at their index fill.ConclusionsRecognizing intervention fidelity was low at the pharmacy level, and no statistically significant post-implementation differences in adherence were found, the trends in this study—coupled with other published retrospective analyses of administrative data—support further evaluation of this simple intervention to improve long-term adherence to cardiac medications.Trial registrationClinicalTrials.gov: NCT03257579, registered June 16, 2017Protocol available at: https://pubmed.ncbi.nlm.nih.gov/33146624/.

Treatment effectiveness in a rare oncology indication: Lessons from an external control cohort study

Real‐world data (RWD) reflecting patient treatment in routine clinical practice can be used to develop external control groups for single‐arm trials. External controls can provide valuable benchmark results on potential comparator drug effectiveness, particularly in rare indications when randomized controlled trials are either infeasible or unethical. This paper describes lessons learned from a descriptive real‐world external control cohort study conducted to provide benchmark data for a single‐arm clinical trial in a rare oncology biomarker driven disease. Conducting external control cohort studies to evaluate treatment effectiveness in rare indications likely will present data and analysis challenges as seen in the example study. However, there are mitigating measures that can be applied in the study design, identification of RWD sources, and data analysis. The lessons learned and reported here with a proposal of an external control study framework can provide guidance for future research in this area, and may be applicable as well in other rare indications. Taking these learnings into consideration, the use of real‐world external controls to contextualize treatment effectiveness in rare indications is a valuable approach and warrants further application in the future.

Using observational study data as an external control group for a clinical trial: an empirical comparison of methods to account for longitudinal missing data

BackgroundObservational data are increasingly being used to conduct external comparisons to clinical trials. In this study, we empirically examined whether different methodological approaches to longitudinal missing data affected study conclusions in this setting.MethodsWe used data from one clinical trial and one prospective observational study, both Norwegian multicenter studies including patients with recently diagnosed rheumatoid arthritis and implementing similar treatment strategies, but with different stringency. A binary disease remission status was defined at 6, 12, and 24 months in both studies. After identifying patterns of longitudinal missing outcome data, we evaluated the following five approaches to handle missingness: analyses of patients with complete follow-up data, multiple imputation (MI), inverse probability of censoring weighting (IPCW), and two combinations of MI and IPCW.ResultsWe found a complex non-monotone missing data pattern in the observational study (N = 328), while missing data in the trial (N = 188) was monotone due to drop-out. In the observational study, only 39.0% of patients had complete outcome data, compared to 89.9% in the trial. All approaches to missing data indicated favorable outcomes of the treatment strategy in the trial and resulted in similar study conclusions. Variations in results across approaches were mainly due to variations in estimated outcomes for the observational data.ConclusionsFive different approaches to handle longitudinal missing data resulted in similar conclusions in our example. However, the extent and complexity of missing observational data affected estimated comparative outcomes across approaches, highlighting the need for careful consideration of methods to account for missingness in this setting. Based on this empirical examination, we recommend using a prespecified advanced missing data approach to account for longitudinal missing data, and to conduct alternative approaches in sensitivity analyses.

Measures of Maternal Metabolic Health as Predictors of Severely Low Milk Production.

Background:A comprehensive approach to breastfeeding support requires elucidation of how metabolic health influences milk production.Objective:We compared metabolic health indicators in women with severely low milk output versus those with moderate/normal milk output using a case–control study design, with nested and external control groups.Design:Cases and nested controls were derived from women screened for a low milk supply trial, with cases defined as severely low milk output (<300 mL/24 hours), and nested controls defined as moderate/normal milk output (>300 mL/24 hours). In addition, we included an external control group of exclusively breastfeeding women. All were enrolled at 2–10 weeks postdelivery of a healthy term infant. Milk output and breast emptying frequency were recorded through test-weigh. Metabolic health variables included all components of the metabolic syndrome, homeostatic model assessment of insulin resistance (HOMA-IR), and diagnosis of gestational diabetes mellitus (GDM).Results:Maximum milk output, mL/24 hours, ranged as follows: 30–281 in cases (n = 18), 372–801 in nested controls (n = 12), and 661–915 in external controls (n = 12). Mean breast emptying frequency in cases was not significantly different from nested or external controls. All metabolic syndrome components and HOMA-IR were significantly worse in cases as compared with both nested and external control groups (p < 0.05). There was no significant difference between the nested and external control groups for these variables. GDM prevalence was 39%, 0%, and 8%, across cases, nested control, and external control groups, respectively (chi-square p-value = 0.02).Conclusion:Results from this small case–control study identify class 2+ obesity and poor metabolic health as strong risk factors for severely low milk production. These findings should be further validated in larger prospective cohort studies designed to identify individuals at risk for metabolically driven low milk supply. In addition, clinical and qualitative research studies aimed at improving patient-centered approaches to the management of persistent low milk supply are needed.

A Multicenter Evaluation of the Seraph 100 Microbind Affinity Blood Filter for the Treatment of Severe COVID-19.

OBJECTIVES:The Seraph100 Microbind Affinity Blood Filter (Seraph 100) (ExThera Medical, Martinez, CA) is an extracorporeal therapy that can remove pathogens from blood, including severe acute respiratory syndrome coronavirus 2. The aim of this study was to evaluate safety and efficacy of Seraph 100 treatment for COVID-19.DESIGN:Retrospective cohort study.SETTING:Nine participating ICUs.PATIENTS:COVID-19 patients treated with Seraph 100 (n = 53) and control patients matched by study site (n = 53).INTERVENTION:Treatment with Seraph 100.MEASUREMENTS AND MAIN RESULTS:At baseline, there were no differences between the groups in terms of sex, race/ethnicity, body mass index, and need for mechanical ventilation. However, patients in the Seraph 100 group were younger (median age, 54 yr; interquartile range [IQR], 41–65) compared with controls (median age, 64 yr; IQR, 56–69; p = 0.009). Charlson comorbidity index scores were lower in the Seraph 100 group (2; IQR, 0–3) compared with the control group (3; IQR, 2–4; p = 0.006). Acute Physiology and Chronic Health Evaluation II scores were also lower in Seraph 100 subjects (12; IQR, 9–17) compared with controls (16; IQR, 12–21; p = 0.011). The Seraph 100 group had higher vasopressor-free days with an incidence rate ratio of 1.30 on univariate analysis. This difference was not significant after adjustment. Seraph 100-treated subjects were less likely to die compared with controls (32.1% vs 64.2%; p = 0.001), a difference that remained significant after adjustment. However, no difference in mortality was observed in a post hoc analysis utilizing an external control group. In the full cohort of 86 treated patients, there were 177 total treatments, in which only three serious adverse events were recorded.CONCLUSIONS:Although this study did not demonstrate consistently significant clinical benefit across all endpoints and comparisons, the findings suggest that broad spectrum, pathogen agnostic, blood purification can be safely deployed to meet new pathogen threats while awaiting targeted therapies and vaccines.