a b s t r a c t

Objective: A recent academic-government partnership demonstrated the feasibility of utilizing Emergency De- partments (ED) as a primary site for subject enrollment in clinical trials and achieved high rates of recruitment in two U.S. EDs. Given the ongoing need to test new therapeutics for influenza And other emerging infections, we sought to describe the historical rates of participant recruitment into influenza Phase III therapeutic RCTs in various clinical venues, including EDs.

Study design: A cross-sectional study was performed of influenza therapeutic Phase III RCTs published in PubMed, Embase, Scopus, and Clinicaltrials.gov from January 2000 to June 2019.

Main outcome: To estimate the weighted-average number of influenza-positive participants enrolled per site per season in influenza therapeutic RCT conducted in clinical settings, and to describe basic trial site characteristics. Results: 47 (0.7%) of 7008 articles were included for review of which 43 of 47 (91%) included information regard- ing enrollment sites; of these, 2 (5%) recruited exclusively from EDs with the remainder recruiting from mixed clinical settings (inpatient, outpatient, and ED). The median enrollment per study was 326 (IQR: 110, 502.5) with a median of 11 sites per study (IQR: 2, 59.5). Included studies reported a median of 201 (IQR: 74, 344.5) confirmed influenza-positive participants per study. The pooled number of participants enrolled per site per season was 11 (95% CI: 10, 12). The pooled enrollment numbers per clinical site after excluding the two ‘ED only recruitment’ studies were less [10.7 (95% CI: 9.9, 11.6)] than the pooled enrollment numbers per clinical site for the two ‘ED only recruitment’ studies [89.5 (95% CI 89.2-89.27)].

Conclusion and relevance: Published RCTs evaluating influenza therapeutics in clinical settings recruit participants from multiple sites but enroll relatively few participants, per site, per season. The few ED-based studies reported recruited more subjects per site per season. Untapped opportunities likely exist for EDs to participate and/or lead therapeutic RCTs for influenza or other emerging Respiratory pathogens.

(C) 2022

1. Introduction
   1. Background

? Presented in part: 2021 Society for Academic Emergency Medicine Virtual Annual Meeting, May 11-14, 2021.

* Corresponding author at: Johns Hopkins University Department of Emergency Medicine, 5801 Smith Avenue, Suite 3220 Davis Building, Baltimore, MD 21209, United States of America.

E-mail address: [email protected] (Y.-H. Hsieh).

¹ Rothman and Niforatos contributed equally to this manuscript and should be consid- ered co-first authors.

Seasonal influenza accounts for an estimated 290,000 to 650,000 deaths annually [1]. Despite efforts to produce a targeted vaccine, the ef- fectiveness of seasonal Influenza vaccine has ranged from 19% to 60% over the last decade amongst recipients in the United States [2,3]. Given less than ideal efficacy of vaccines, there exists an ongoing need for development and evaluation of targeted therapeutics for influenza, to prevent and treat complications. The same holds true for current and future planning and response to respiratory virus epidemic and

https://doi.org/10.1016/j.ajem.2022.09.003

0735-6757/(C) 2022

pandemics, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Approval from the Food and Drug Administration is required for the use of therapeutics for treatment of respiratory Viral illness, in- cluding influenza. The process for approval can be lengthy, culminating in Phase III Randomized controlled trials to demonstrate efficacy (superiority, non-inferiority, or equivalence). Currently, several neuraminidase inhibitors (e.g. oseltamivir, peramivir, and zanamivir) and polymerase acidic protein inhibitors (baloxavir) are FDA approved for influenza treatment [4]. Challenges remains, however, with regard to optimizing the operations of Phase III RCTs for seasonal and pandemic viral respiratory illnesses. Amongst these are the time, efforts and costs required to set-up and administer clinical trials (particularly multi- center and multi-national trials), the potential for emergence of viral re- sistance associated with the therapeutic agent under investigation, and the varied severity of illness amongst patients and seasons, which may require testing of the antiviral for specific indications [5,6]. Clinical trialists and government sponsors have also reported difficulties with recruitment of adequate numbers of participants, as a major barrier [7,8]. A potential untapped resource for improving clinical trial recruit- ment is emergency departments (ED).

• 1. Importance

Each year, EDs evaluate and care for a substantial proportion of all

U.S. patients with influenza-like illness who have acute Respiratory infections, a subset of whom are ultimately diagnosed with influenza [9,10]. Historically, EDs have been under-utilized as a primary clinical venue for recruitment and enrollment of patients into RCTs designed to evaluate new influenza therapeutics, despite the fact that they repre- sent the front lines of our health care setting for both diagnosis and treatment [7]. Recently, an academic-government partnership was commissioned by the Biomedical Advance research and development Authority (BARDA) with the expressed purpose of assessing the feasibil- ity of utilizing EDs as a primary site for subject enrollment in clinical trials; that study evaluated as a prototype, rates of recruitment as well as clinical outcomes of subjects treated with one of the newer influenza agent (intravenous peramivir), in comparison with those treated with oral oseltamivir, providing pilot data for future clinical trial design and planning [11]. Results from that study demonstrated comparable clini- cal outcomes, as well as the ability to achieve high rates of patient re- cruitment in two U.S. EDs, with an average of 60 patients enrolled per ED, per season (or a total of 179 subjects enrolled with site 1 enrolling for 2 consecutive seasons, and site 2 enrolling for 1 season) [12].

• 1. Goals of this investigation

Given this background, we conducted a cross-sectional analysis of the literature to ascertain the historical rates of patient recruitment into published influenza therapeutic RCTs in varied clinical settings, de- scribing basic trial site characteristics, and compare findings with what was reported from the recent BARDA sponsored ED-initiated influenza RCT described above [11].

1. Methods
   1. Study design

A cross-sectional analysis of published Phase III influenza therapeu- tic RCTs published in PubMed, Embase, Scopus, and Clinicaltrials.gov was conducted in accordance with Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines [13]. Inclu- sion criteria was restricted to human RCTs reported in the published literature from January 2000 to June 2019, in which enrolled subjects were tested and confirmed to have influenza. There was no restriction

on participant age, sex, or health status. Studies that were not random- ized Controlled clinical trials were excluded.

• 1. Literature search

A search construct to capture influenza therapeutic RCTs was devel- oped with the aid of a medical research librarian. The complete search strategy detailed in supplementary document was applied to Pubmed, Embase, Scopus, and Clinicaltrials.gov.

• 1. Study selection

Two authors (M.Y. and N.P.) independently applied the inclusion criteria to all identified and retrieved articles (Fig. 1, Flow diagram). A third person (Y-H.H.), an experienced infectious disease epidemiolo- gist, supervised the procedure and resolved any disagreements via discussion serving as a tie-breaker to achieve consensus.

• 1. Data extraction

A structured data extraction tool was used to collect study character- istics. The authors (M.Y. and N.P.) who reviewed the articles extracted data from all included publications independently. Results were compared and differences were resolved by consensus, as described above. The following characteristics were extracted from all included studies: author, Publication year, location of study, clinical setting type (outpatient or inpatient), primary outcome, study duration, number of influenza seasons included in the study, age range of the study popula- tion, numbers of participants randomized, numbers of participants with a confirmed influenza test, and whether or not an ED was included as a site of recruitment for study participants, as determined by a systematic search for the term emergency room or ED in the text of the Methods. Lack of information was recorded and used for the assessment for risk of biases.

• 1. Outcomes

The primary outcome of this study was to estimate the weighted average number of influenza-positive participants enrolled per site per season in Phase III influenza therapeutic RCT conducted in clinical settings, and to describe basic trial site characteristics. Basic trial site characteristics included clinical setting (e.g., inpatient, outpatient, ED), duration of the study, number of study site, participant’s age range, number of participants randomized, number of participants with confirmed influenza, and therapeutics studied.

• 1. Statistical analysis

Data extracted from included studies were described using descrip- tive statistics. The overall pooled number of participants enrolled per site per influenza season and the corresponding 95% confidence intervals (CI) were calculated use a meta-analytic estimate with ran- dom effects model as described by Neyeloff and colleagues for Microsoft Excel v16 [14]. A DerSimonian and Laird random-effects model was used with the assumption there exists high variability in sampling errors and study populations across included studies [15]. Heterogene- ity was assessed for pooled estimates using the Cochran’s Q and I² statis- tics. Sensitivity analysis was performed on sites that did not use ED use the sole participant enrollment site.

1. Results
   1. Study screening and selection

Overall, 7008 unique articles were identified from the initial search of 7384 articles after removal of duplicates (Fig. 1). Title and abstract

Records identified through database searching

(n = 7384)

Fig. 1. Flow Diagram.

Articles excluded due to lack of information on the number of enrollment sites (n = 4)

Full-text articles excluded, with reasons

(n = 280)

Records excluded (n =6682)

Studies included in quantitative synthesis (meta-analysis)

(n = 43)

Full-text articles assessed for eligibility

(n = 326)

Studies included in qualitative synthesis (n = 47)

Records screened (n =7008)

Additional records identified through other sources

(n = 0)

Records after duplicates removed (n = 7384)

Duplicates (n =376)

Hand picked articles included (n = 1)

Included

screening identified 326 articles (4.6%) that met inclusion criteria of which 47 articles (14.4%) fully met eligibility criteria and were included for review.

Eligibility

Screening

Identification

• 1. Study characteristics

The majority of included RCT studies enrolled participants in Asia (47%), followed by Americas (17%), multi-continental (19%), Europe (13%), and Oceania (4%). Clinical enrollment sites included outpatient (12 studies), inpatient (14 studies), inpatient and outpatient (5 stud- ies), undisclosed (14 studies), ED and outpatient (1 study), and the ED only (2 studies). On average, each study enrolled participants through- out 1.5 (median: 1; IQR 1, 2) influenza seasons with one study taking place over 4 influenza seasons. The vast majority of studies (81%) enrolled participants across multiple sites rather than utilizing a single enrollment location. The average number of participants per study was 365 (median: 326; IQR: 110, 502.5, Range: 21, 1138), and the aver- age number of sites per study was 41 (median: 11; IQR: 2, 59.5, Range: 1, 323). The average number of confirmed influenza positive participants per study was 256 (median: 201; IQR: 74, 344.5, Range:

21, 1099).

The 3 studies that included ED patients were all conducted outside the United States. In the 1 mixed study (ED and outpatient recruitment), Dixit et al. [16] carried out a multicenter RCT over one season in Australia utilizing both a pediatric ED and an outpatient family practice location to recruit enrolling 52 participants with confirmed influenza. The two ED only studies included (1) a multicenter single season RCT conducted in China with 8 different EDs, and recruited 480 adult patients, of which 225 patients had confirmed influenza; and; (2) a multicenter RCT over one season conducted in El Salvador and Panama utilizing 5 different EDs with 683 pediatric patients recruited, of which only 30 were confirmed to have influenza.

• 1. Treatment and outcomes

The most frequently studied therapeutics were the antivirals oseltamivir (51%), followed by zanamivir (18%), peramivir (12%), and laninamivir (9%), followed by 10% other agents (including herbal supplements, and varied experimental therapeutics). Most of the stud- ies assessing the newer antivirals were direct head-to-head compari- sons with oseltamivir, given that oseltamivir is often regarded as the standard of care comparator (Table 1). The majority of published studies (n = 38, 80.8%) reported favorable outcomes.

• 1. Weighted-average patient enrollment in influenza therapeutic RCTs

Four studies that did not provide exact number of sites for partici- pant enrollment were excluded from the analysis (n = 43). The number of influenza confirmed positive participants enrolled in influenza RCTs ranged from 21 to 1099. The number of influenza positive participants enrolled per site per season ranged from 0.3 to 112. The weighted- average of participants enrolled per clinical enrollment site per influenza season was 11.0 (95% CI: 10.2, 11.8; Cochran’s Q: 8546.6; I²: 99.5) (Fig. 2). The average enrollment numbers per clinical site was sim- ilar, after excluding the two ‘ED only recruitment’ studies [10.7 (95% CI: 9.9, 11.6)]. The average enrollment numbers per clinical site for the two ‘ED only recruitment’ studies was 89.5 95% CI 89.2-89.27).

1. Discussion

In this study of Phase III RCTs, we found that the majority of studies evaluating influenza therapeutic agents were conducted either in Asia and the Americas, or were multicontinental. For RCTs that disclosed re- cruitment site locations, there was approximately an equal distribution of participant recruitment from outpatient and inpatient settings. The most frequently studied therapeutic agent was oseltamivir. Our study found very few RCTs (3/47) reported using the ED as a recruitment site. Notably, we found that the vast majority of published RCT studies included a large number of sites, with an average of 41 sites per study. However, there were relatively few subjects enrolled per site (pooled average number of participants enrolled per site, per influenza season was 11).

These findings, placed in the context of our recent ED-based influ- enza therapeutic RCT, where we achieved relatively high recruitment rates (60 participants per season per site) [12], suggest that EDs repre- sent a potential, but as yet relatively untapped clinical venue for future recruitment and enrollment of participants into clinical trials for evalu- ation of therapeutics against influenza (and other respiratory viruses). The advantages and limitations of using the ED as a clinical site for re- cruitment into infectious disease therapeutic RCTs are discussed below. Intuitively, therapeutics should be tested in the clinical setting in which they are likely to be used and amongst patients who are most likely to benefit from these interventions. EDs are responsible for a sig- nificant proportion of all patient visits annually across the United States [17-20]. Those EDs which are situated in large academic centers and lo- cated in high density catchment areas, and care for very high numbers of patients, with many seeing over 100,000 patients annually [21]. EDs also represent a primary clinical site for patients presenting with ILI, who are often significantly more sick and with more comorbid condi- tions compared to patients presenting to outpatient clinics [9,10]. Most recently during the coronavirus disease 2019 (COVID-19) pandemic, EDs have been reported to be responsible for a significant proportion of outpatient clinical visits for patients presenting with signs and symptoms consistent with COVID-19, for diagnosing those with confirmed COVID-19, and serving as the most frequent site for initial evaluation of patients, prior to hospital admission [22]. As the proverbial ‘front door’ to hospitals, and the aforementioned high annual volume of patient encounters, EDs thus represent a potential valuable recruitment site (in terms of patient’s with the target disease) for clini-

cal trials.

The recent expansion of ED research networks provides additional evidence and the foundation for an evolving role of ED in clinic trials research. Some well-known ED Networks include Pediatric Emergency Care Applied Research Network [23], EmeRgENcy Care Clinical Trials Network (SIREN) [24], and EMERGEncy ID NET, the later principally focused on infectious disease surveillance [25]. EMERGEncy ID NET a national, CDC (Centers for Disease Control and Prevention) net- work of academic EDs studying infectious diseases in patients seen in the ED, also has served as organizational network for the conduct of therapeutic RCTs; the “STOP-MRSA” trial as examples was led by core

participating sites in the EMERGency ID group, with findings published in The New England Journal of Medicine [26]. Another recently formed tri- als network, which was advanced as an ED-ICU collaborative, conducted one of the largest trials to date, to test the role of a novel therapeutic cocktail for treating sepsis, with findings published in JAMA [27]. Nota- bly, that study was successfully organized, implemented and completed in less than two years.

While EDs represent a substantial portion of total annual patient encounters nationally, conducting clinical trials in EDs is associated with unique challenges, including ED overcrowding and long wait times, the unpredictable nature of the ED course for any given patient, as well as limited resources and time for ED staff to engage in research during shift. Challenges also exist with regard to retention, given the episodic nature of care [28-33], with the potential of increased risk of subjects being “lost to follow-up” as compared to trials initiated in the outpatient or inpatient clinical setting, where additional time is avail- able [34]. Given that EDs are largely regarded as the “safety net” of the

U.S. healthcare system and are responsible for a substantial proportion of uninsured and underinsurED patient encounters, these challenges have and may continue to represents a potential threat to conducting RCTs in EDs [35-37].

These issues can be largely mitigated by conducting research through well-funded ED Networks that have the support staff, infra- structure, and experience to conduct ED-based clinical trials. The numer- ous RCTs published by PECARN, EMERGEncy ID NET, and SIREN suggest that RCTs conducted in settings with established research infrastructure do not suffer from significant attrition for either patients discharged from the ED or admitted to the hospital. Furthermore, inclusion of EDs for patient recruitment provides an increased opportunity to improve engagement with minority and/or other marginalized populations, who have historically been underrepresented in clinical trials [38]. For EDs without established research teams or those who are not associated with ED Networks, financing such teams may be difficult and remains a potential barrier to ensuring diversity of clinical enrollment sites beyond academic health systems.

1. Limitations

There are a few limitations to this study that are worth noting. We found a paucity of influenza trials that reported utilizing the ED as a clinical enrollment site but some of the methods section of the studies did not fully detail the specific characteristics regarding exactly where recruitment, consent, enrollment and randomization occurred (beyond inpatient and outpatient). Nevertheless, based on the known historical limitations of confirming influenza positivity during the ED encounter (based on limitation of prior diagnostic assay), and the information we could glean from the methods section, it is highly likely that EDs have historically been under-utilized as primary source for subject re- cruitment and enrollment. Additionally, a number of the trials included this study required relatively small sample size needs to determine efficacy, and multicenter studies often specifically focus on achieving geographic representativeness (rather than high number of patients per site). Accordingly, our analysis does not truly capture the overall capacity of individual sites to have enrolled larger numbers of patients. Further, some trials (e.g. those therapeutic studies that are focused on patients with higher disease severity) had stringent inclusion and exclusion criteria. This heterogeneity across therapeutic influenza RCTs influences the findings reported here. Finally, while the Hsieh et al study sponsored by BARDA enrolled relatively high numbers of pa- tients per site, that trial evaluated a relatively simple to test therapeutic agent (peramivir) for uncomplicated influenza and was designed in part, to explicitly test EDs ability to enroll patients in a clinical trial [12]. Additional direct experience engaging ED trialists will be required to assess the true opportunities associated with increased engagement of EDs across the range of therapeutic agents of interest.

Table 1

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American Journal of Emergency Medicine 61 (2022) 184-191

188

Description of included studies

First author & year	Setting	Age range	Setting	Sites	Participants randomized	Confirmed influenza	Study duration	Treatment used	Outcome
Hedrick JA 200039	US, Canada, Europe,	5-12	Outpatient	67	471	346	01/11/ 1999-04/19/1999	Zanamivir or placebo	Zanamivir was effective in shortening the duration
Nicholson KG 200040	Israel Europe, China,	>=18	Undisclosed	63	726	475	01/1998-03/1998	Oseltamivir or placebo	and severity of influenza symptoms Oseltamivir was effective and well tolerated in the
Treanor JJ 200041	Canada USA	18-65	Inpatient/	60	629	374	01/1998-03/1998	Oseltamivir or placebo	treatment of natural influenza in adults Oseltamivir reduces the duration and severity of
Aoki FY 200042	Europe, USA	>=13	Outpatient Undisclosed	14	722	722	Winter of 1995 and 1996	Zanamivir or placebo	acute influenza in Healthy adults Zanamivir treatment reduced absenteeism, improved
									patient productivity and well-being, and reduced the
Murphy KR 200043	International	>=12	Undisclosed	159	525	313	04/25/1998-02/19/2000	Zanamivir or placebo	additional use of healthcare resources Zanamivir is an effective treatment for influenza in
Makela MJ 200044	11 European coun-	>=12	Outpatient	42	356	277	Winter of 1997 and 1998	Zanamivir or placebo	patients with asthma or COPD Zanamivir is effective in reducing the duration and
Kaiser L 2000?45	tries Europe and North	13-77	Undisclosed	Multi	575	N/A	11/1995-03/1996	Zanamivir or placebo	severity of influenza illness and is well tolerated Zanamivir is effective and well tolerated
	America
Boivin G 2000	Canada	>=12	Undisclosed	2	35	27	1997-1998	Zanamivir or placebo	Zanamivir reduces viral titers greater than the
Whitley RJ 200146	USA	1-12	Undisclosed	80	698	452	Influenza season 1998 to	Oseltamivir or placebo	placebo Oseltamivir administration is an efficacious and
							1999		well-tolerated therapy for influenza in children when
Martin C 2001?48	UK, Switzerland	13-97	Undisclosed	Multi	1138	N/A	Undisclosed	Oseltamivir or placebo	given 48 h of onset of illness Oseltamivir is effective and well tolerated in high-risk
Li L. 200349	China	18-65	Undisclosed	7	478	273	01/2001-04/2001	Oseltamivir or placebo	patients with influenza Oseltamivir was effective and well tolerated as
Johnston SL 2005?50	International	6-12	Inpatient	Multi	335	N/A	1998 to 1999 (2 influenza	Oseltamivir or placebo	treatment Oseltamivir is effective and well tolerated in
							seasons in northern and		asthmatic children
Lin J 200651	China	>=18	Inpatient/	9	118	56	southern hemispheres) 2002-2003	Oseltamivir or SOC	Oseltamivir was effective and well tolerated as
Sugaya N 201052	Japan	<=9	Outpatient Inpatient/	43	186	182	12/2008-03/2009	Laninamivir or	treatment Laninamivir octaonate was effective and well
			Outpatient					Oseltamivir	tolerated drug for treatment of children with
Wang L 201053	China	18-65	Undisclosed	8	480	225	01/2007-06/2007	Antiwei or placebo	oseltamivir-resistant H1N1 Antiwei was effective and well tolerated in treatment
Watanabe A 201054	Japan, Taiwan,	>=20	(ED) Undisclosed	117	1003	977	11/2008-03/2009	Laninamivir or	of natural Influenza infection in adults Single inhalation of Laninamivir octaonate is effective
Duval X 201055	Korea, Hong-Kong France	>=18	Outpatient	19	541	447	01/07/2009-03/15/2009	Oseltamivir Oseltamivir or	for the treatment of seasonal influenza Oseltamivir-Zanamivir combination appeared less
								Zanamivir	effective than Oseltamivir monotherapy and not
									significantly more effective than Zanamivir
Heinonen S 201056	Finland	1-3	Outpatient	1	409	98	2007 to 2009	Oseltamivir or placebo	monotherapy Oseltamivir treatment started within 24 h of
									symptom onset provides substantial benefits to
Kohno S 201057	Japan	20-64	Inpatient	75	300	299	12/2007-04/2008	Peramivir or placebo	children with influenza A infection Single IV dose of Peramivir is effective and well
Wang C 201158	China	15-69	Inpatient	11	410	410	07/2009-11/2009	Oseltamivir or	tolerated Oseltamivir and MY alone and in combination
								Maxingshigan-	reduced time to fever resolution in patients with
Kohno S 201159	Japan, South Korea,	>=20	Inpatient	146	1099	1099	11/2008-04/2009	yinqiaosan (MY) Peramivir or Oseltamivir	H1N1. Single IV Peramivir may be an alternative to a 5 day
Duan Z.P 201160	Taiwan China	16-65	Undisclosed	8	256	244	10/242009-11/23/2009	Lianhuaqingwen capsule	oral dose of Oseltamivir LHC achieved similar Therapeutic effectiveness
Nabeshima S 201261	Japan	20-64	Outpatient	1	33	33	01/2009-05/2009	or Oseltamivir Maoto, Oseltamivir,	Oral maoto granules in healthy adults with influenza
								Zanamivir	was well tolerated and associated with equivalent
									clinical and virological efficacy to neuraminidase
Dharan N.J 201262	USA	1-79	Outpatient	1	21	21	01/19/2009-02/11/2009	Oseltamivir or placebo	inhibitors Benefits were observed in early treatment group but
									small sample size

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American Journal of Emergency Medicine 61 (2022) 184-191

189

Katsumi Y 201263	Japan	<= 15	Inpatient	1	112	112	01/2011-05/2011	Laninamivir, Zanamivir	Efficiency and safety of Laninamivir and Zanamivir
Watanabe A 201364	Japan	>=20	Undisclosed	53	203	201	11/2009-03/2011	Laninamivir or	are the same Single inhalation of Laninamivir octaonate is effective
Lee N 201365	Hong-Kong	>=18	Inpatient	2	157	50	01/2010-06/2012	Oseltamivir Oseltamivir	for the treatment of seasonal influenza No additional benefit of higher-dose Oseltamivir
Durigon EL 201366	Brazil	>= 5	Undisclosed	2	37	37	04/2009-08/2010	Oseltamivir	treatment Standard and double dose Oseltamivir were well
									tolerated
South East Asia Infec-	South East Asia	>=1	Inpatient	13	326	260	04/2007-02/2010	Oseltamivir	No virological or clinical advantages with double dose
tious Disease Clinical									of Oseltamivir
Research Network, 201367 Liu Y 201468	China	18-65	Inpatient/	5	48	34	01/2011-03/2011	Clearing Heat and	CHDI have a similar effect to Oseltamivir in reducing
			Outpatient					Detoxifying Injection	the duration of influenza illness
deJong MD 201469	21 countries	>=6	Inpatient	323	398	338	09/2009-11/2012	(CHDI) or Oseltamivir Peramivir or placebo	No significant benefit for Peramivir plus SOC
Higashi F 201470	Japan	>15	Outpatient	1	79	49	12/2010-03/2011,	Oseltamivir, Zanamivir,	compared with placebo plus SOC Clarithromycin may have the additional clinical
							12/2012-03/2013	Peramivir,	benefit of improving fever, in patients treated with
Ison MG 201471	USA, Canada,	>=6	Inpatient	59	234	127	10/2009-10/2010	Clarithromycin Peramivir	neuraminidase inhibitors IV Peramivir in hospitalized subjects demonstrates
	Mexico, Australia								that 1x or 2x daily administration is associated with
Kakeya H 201472	Japan	20-91	Undisclosed	14	107	107	12/2010-03/2011	Azithromycin,	decrease in viral shedding and clinical improvement No significant difference in inflammatory cytokine
								Oseltamivir	expression level. Combination therapy showed an
Raus K 201573	Czech Republic	>=18	Outpatient	29	473	473	11/2011-04/2013	Oseltamivir + placebo,	early resolution of some symptoms Echinacea Purpurea is as effective as Oseltamivir in
Dixit R 2015?? [16]	Australia	>=5	Inpatient/-	2	52	52	04/2011-08/2011	Echinacea Purpurea Oseltamivir	early treatment of influenza DD Oseltamivir did not appear to provide a clinical or
Nakano T 201674	Japan	<=10	Outpatient Outpatient	50	343	343	11/2014-03/2015	Laninamivir octanoate	virological advantage, but small sample size A single dose of Laninamivir octanoate was effective
Dawood FS 2016??75	El Salvador, Panama	0-9	Inpatient	5	405	30	09/2012-10/2012,	or placebo Oseltamivir or placebo	and well tolerated as prophylaxis for influenza Oseltamivir treatment was well tolerated amongst
							04/2013-10/2013		hospitalized children, including amongst infants aged
Jefferies S 201676	New Zealand	18-65	Inpatient	1	80	46	07/2011-09/2012	Paracetamol or placebo	<1 year Regular paracetamol had no effect on viral shedding,
Nakamura S 201777	Japan	>=18	Inpatient/	16	92	92	12/2012-05/2014	Peramivir or Oseltamivir	temperature or clinical symptoms Peramivir is a useful option for treatment of
Vanchiere J 2017?78	USA	0-17	Outpatient Undisclosed	Multi	108	N/A	Undisclosed		influenza-infected patients with high risk factors. Treatment with Peramivir and Oseltamivir are well
Marty FM 201779	International	>=16	Inpatient	97	626	488	01/15/2011 02/12/2015	Zanamivir or	tolerated and safe. Time to Clinical response to intravenous Zanamivir
								Oseltamivir	dosed at 600 mg was not superior to Oseltamivir or
Liu Y 201780	China	18-65	Outpatient	9	236	223	01/2014-03/2014	Re-Du-Ning or	300 mg intravenous Zanamivir RDNI was well tolerated with no significant
Lee N 201781	Hong-Kong	>=18	Inpatient	2	50	50	2013-2014 through	Oseltamivir Oseltamivir and	difference compared to Oseltamivir Found significant anti-inflammatory effects with
							2015-2016	azythromycin	adjunctive macrolide treatment in adults with severe
Popov AF 201882	Russia	21-60	Inpatient	1	200	200	12/2013-03/2016	Umifenovir (UMI) UMI	influenza infection Study demonstrated that combination of Oseltamivir
								+ oseltamivir, UMI +	and Umifenovir with Kagocel significantly increases
								Kagocel, Oseltamivir +	therapeutic efficacy compared with monotherapy.
Ramirez J 201883	USA	>=18	Inpatient	9	1107	96	2010-2013	Kagocel SOC, SOC + Oseltamivir	Initiation of Oseltamivir >5 days after illness onset
									did not reduce clinical failures amongst hospitalized
Hirotsu N 201884	Japan	4-12	Outpatient	1	123	123	01/2014-03/2015	Oseltamivir, Zanamivir,	patients. Time to virus clearance was significantly shorter with
								Peramivir, Laninamivir	Peramivir vs Oseltamivir

References in supplement

* Numbers of confirmed influenza patients not provided by study.

?? Study using ED as primary recruiting site.

Fig. 2. Average number of confirmed influenza positive patients enrolled per study, per site, per season.

Blank diamond shape and the dark vertical line indicate the point estimate [11.0, (95%CI: 10.2, 11.8)] and the x-axis value of the pooled average number of confirmed influenza-positive participants enrolled per site per season. Solid diamond shape and the flanking horizontal lines indicate the average number of confirmed influenza-positive participants enrolled per site per season and its corresponding 95% confidence interval of each study included.

1. Conclusion

Randomized phase III clinical trials of influenza therapeutic trials have principally enrolled patients in inpatient or outpatient (non-ED) clinical settings and enrolled 11 participants on average, a relatively low number of subject enrollment per site per season. Most have relied on using many sites to achieve targeted sample sizes. Based on our recently published ED demonstration study, in which we enrolled 60 patients per site per season, as well as the known high rates of ED visits for respiratory illness during pandemics (including the COVID-19 pandemic), untapped likely opportunities exist for EDs to lead and/or participate more broadly in therapeutic RCTs for influenza and other emerging respiratory pathogens.

Funding

This project has been funded in whole or in part with Federal funds from the Department of Health and Human Services (HHS); Office of the Assistant Secretary for Preparedness and Response (ASPR); Biomedical Advanced Research and Development Authority (BARDA), under Grant No. IDSEP130014-01-00. RR, MY, KS-S, and Y-HH received funding (IDSEP130014-01-00) from BARDA (https://www.phe.gov/ about/barda/Pages/default.aspx) for the work included in this submission. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

Y-HH, and RER conceptualized the study. Y-HH, MY, NP, AH, M-CA, KL, and RER developed the study methodology. MY, NP, AH, and M-CA did the initial curation of data. MY and NP did the final curation of data. Y-HH, MY, and JDN conducted the formal analysis. Y-HH, MY,

JDN, RER, and KS-S validated the results. JDN, MY, RER, and Y-HH drafted the manuscript. All authors critically reviewed all drafts of the manuscript.. All authors have seen and approved the final version of this manuscript.

CRediT authorship contribution statement Richard E. Rothman: Writing - review & editing, Writing - original

draft, Supervision, Resources, Project administration, Methodology, In- vestigation, Funding acquisition, Conceptualization. Joshua D. Niforatos: Writing - review & editing, Writing - original draft, Valida- tion, Supervision, Formal analysis, Data curation. Mehdi Youbi: Writing - review & editing, Writing - original draft, Validation, Software, Methodology, Investigation, Formal analysis, Data curation, Conceptual- ization. Nicholas Polydefkis: Writing - original draft, Investigation, Data curation, Conceptualization. Alaina Hergenroeder: Writing - review & editing, Visualization, Validation, Software, Methodology, In- vestigation, Formal analysis, Data curation. Michele-Corinne Ako: Writing - original draft, Visualization, Validation, Software, Resources, Formal analysis, Data curation, Conceptualization. Katie Lobner: Writing - review & editing, Supervision, Software, Resources, Project administration, Methodology, Investigation, Data curation, Conceptual- ization. Kathryn Shaw-Saliba: Writing - review & editing, Visualiza- tion, Software, Project administration, Methodology, Formal analysis, Data curation, Conceptualization. Yu-Hsiang Hsieh: Writing - review & editing, Writing - original draft, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisi- tion, Formal analysis, Data curation, Conceptualization.

Declaration of Competing Interest

The authors have declared that no competing interests exist.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2022.09.003.

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