Emergency Medicine

A cross-sectional study of participant recruitment rates in published phase III influenza therapeutic randomized controlled trials conducted in the clinical setting

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

R.E. Rothman, J.D. Niforatos, M. Youbi et al.

American Journal of Emergency Medicine 61 (2022) 184191

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

R.E. Rothman, J.D. Niforatos, M. Youbi et al.

American Journal of Emergency Medicine 61 (2022) 184191

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.

Image of Fig. 2

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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