Hospitalization Endpoint in Clinical Trials of Outpatient Settings: using Anti-SARS-COV-2 Therapy as an Example

Figures & data

Figure 1 Flowchart Identifying Trials Included in the Study. Adapted from Moher D, Liberati A, Tetzlaff J, Altman DG: The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med. 2009;6(6): e1000097. Creative Commons.

Table 1 Summary of the Current Clinical Trials Evaluating Monoclonal Antibodies (MAB) in COVID-19 Outpatients

Study Identifier	Date and Author	Intervention	Comparator	Primary Objective	Primary Efficacy Endpoints
COV-2067/ (NCT04425629)	(Weinreich et al, 2021)^Citation9	REGN-COV2 2400 mg, n=1355, 1200 mg, n= 736	Placebo 2400 mg, n=1341, 1200 mg, n= 748	To evaluate the efficacy and safety of REGN-COV2.	Proportion of patients with at least one (≥1) COVID-19-related hospitalization or all-cause death through Day 29.
BLAZE-1 /PYAB (NCT04427501)	(Dougan et al, 2021)^Citation7	Bamlanivimab plus Etesevimab, n=518	Placebo, n=517	To evaluate the efficacy and safety of Bamlanivimab plus Etesevimab.	Percentage of participants who experience COVID-19-related hospitalisation (acute care for ≥24 hours) or death from any cause by Day 29.
VIR-7831-5001/COMET-ICE (NCT04545060)	(Gupta et al, 2021)^Citation8	Sotrovimab (VIR-7831) 500 mg, n=291	Placebo, n=292	To evaluate the efficacy of VIR-7831.	Proportion of participants who have progression of COVID-19 to hospitalisation >24 hours for acute management of illness or death through Day 29.

Table 2 Summary of the Current Clinical Trials Evaluating Antiviral Treatment in COVID-19 Outpatients

Study Identifier	Date and Author	Intervention	Comparator	Primary Objective	Primary Efficacy Endpoints
NA	(Ramachandran et al, 2022)^Citation11	Umifenovir n=60	Placebo n=63	To test the efficacy, safety and tolerability of Umifenovir in non-severe COVID-19 adult patients.	- For asymptotic-mild patients was time to nasopharyngeal swab RT-PCR test negativity. - For moderate patients, the average change in the ordinal scale from the baseline scores on the eight-point WHO ordinal scale.
GS-US-540-9012 (NCT04501952)	(Gottlieb et al, 2022)^Citation12	Remdesivir (RDV): 279 patients received 200 mg intravenous (IV) single dose on Day 1.100 mg IV of RDV on Days 2 and 3.	283 patients received IV placebo to match (PTM) RDV on Days 1 to 3.	To evaluate the efficacy and safety of Remdesivir (GS-5734™).	The composite outcome of COVID-19-related hospitalisation (defined as at least 24 hours of acute care) or all-cause death by Day 28.
EPIC-HR (NCT04960202)	(Hammond et al, 2022)^Citation10	Orally administered PF-07321332 (nirmatrelvir) + ritonavir in 1120 patients.	Orally administered placebo in 1126 patients.	To evaluate the efficacy and safety of PF-07321332 (nirmatrelvir) / ritonavir.	Proportion of participants with COVID-19-related hospitalisation or death from any cause by Day 28.
MOVe-OUT/MK-4482-002	(Jayk Bernal et al, 2022)^Citation13	Molnupiravir 800mg administered orally twice for 5 days. n=716	Placebo n=717	To evaluate the safety and efficacy of molnupiravir in non-hospitalized adults with COVID-19	The incidence of hospitalisation for any cause (defined as ≥24 hours of acute care in a hospital or any similar facility) or death through Day 29.
The TOGETHER trial/ NCT04403100	(Reis et al, 2021)^Citation17	Hydroxychloroquine (800 mg loading dose, then 400 mg), n=214 or lopinavir-ritonavir (loading dose of 800 mg and 200 mg, then 400 mg and 100 mg), n=244	Placebo, n=227	To evaluate the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19.	COVID-19-associated hospitalisation and death assessed at 28 days after randomisation.
IRCT20200403046926N1	(Roozbeh et al, 2021)^Citation16	Sofosbuvir/daclatasvir plus hydroxychloroquine, n = 27	Hydroxychloroquine alone, n=28	To evaluate the effectiveness and safety of adding sofosbuvir/daclatasvir to the routine protocol of COVID-19 outpatients.	Symptom alleviation by Day 7.
NA	(Udwadia et al, 2021)^Citation15	Oral favipiravir plus standard supportive care, n=75	Supportive care alone, n=75	To assess the efficacy and safety of favipiravir in adults with mild-to-moderate coronavirus disease 2019 (COVID-19).	Specified as a negative RT-PCR result for both oropharyngeal and nasopharyngeal swabs on day 28.
FMASU P14 / 2020 /NCT04349241	Dabbous et al, 2021)^Citation14	Favipiravir, n=50.	Standard of care 9 (hydroxychloroquine), n=50.	To evaluate the safety and efficacy of favipiravir in the treatment of COVID-19 mild-to-moderate cases.	Two successive negative COVID-19 PCR analysis tests were 48–72 hours apart on day 14 and clinical improvement was measured by normal body temperature for 48 hours on Day 14.
NA	(Nourian et al, 2020)^Citation18	Sofosbuvir/ledipasvir 400/90 mg daily for 10 days plus standard of care.n=40	The only standard of care: hydroxychloroquine (HCQ 400 mg BD on the first day then 200 mg BD for 7 days) plus atazanavir/ritonavir 300/100 mg daily for 7 days.n=42	To assess the efficacy and safety of sofosbuvir/ledipasvir in the treatment of patients with mild-to-moderate COVID-19	Clinical response and time to clinical response.Clinical response was defined as one order decline in disease category in the five-category ordinal scale. The categories are death, mechanical ventilation, non-invasive ventilation, oxygen mask or nasal cannula, and discharge.

Abbreviations: NA, not available; n, number of subjects; mg, milligram; CI; Confidence Interval; HR, Hazard Ratio; BD, twice a da.

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