Published RCTs
A flowchart of the trials is presented in Figure 1. The search yielded 2,191 RCTs; after applying eligibility criteria, 12 full-text trials assessing various treatment options for COVID-19 were included. Risk of bias assessment of these trials is detailed in Supplementary Table 1. All trials but one were judged low risk of bias for allocation generation; eight for allocation concealment; and four were double blind studies. (For full data see Supplementary Table 1). All trials addressed drug therapy, of which eight were performed in China. Table 1 summarizes characteristics of included trials. Two were published in PubMed 14,15, four at journal websites 16-19 and six in medRxiv 20-25. Five evaluated lopinavir/ritonavir-based therapy 14,17,18,24,26, three chloroquine or hydroxychloroquine therapy 15,20,23, two favipiravir or baloxavir 21-23, two remdesivir 16,19 and one α-lipoic-acid. 25 The mean age of patients included in RCTs was 56.3 years. No trial specifically targeted the elderly. An upper age limit was reported in three studies (25%). Chen et al. reported 60/240 patients aged ≥65 years (25%) 20, Beigel 382/1063 (36%) patients aged ≥65 years, 19 and Zhong nine patients between 60 and 70 and two >70 years among a total of 17 patients (53%). 25 Three studies performed age-specific subgroup analyses, among which one for patients ≥65 23 (Table 1) . Eight, six and five trials had exclusion criteria of liver function abnormalities or severe liver disease, 14,16,18,20-24 severe kidney disease, 16,18,20,22-24 and heart disease/arrhythmia/prolonged QT, respectively. 17,18,20,23,24 No study excluded patients due to polypharmacy but three excluded patients taking medication potentially interacting with lopinavir/ritonavir, ribavirin, interferon or arbidol. 14,17,24 Four trials excluded patients due to the presence of a mental or cognitive criteria: “a mental illness affecting therapeutic compliance”, 24 “unable to cooperate with investigators due to cognitive impairment or poor mental status”, 23 “inability to comprehend and to follow all required study procedures”. 17,19 One study used an exclusion criterion of patients who would probably not cooperate or finish the study: “base on the researcher's judgment, there are other factors that may cause the subject to be forced to terminate the study midway, such as other serious diseases, serious laboratory examination abnormalities, other factors that affect the safety of the subject or study data and blood sample collection”. 22 Five trials excluded patients for expected survival time under 48 hours or for critical illness. 20-22,24,25 Only six trials allowed consent to be provided by a legal guardian, 14-17,19,21 and three reported allowing a family member to provide consent. 6,15,17 Primary outcomes varied: only seven RCTs chose a clinical outcome (one reported 28-day mortality and six clinical improvement or recovery); five RCTs reported virologic outcomes (time to or rate of negative polymerase chain reaction (PCR)). None of these studies reported on discharge to rehabilitation or long-term care facilities (LTCF) or other clinical outcomes relevant for the geriatric population, such as cognitive or functional decline.
Table 1. Characteristics of Included Randomized Controlled Trials
Study ID
|
Intervention
|
Publication site
|
Country
|
Disease severity included (most patients)
|
No randomized
|
Primary outcome
|
Age
|
Upper age limit inclusion
|
No. age ≥ 65 y
|
Sub-group of elderly reported
|
Exclusion by mental or cognitive disorder
|
Consent options
|
Cao 2020 14
|
LPV/r
|
PubMed
|
China
|
Severe
|
199
|
Time to clinical improvement
|
58.0 (49.0–68.0)
|
NS
|
NS
|
NS
|
NS
|
Patient/legal guardian
|
Borba 2020 15
|
High-dose CQ
|
PubMed
|
Brazil
|
Severe
|
81
|
Mortality (28 day)
|
51.1 (13.9)
|
NS
|
NS
|
NS
|
NS
|
Patient/legal guardian/family
|
Wang 2020 16
|
Remdesivir
|
Journal site (Lancet)
|
China
|
Severe
|
237
|
Time to clinical improvement
|
65 (56–71)
|
NS
|
NS
|
NS
|
NS
|
Patient/legal guardian
|
Hung 2020 17
|
LPV/r based combinations
|
Journal site (Lancet)
|
Hong Kong
|
Mild/moderate
|
127
|
Time to negative RT-PCR
|
52 (32–62)
|
NS
|
NS
|
NS
|
Inability to comprehend and to follow all required study procedures
|
Patient/legal guardian/family
|
Chen YK 2020 26
|
LPV/r based combinations
|
Journal site (Lancet Infectious Diseases)
|
China
|
Mild/moderate
|
101
|
Time to negative RT-PCR
|
42.5 (11.5)
|
65
|
NS
|
For safety - 18-40 vs 41-65
|
NS
|
NS ("Written informed consent")
|
Beigel 2020 19
|
Remdesivir
|
Journal site (NEJM)
|
Multinational (mainly USA)
|
Severe
|
1063
|
Time to recovery
|
58.9 (15.0)
|
NS
|
382
|
For age ≥65
|
Understands planned study procedures
|
Patient/legal guardian
|
Chen Z 2020 20
|
Favipiravir vs arbidol
|
medRxiv
|
China
|
Moderate
|
240
|
Clinical recovery rate at 7 days
|
NS
|
NS
|
60/240
|
NS
|
NS
|
NS ("Informed consent was obtained from all patients")
|
Chen C 2020 21
|
HCQ
|
medRxiv
|
China
|
Mild
|
62
|
Time to clinical recovery
|
44.7 (15.3)
|
NS
|
NS
|
NS
|
NS
|
Patient/legal guardian
|
Lou 2020 22
|
baloxavir marboxil vs favipiravir
|
medRxiv
|
China
|
NS
|
30
|
Rate of RT-PCR negativity at 14 days and time to clinical improvement
|
52.5 (12.5)
|
85
|
NS
|
NS
|
|
NS ("Consent was obtained")
|
Tang 2020 23
|
HCQ
|
medRxiv
|
China
|
Mild/moderate
|
150
|
Rate of RT-PCR negativity at 28 days
|
46.1 (14.7)
|
NS
|
72/150 age≥45
|
For primary outcome age>=45 vs <45
|
Unable to cooperate with investigators due to cognitive impairment or poor mental status
|
NS ("Written informed consent was obtained from all patients")
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Li 2020 24
|
LPV/r vs arbidol
|
medRxiv
|
China
|
Mild/moderate
|
86
|
Time to negative RT-PCR
|
49.4 (14.7)
|
80
|
NS
|
NS
|
Mental illnesses affecting treatment compliance
|
NS ("Written informed
consent was obtained from all screened patients")
|
Zhong 2020 25
|
α-Lipoic acid
|
medRxiv
|
China
|
Critical
|
17
|
SOFA Score
|
63 (59-66)
|
NS
|
9/17 age 60-70, 2/17 age>70
|
NS
|
NS
|
NS ("Patients who cannot sign informed consent must obtain informed consent from the
independent authorized nurse")
|
LPV/r - Lopinavir–Ritonavir; HCQ – Hydroxychloroquine; CQ – chloroquine; NS – non-specified; RT-PCR – Reverse-Transcription-Polymerase Chain Reaction
Ongoing RCTs
Our clinicaltrials.gov search yielded 1,651 registered studies addressing COVID-19; among these, 870 interventional studies included only adults, and 650 were RCTs evaluating therapeutic and prophylactic interventions for COVID-19. Two hundred RCTs (200/650, 31%) had an upper age limit: 56 used a cutoff of 65 years, 153 of 80 years, and 47 of 99 years.
Observational studies
We reviewed 881 titles from PubMed searching for observational studies including over 1,000 patients and reporting clinical outcomes. We found two such cohorts, from which we extracted data on age and mortality: Guan et al. (China) described 1099 COVID-19 patients hospitalized in 552 hospitals. 27 Median age was 47 (IQR 35-58). Of the entire cohort, only 15.1% were 65 or older. When stratified according to disease severity, patients ≥65 years old made up 27% of severe patients but only 12.9% of non-severe patients. Overall mortality was 1.4%; it was not reported by age group. Richardson et al. (USA) reported the outcomes of 5,700 patients hospitalized with COVID-19 in the New York City area. 28 Here the median age was 63 (IQR 52-75, range 0-107); 36% were ≥70 years old. Overall mortality was 9.7% (2,634 were discharged or had died at the study’s end of follow-up). In the 60-69, 70-79, 80-89 and ≥90-year age groups, mortality was 6.4%, 12.6%, 24.9% and 28.6%, respectively. Mortality rates for those receiving mechanical ventilation in the 18-to-65 and >65-year age groups were 76.4% and 97.2%, respectively. In the same age groups, mortality rates for those not requiring mechanical ventilation were 19.8% and 26.6%, respectively. Quality rating of these two studies according to NIH quality assessment tool was judged as good quality for Richardson et al. 28 and fair quality for Guan et al. 27 (Supplemental Table 2).
As of May 6th 2020, the ISARIC database contained information on 20,276 COVID-19 patients from 35 countries. 6 Median age was 72 (range 0-104 years). Here, 53% of the patients were ≥70 years old. Overall mortality was 26.6%, yet in the 60-69 and ≥70-year age groups, it was 21% and 39%, respectively.