Number of COVID-19 clinical trials registered in ChiCTR and ClinicalTrials.gov
According to statistics on COVID-19 clinical trial registrations (Figure 1), it can be seen that very few clinical trials were registered in January. Owing to the outbreak of the pandemic, daily registrations have gone ballistic. In February, a maximum of single-day registrations is 22, with an average number of 11.69. Daily registrations peaked at 32 on March 15, and the average in this month reached 13.79. In a word, overall registrations in March are higher than the previous two months.
By analyzing the trend of overall registrations (Figure 2), it can be observed that the number was a generally uptrend over time, which has declined since March 17 and increased significantly after the 24. In addition, it was predicted that the coming period, registrations would go up continuously because of the activity of vaccine and unlisted drug clinical trials.
Basic characteristics of clinical trials
Across all programs, 355 clinical trials are recruiting volunteers and 316 clinical trials are not yet recruiting. A total of 436 clinical trials have been approved by ethics committees and 97 clinical trials have not been submitted for approval (Table 1). Ethics committee approval is a prerequisite for clinical trial registration, 5 but the timeliness of COVID-19 has resulted in some trials not being registered in time.
Table 1 Statistics of basic characteristics for clinical trial registrations (n=732)
Category
|
Information
|
Number of trials
|
Percentage of total(%)
|
Recruiting status
|
Recruiting
|
355
|
48.50%
|
|
Not yet recruiting
|
316
|
43.17%
|
|
Completed
|
28
|
3.83%
|
|
Withdrawn
|
22
|
3.01%
|
|
Active, not recruiting
|
5
|
0.68%
|
|
Enrolling by invitation
|
3
|
0.41%
|
|
Available
|
3
|
0.41%
|
Approved by the Ethics Committee
|
Yes
|
436
|
59.56%
|
|
No
|
97
|
13.25%
|
|
N/A
|
199
|
27.19%
|
Study Types and Methods
Summary statistics for the study types are in Table 2. There are 406 interventional trials. The main research methods are Randomized Parallel Assignment (38.93%), Non-randomized Assignment (5.33%), and Single Group Assignment (6.83%). Parallel control designs are observed experimentally at the same time, which is beneficial to eliminate errors caused by factors such as time and conditions. Since there is not any specific drug for COVID-19 and it has a longer survival period than other epidemics, most of interventional trials designed by parallel assignment. Among the 271 observational trials, Sequential Assignment (18.72%), Cohort (6.96%), and Factorial Assignment (4.51%) were preferable owing to a largish sample size. In addition, there were 28 Diagnosis, 10 Epidemiological and 17 other trials.
Table 2 Study types for all clinical trials based on ChiCTR and ClinicalTrials.gov (n=732)
Study Type
|
Model
|
ChiCTR
|
ClinicalTrials.gov
|
Total (%)
|
Interventional
|
Randomized Parallel Assignment
|
201
|
84
|
285(38.93%)
|
|
Non-randomized Assignment
|
31
|
8
|
39(5.33%)
|
|
Single Group Assignment
|
22
|
28
|
50(6.83%)
|
|
Sequential Assignment
|
11
|
7
|
18(2.46%)
|
|
Crossover Assignment
|
1
|
2
|
3(0.41%)
|
|
Other
|
11
|
0
|
11(1.50%)
|
Observational
|
Sequential Assignment
|
137
|
0
|
137(18.72%)
|
|
Factorial Assignment
|
33
|
0
|
33(4.51%)
|
|
Case-Only
|
12
|
9
|
21(2.87%)
|
|
Non-randomized Assignment
|
9
|
0
|
9(1.23%)
|
|
Cohort
|
6
|
43
|
49(6.69%)
|
|
Case-Control
|
3
|
9
|
12(1.64%)
|
|
Other
|
4
|
6
|
10(1.37%)
|
Diagnosis
|
Sequential Assignment
|
22
|
0
|
22(3.01%)
|
|
Factorial Assignment
|
5
|
0
|
5(0.68%)
|
|
Cross-Sectional
|
1
|
0
|
1(0.14%)
|
Epidemiological
|
Sequential Assignment
|
8
|
0
|
8(1.09%)
|
|
Case-Control
|
1
|
0
|
1(0.14%)
|
|
Single Group Assignment
|
1
|
0
|
1(0.14%)
|
Other
|
|
14
|
3
|
17(2.32%)
|
Total
|
533
|
199
|
732(100%)
|
Blinding is one of the important tools for reducing subjects' perceptions of treatment allocation schemes between groups, reducing bias and improving the scientific and validity of trials. 6 In this statistic, as can be seen from Table 3, 268 studies were blinded and 464 (26.33%) were unspecified.
In addition, the subgroups of the study are counted in this article. 356 trials involved two groups; 285 trials involved a single group. Fifty-five and 22 trials involved groups three and four, with the remaining groups used less frequently. During COVID-19, most trials were divided into two groups for controlled studies. This grouping allows differences between groups to be efficiently assessed for "potent drugs" to deal with the virus.
Table 3 Blinding and subgroups for all clinical trial registrations (n=732)
Category
|
Information
|
Number of trials
|
Percentage of total(%)
|
Blinding
|
Open Label
|
196
|
26.78%
|
|
Single
|
23
|
3.14%
|
|
Double
|
21
|
2.87%
|
|
Triple
|
7
|
0.96%
|
|
Quadruple
|
21
|
2.87%
|
|
N/A
|
464
|
63.39%
|
Numbers of group
|
1
|
285
|
38.93%
|
|
2
|
356
|
48.63%
|
|
3
|
55
|
7.51%
|
|
4
|
22
|
3.01%
|
|
5
|
9
|
1.23%
|
|
6
|
2
|
0.27%
|
|
7
|
1
|
0.14%
|
|
8
|
2
|
0.27%
|
Sample size
Sample size is an important aspect of clinical trial design, directly related to the reliability, reproducibility, and efficiency of the study. It was noted that the sample size of clinical trials was mainly concentrated in the range of 0-299, with a larger proportion of interventional and observational trials (Figure 3). Whereas, the number of observational trials increased with the expansion of the sample size interval in the larger sample size interval.
Primary endpoint of Interventional study
When designing a clinical trial, one of the most challenging and critical issues is how to select the primary endpoint used to assess efficacy. In view of the reliable evidence for benefits and risks should be provided, the primary endpoint is preferably a outcome measure that clearly reflects the benefit to the patients.7 Among 406 interventional studies, time to clinical recovery accounted for 13.5%, clinical parameters and laboratory index for 11.33%, the change of pneumonia severity for 11.08%, questionnaire or scales for 9.85%, virus negative conversion rate of time for 8.13 %, cure rate for 7.39%, and the mortality for 6.16% (Figure 4).
Interventions
This article counted the interventions of 406 interventional studies. Details are shown in Table 4. Chemical or Biological drugs accounted for 43.60%, of which 14.53% were antivirals, 8.87% were antimalarial drugs, and 7.88% were antineoplastics and immunomodulators. The trials involving Traditional Chinese Medicine (TCM) or Integrated Medicine accounted for 24.14%, and Cell Therapy, Behavioral Intervention and Medical Instruments accounted for 8.62%, 7.14% and 4.93%. In addition, five vaccine clinical trials for COVID-19 are underway and their registration numbers are NCT04299724, NCT04276896, NCT04283461, NCT04313127 and NCT04324606.
Table 4 Statistics of interventions (n=406)
Category
|
Number of trials
|
Percentage of total(%)
|
Chemical or Biological
|
177
|
43.60%
|
Antivirals
|
59
|
14.53%
|
Antimalarials
|
36
|
8.87%
|
Antineoplastics and Immunomodulators
|
32
|
7.88%
|
Antipyretic Analgesics
|
19
|
4.68%
|
Glucocorticoids
|
9
|
2.22%
|
Mucolytics
|
6
|
1.48%
|
Other
|
16
|
3.94%
|
Traditional Chinese Medicine or Integrated Medicine
|
98
|
24.14%
|
Cell Therapy
|
35
|
8.62%
|
Plasma
|
15
|
3.69%
|
Vaccine
|
5
|
1.23%
|
Medical Instruments
|
20
|
4.93%
|
Behavioral Intervention
|
29
|
7.14%
|
Psychological intervention
|
4
|
0.99%
|
Other
|
23
|
5.67%
|
Total
|
406
|
100%
|
Combination of antiviral drugs and other drugs
This part of the research further studied the clinical trials of the 59 antiviral drugs mentioned, and analyzed the combined use of antivirals with other drugs (Figure 5). Among them, the most commonly used antivirals are Lopinavir/ritonavir (LPV/r), Arbidol and Ribavirin. The drug with which they are most frequently combined is Interferon, followed by Favipiravir with Tocilzumab and Darunavir with Cobicistat.