Clinical use of chloroquine phosphate
Demographic status is shown in Table 2.
Table 2. Demographic indicator
|
Gender(male/female)
|
Age (years)
|
Average length of stay duration (days)
|
Patients
|
23/19
|
42.19±14.29
|
19.07±7.65
|
COVID-19 severity and underlying diseases
Among the 42 patients included in the study, none were critical case, 3 (7.14%) were mild ones, 36 (85.72%) were moderate ones and 3 (7.14%) were severe ones. Nine (21.43%) patients had at least one underlying diseases, including hypertension (6 patients), hepatitis B (2 patients), hypothyroidism (1 patient), gout (1 patient), deafness (1 patient) and asthma (1 patient).
Previous history of allergy and medication
Among the 42 patients who received low-dose chloroquine phosphate, 3 had a history of allergy, including 1 patient with penicillin allergy and 2 patients with cephalosporin allergy.
Treatment course
The mean duration of chloroquine phosphate administration was 6.57 days (SD, 3.16 days; range: 1 day to 16 days), and 52.4% of the patients received treatment 7–9 days.
Drug combinations
Up to 5 March, chloroquine phosphate for COVID-19 treatment was tested in 42 patients. The medication status of the patients is shown in Table 3. The mean number of drug varieties that the patients were receiving simultaneously was 6.93 (SD, 5.38; range: 2–27). Of the 42 patients, 33 were receiving Chinese herbal medicine and 35 were receiving antibiotics simultaneously.
There were no cases in which three or more kinds of drugs were tried for antiviral treatment. Considering the therapeutic treatment course (as mentioned in 2.1.4) and drug combinations, the medication statuses of patients were significantly different. The patients’ medical records were reviewed by clinical pharmacists to assess and record the risks of all medications. In one patient, chloroquine phosphate was discontinued after day 1 of the trial due to the change in the medical protocol and was resumed after 8 days. Overall, the medication administration was in accordance with the diagnosis and treatment protocol prescribed at the corresponding time (sixth or seventh version).
Table 3. Clinical trial of chloroquine phosphate
|
Number of cases
|
Gender
(male/female)
|
Number of drug varieties *
|
Type composition #
|
Chloroquine alone
|
22
|
11/11
|
7.05±6.00
|
2/17/3/0
|
Chloroquine with kaletra
|
9
|
5/4
|
7.00±5.31
|
0/9/0/0
|
Chloroquine with
arbidol
|
11
|
7/4
|
6.64±3.89
|
1/10/0/0
|
Chloroquine with antiviral agents
|
0
|
0
|
0
|
0
|
Summary
|
42
|
23/19
|
6.93±5.38
|
3/36/3/0
|
* Number of drug varieties during and before and after chloroquine administration (excluding traditional Chinese medicine)
# Type composition is mild/ ordinary /severe/ critical in turn
Occurrence of adverse reactions
Adverse events in this clinical trial
The data on adverse events were extracted from the medical records. Two cases of adverse events were found during follow-up by clinical pharmacists and stool ≥3 times a day was recorded as diarrhoea.
Among the 42 patients receiving low-dose chloroquine phosphate, 22 had suspected adverse events related to chloroquine phosphate, and the correlation was evaluated according to the standards developed by the national monitoring centre for adverse drug reactions. The evaluation results were as follows: the correlation was positive in 3 patients, probable in 5, possible in 12, and irrelevant in 2, giving a total of 20 adverse events in 18 patients(42.86%). The classification and clinical manifestations of adverse events are listed in Table 4. The adverse events were graded according to the US CTCAE, and the results are shown in Table 5.
A severe clinical manifestation of adverse event was observed. One patient developed a mental disorder on the afternoon of the eighth day of treatment, showed abnormal mental behaviour, complaining of being monitored and becoming fidgety. The patient stopped taking chloroquine phosphate the next day and received symptomatic treatment. The delusions and hyperactivity disappeared on the third day.
In addition, there was another typical manifestation of adverse event, but it was grade 2. A patient with abdominal pain and diarrhoea, excluding or considering the effect of the combination of drugs, did not show improvement until 4 days after the cessation of chloroquine administration. Patients with other adverse events for digestive system such as gastric uneasiness were given medicine to relieve belching and bloating. Tachycardia and arrhythmia in patients with heart disease were assessed by electrocardiogram (ECG) examination, but a contrast for this assessment wasn’t conducted before and after treatment with chloroquine phosphate, which may lead to misjudgement. The liver function of patients was assessed in accordance with the criteria for liver function impairment reported in the CTCAE.
Table 4. Classification and clinical manifestations of chloroquine phosphate adverse reactions
Classification and clinical manifestations of adverse reactions
|
Cases
|
Incidence rate
|
Digestive system
|
12
|
28.57%
|
Diarrhea and abdominal pain
|
3
|
|
Nausea, vomiting, loss of appetite
|
4
|
|
Other stomach discomfort
|
4
|
|
Cardiac system
|
5
|
11.90%
|
Bradycardia
|
2
|
|
Arrhythmia
|
2
|
|
Myocardial damage
|
1
|
|
Liver system
|
2
|
4.76%
|
Liver damage
|
2
|
|
Mental illness
|
1
|
2.38%
|
Anxiety delusion
|
1
|
|
In this retrospective analysis, we found that the incidence of adverse events related to chloroquine phosphate was high: 13 patients had grade 2 adverse events (affecting daily activities), and 1 patient had grade 3 adverse event (severe symptoms with limited self-care ability).
Table 5. Classification of adverse events of chloroquine phosphate
|
Grade 1
|
Grade 2
|
Grade 3
|
Grade 4
|
Grade 5
|
Occurrences
|
6
|
13
|
1
|
0
|
0
|
Proportion
|
30%
|
65%
|
5%
|
0%
|
0%
|
The influence of dosage and course of treatment
All 42 patients were orally administered 500 mg chloroquine phosphate once a day. The associations of adverse events and their time of occurrence with the course of treatment are described in Tables 6 and 7.
Table 6. Trial course of chloroquine phosphate and number of corresponding adverse reactions
Course of treatment
|
Number of cases
|
Constituent ratio
|
Number of adverse reactions
|
≤2 days
|
7
|
16.67%
|
3
|
3-6 days
|
9
|
21.43%
|
5
|
7-9 days
|
20
|
47.62%
|
11
|
10 days≤
|
6
|
14.28%
|
1
|
Table 7. Time of occurrence of adverse events to chloroquine phosphate
Time of occurrence
|
Number of cases
|
Adverse reaction classification #
|
Day 1
|
1
|
1/0/0
|
Day 2
|
2
|
0/2/0
|
Day 3
|
2
|
2/0/0
|
Day 4
|
2
|
1/1/0
|
Day 6
|
4
|
1/3/0
|
Day 7
|
4
|
0/4/0
|
Day 8
|
3
|
1/2/0
|
Day 9
|
1
|
0/1/0
|
Day 10
|
1
|
0/0/1
|
# Note: Adverse reaction classification is grade1 /grade 2 / grade 3 in turn
As shown in Tables 6 and 7, nearly half of the 42 patients received chloroquine phosphate for 7–9 days, and the incidence of adverse events corresponded to this duration. In patients whose treatment course lasted ≥10 days, the incidence of adverse events was low, probably because they had good tolerance or the observation days were insufficient to notice the effects of drug accumulation. The occurrence time of adverse events was relatively concentrated on the sixth to eight days of the treatment course, as shown in Table 3.
According to the above two Tables 6 and 7, the incidence of adverse events was more than 50% among patients whose treatment course lasted <10 days. According to the pharmacokinetic data, 500 mg chloroquine phosphate can accumulate in vivo when administered for more than 7 days. Patients whose treatment course lasts ≥6 days may develop liver damage or psychiatric symptoms due to drug accumulation, and most of these adverse events require drug withdrawal and symptomatic treatment. According to the literature, even if a patient tolerates chloroquine phosphate well, he/she may subsequently develop liver damage, psychiatric symptoms, cardiotoxicity, eye problems, etc.
The influence of drug using
The specific adverse events of chloroquine phosphate when administered in combination with other drugs are shown in Table 8.
Table 8. Number of adverse events occurred with chloroquine phosphate and other antiviral drugs
Medication
status
|
Number of cases
|
Proportion of cases
|
Number of adverse reactions
|
Proportion of adverse reactions
|
Chloroquine alone
|
22
|
52.38%
|
8
|
40%
|
Chloroquine with kaletra
|
9
|
21.43%
|
8
|
40%
|
Chloroquine with
arbidol
|
11
|
26.19%
|
4
|
20%
|
Among the 9 patients who received chloroquine phosphate combined with Kaletra antiviral treatment, 6 received sequential treatment, with Kaletra prior to chloroquine phosphate. Among the 11 patients who received chloroquine phosphate combined with abidol antiviral treatment, 4 received sequential treatment, with abidol prior to chloroquine phosphate. This finding shows that the incidence of adverse events of chloroquine combined with Kaletra is relatively high, and these adverse events are related to not only to the digestive system but also to the cardiac and hepatic systems.
In this retrospective analysis, we found that 42 COVID-19 patients received chloroquine, 9 did not receive antiviral treatment during the same period, and 155 received other antiviral drugs during the same period. The details of these treatments are shown in Table 9. Although the incidence of adverse events was not significantly different between these treatment groups, the incidence of adverse events was higher with chloroquine than with other treatments.
Table 9. Comparison of adverse events between patients trying chloroquine phosphate and other patients
|
Number of adverse events occurred
|
Number of adverse events not occurred
|
No antiviral agents
|
2
|
7
|
Patients who try chloroquine phosphate
|
18
|
24
|
Patients who try other antiviral agents
|
48
|
107
|
Risk factors for adverse reactions
Comprehensive clinical records and supporting materials, because various factors do not show a normal distribution and there are many factors related to adverse events caused by chloroquine phosphate, we use chi-square test. We evaluated the influence of factors such as underlying disease type, sex, age, comorbidity, drug combinations, and allergy history on the incidence of adverse events caused by chloroquine phosphate using factor analysis, and the results are shown in Table 10.
Table 10. Analysis of influencing factors of adverse events related to chloroquine phosphate(n[%])
|
Occurrence group(n=18)
|
No occurrence group(n=24)
|
P
|
Gender
|
|
|
|
Male
|
13 (72.2)
|
10 (41.7)
|
0.049
|
Female
|
5 (27.8)
|
14 (58.3)
|
Age
|
|
|
|
<50 years old
|
11 (61.1)
|
16 (66.7)
|
0.710
|
>50 years old
|
7 (38.9)
|
8 (33.3)
|
Clinical type
|
|
|
|
Mild
|
2 (11.1)
|
1 (4.2)
|
0.445
|
Ordinary
|
14 (77.8)
|
22 (91.7)
|
Severe
|
2 (11.1)
|
1 (4.2)
|
Comorbidity
|
|
|
|
Yes
|
5 (27.8)
|
4 (16.7)
|
0.625
|
No
|
13 (72.2)
|
20 (83.3)
|
Combination of drugs
|
|
|
|
Yes
|
10(55.6)
|
10(41.7)
|
0.372
|
No
|
8(44.4)
|
14(58.3)
|
Allergic history
|
|
|
|
Yes
|
1 (5.6)
|
2 (8.3)
|
1.000
|
No
|
17 (94.4)
|
22 (91.7)
|
The findings showed that the proportion of male patients in the occurrence group (patients who showed adverse reactions) was higher than that in the no occurrence group (patients who showed no adverse reactions) (P < 0.05). However, no statistically significant difference was found between the two groups in terms of age, underlying disease type, comorbidity, drug combinations or allergy history (P > 0.05).