The Efficacy and Safety of Carrimycin Treatment in Patients With Novel Coronavirus Infectious Disease (COVID-19) : A Multicenter, Randomized, Open-controlled Study
Phase: PHASE4
Conditions: Novel Coronavirus Infectious Disease (COVID-19)
Sponsor: Beijing YouAn Hospital

The efficacy and safety of carrimycin treatment in patients 
with novel coronavirus infectious disease (COVID-19) : A 
multicenter, randomized, open-controlled study   
Study protocol 
Version No.: 
V5.0 
Version date: 
February 20, 2020 
Study sites: 
Beijing YouAn Hospital, Capital Medical 
University 
Shenyang Tonglian Group Co., Ltd. 
Institute of Medicinal Biotechnology, Chinese 
Academy of Medical Sciences 
Huangshi Central Hospital 
Shenyang Pharmaceutical University 
The First Affiliated Hospital of Chongqing 
University of Medical Science 
The Second Affiliated Hospital of Harbin 
Medical University 
No.2 People’s Hospital of Fuyang City 
The First Affiliated Hospital of Bengbu 
Medical College 
Renmin Hospital of Wuhan University 
The Six People’s Hospital of Shenyang 
Nanyang Central Hospital 
Principal investigators: 
Director Jin Ronghua 

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Project Consultant: 
Academician Yang Baofeng 
 
Confidentiality 
This clinical study protocol is a confidential document for the purpose of this clinical study and shall not be disclosed to 
anyone other than the investigators involved and members of the institutional review board. 
 

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Synopsis 
Name of study 
The efficacy and safety of carrimycin treatment in patients with novel 
coronavirus 
infectious 
disease 
(COVID-19): 
A 
multicenter, 
randomized, open-controlled study 
Study Objectives 
Evaluate the efficiency and safety of Carrimycin in the patients with 
2019-nCoV pneumonia, establish the criteria for clinical cure and 
the early predictive model of COVID-19 progression. 
Study design 
A randomized, open, positive-controlled and multi-center clinical 
study 
Planned 
sample 
size 
520 subjects planned. 
Inclusion/exclusion 
criteria 
Subjects shall meet all the following criteria before being 
included: 
Inclusion criteria 
(1) Subjects or their legal representatives have signed the informed 
consent form(ICF); agree not to participate in other clinical 
studies within 30 days after the last administration from the first 
administration of the study drug. 
(2) Subjects are aged ≥ 18 and ≤ 75; 
(3) Meet the diagnostic criteria for 2019-nCoV pneumonia (V5.0); 
(4) SOFA score: 1 ~ 13 points. 
(5) A retreated patient or the relapsed patient meets any of the 
following criteria: 
① Have fever again or aggravated clinical symptoms; ② 
2019nCOVRNA in the throat swabs converts from negative to 
positive; ③ The clinical symptoms don’t improve or 
2019nCOVRNA continues to be positive; ④ The chest CT 
shows pneumonia or fibrosis progression. 
 
Clinical stratification: 
1. Mild type: clinical symptoms mild or asymptomatic, no 

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pneumonia performance in CT, but positive 2019-nCoV in throat 
swabs or gargle. 
2. Ordinary type: fever, respiratory symptoms, etc., pneumonia 
performance visible in CT. 
3. Severe type: meeting any of the following criteria: 
(1) Respiratory distress, RR≥30 times/min; 
(2) Finger oxygen saturation ≤93% in rest state; 
(3) Arterial partial pressure of oxygen (PaO2)/concentration of 
oxygen inhalation (FiO2)≤300mmHg (1mmHg=0.133kPa). 
4. Critical type: meeting any of the following criteria: 
(1) Respiratory failure occurs and mechanical ventilation is 
required; 
(2) Patients go into shock; 
(3) ICU is needed for other organ failure. 
 
Exclusion criteria 
(1) Other viral pneumonia 
(2) Patients who have received tumor immunotherapy (such as 
PD-1/L1, CTLA4, etc.) in the past 1 month, and inflammatory 
factor modulators such as Ulinastatin; 
(3) Patients who have taken anti-bacterial drugs such as macrolide 
in the past 1 week; 
(4) Patients who have received organ transplantation or surgery 
planning in the past 6 months; 
(5) Patients who can't take food or drugs due to coma or intestinal 
obstruction; 
(6) Patients who have severe underlying diseases that affects 
survival, including uncontrolled malignant tumor with multiple 
metastases that cannot be resected, blood diseases, dyscrasia, 
active bleeding, severe malnutrition, etc. 
(7) Women subjects that are pregnant or lactating, or subjects 
(including male subjects) having a pregnancy plan (including 

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plans for sperm donation or egg donation), or subjects that may 
fail to take effective contraceptive measures within the next 6 
months; 
(8) Patients with allergic constitution, or patients allergic to 
macrolides and lopinavir/ritonavir tablets; 
(9) Patients with contraindications to lopinavir/ritonavir tablets who 
plan or are using drugs that interact with the drug (including: 
drugs that are highly dependent on CYP3A clearance and 
whose elevated plasma concentrations can be associated with 
severe and/or life-threatening events [with a narrow therapeutic 
index], CYP3A inducer [see instruction for details]) and cannot 
stop using or use other drugs instead; 
(10) Patients whose ALT/AST levels are 5 times higher than the 
normal upper limit and total bilirubin is 3 times higher than the 
upper limit of normal, or patients with child-Pugh grade C 
cirrhosis. 
(11) ECLS (ECMO, ECCO2R, RRT) 
(12) Critical patients with expected life＜48 hours 
(13) Patients who have participated in any other clinical study within 
1 month; 
(14) The investigators conclude that the patients not suitable for the 
study. 
Trial 
drugs 
and 
medication 
methods 
The trail group and the control group were randomized according to 
1: 1. 
(1) Trial group: basic treatment + Carrimycin 
Mild type: 0.4g of Carrimycin tablets, p.o. after meal once a day for 7 
consecutive days, followed up for observation after the end of 
treatment. 
Ordinary type: 0.4g of Carrimycin tablets, p.o. after meal once a day 
for 10 days, followed up for observation after the end of treatment. 
Severe and critical: 0.4g of Carrimycin tablets, p.o. after meal once 
a day for 14 consecutive days. If oral administration is not possible, 

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the drug should be administered through a nasal feeding tube.  
For the combination drugs of basic treatment according to the 
Diagnosis and Treatment Program for 2019-nCoV ( V5.0,Chinese) 
 
(2) Control group: any of basic treatment + lopinavir/ritonavir tablets 
or Arbidol or chloroquine phosphate: 
Mild and ordinary type: 400mg/100mg, bid of lopinavir/ritonavir 
tablets each time; or 500mg bid of chloroquine phosphate; or 200mg 
tid of Arbidol for 7 consecutive days, followed up for observation 
after the end of treatment. 
 
Severe and critical type: 400mg/100mg, bid of lopinavir/ritonavir 
tablets each time; or 500mg bid of chloroquine phosphate; or 200mg 
tid of Arbidol for 10 consecutive days, followed up for observation 
after the end of treatment. 
For the combination drugs of basic treatment according to the 
Diagnosis and Treatment Program for 2019-nCoV ( V5.0,Chinese) 
 
Therapy/drug 
combination 
Permitted therapy combination and/or drug combination: 
Clinical treatment schemes other than antiviral therapy in the 
Diagnosis and Treatment Program for 2019-nCoV (V5.0,Chinese) 
are permitted. 
Acetaminophen (paracetamol), diclofenac sodium suppositories, 
lyripine (lysisin aspirin) antipyretics are prohibited. 
 
Prohibited therapy combination and/or drug combination: 
No other antiviral drugs or antibiotics are allowed during the trial 
(except retreated or relapsed patients or in severe and critical type 
cases). 
Keep a detailed record of the dugs combination, especially the 
glucocorticoids. 
Observation period 
Screening period: -2 days~ 0 day; 
Treatment period: 7-14 days; 

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Follow-up observation period: follow up to 30 days after the first 
administration. 
Effectiveness 
indicators 
Primary efficiency indicators 
(1) Fever to normal time (day) 
(2) Pulmonary inflammation resolution time (HRCT) (day) 
(3) Negative conversion (%) of 2019-nCOVRNA in gargle (throat 
swabs) at the end of treatment 
Secondary efficiency indicators 
(1) Negative conversion ratio of 2019-nCOVRNA in gargle (throat 
swabs), urine and stool on Day 1, 3, 5 and 14 after 
administration; 
(2) Progress rate of 2019-nCoV pneumonia 
(3) Changes in immune-related indicators (lymphocyte count, 
lymphocyte percentage, counts and percentages of CD4 and 
CD8, and inflammatory cytokines) from baseline on Day 1, 3, 5 
and 7-10 after administration. 
(4) Changes in SOFA score from baseline on Day 1, 3, 5 and 7-10 
after administration; 
(5) Changes in white blood cell count from baseline on Day 1, 3, 5 
and 7-10 after administration; 
(6) Changes in PCT and C-reactive protein from baseline on Day 1, 
3, 5 and 7-10 after administration;  
(7) Changes in CT features from baseline on Day 7-10 and 14 after 
administration; 
(8) Length of stay in hospital and mortality rate. 
 
There are currently criteria for release from clinical isolation and 
discharge on 2019-nCoV pneumonia (V5.0,Chinese), and there is 
no "gold standard" for clinical cure, and it is difficult to obtain the 
basis for pulmonary diagnosis. Therefore, the following criteria are 
currently used clinically (empirical evidence, lack of scientific 
evidence) and it is not known whether there is a chronic infection or 

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virus carrying. Therefore, the following criteria are used for the 
clinical assessment in this project: 
Criteria for clinical cure: 
1) The clinical symptoms disappear and the quality of life is 
normal. 
2) Lung CT/HRCT is normal. 
3) T lymphocyte function and count return to normal. 
4) Negative 2019-nCOV in secretions (gargle, urine and stool) 
Clinical chronic or complications: 
1) Gastrointestinal 
and 
respiratory 
symptoms 
completely 
disappear, the quality of life is lowered (anxiety, insomnia and 
other mental disorders) or the lung CT/HRCT lesions exist, or 
lung fibrosis is formed. 
2) Or laboratory abnormalities (blood routine, T lymphocyte count 
or function). 
3) Negative 2019-nCOV in secretions (gargle, urine and stool) 
Safety indicators 
(1) AE, SAE. 
(2) Vital signs: breath, 
blood 
pressure, heart 
rate, 
body 
temperature. 
(3) Laboratory examination: blood routine (WBC, RBC, Hb, HCT, PLT, 
LY and LY%), urine routine (WBC, RBC, Pro), blood 
biochemical examinations (ALT, AST, TBIL, ALP, GGT, Cr, BUN, 
Glu) and coagulation function (PT, APTT, TT, FIB). 
(4) Routine ECG: heart rate, Q-Td, ST segment and T wave 
changes. 
Statistical analysis 
(1) General principle 
1) Description of statistics 
The primary indicators collected in this study are described with 
statistical method. Quantitative indicators are described by means of 
mean, standard deviation, median, quartile, maximum, minimum 
and the like; qualitative indicators are described by frequency, 
percentage and the relationship. 

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2) Statistical test 
Unless otherwise specified, the statistical significance level is 
0.05 by two-sided test (one-sided 0.025) and the 95% confidence 
interval shall be provided for the estimation of inter-group variance 
parameters. 
3)Random grouping: The hierarchical random grouping method 
is adopted 
 
(2) Characteristics of cases 
1) Subject distribution 
① The population and the number of enrolled and completed 
cases in each center are listed, and three analysis data sets 
(FAS, PPS, SS) are determined.  
② A detailed list of the data set categories is made. 
③ The number and ratio of subjects who are randomly 
enrolled, complete the trial, and withdraw from the trial early 
and the reasons are calculated. 
④ The subject distribution flow chart is plotted. 
2) General information and baseline characteristics 
The demographic information, previous medication history and 
history of other diseases of the patients are described with statistical 
method. General information and baseline characteristics are 
described based on FAS. 
 
(3) Analysis of drug exposure and drug combination 
Analysis based on SS. 
1) Drug exposure, dose intensity and exposure time of each 
group are calculated. 
2) The drug combination is coded by WHO ATC and 
summarized according to the ATC secondary classification 
and PT. The number and ratio of cases are calculated. 
 

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(4) Efficiency analysis 
Analysis based on FAS and PPS. 
The primary effective indicator are:(1) Fever to normal time 
(day),(2)Pulmonary 
inflammation 
resolution 
time 
(HRCT) 
(day),(3)Negative conversion (%) of 2019-nCOVRNA in gargle 
(throat swabs) at the end of treatment on Days 7-10 after 
administration. The statistical significance level is set to one-sided 
0.025. The two-sided 95% confidence interval (95%CI) are 
calculated. 
The 
confidence 
interval 
is 
estimated 
by 
Miettinen-Nurminen. 
The 
secondary 
efficiency 
indicators 
include 
negative 
conversion ratio of 2019-nCOVRNA from samples, immune-related 
indicators (lymphocyte count, lymphocyte percentage, counts and 
percentages of CD4 and CD8), SOFA score, white blood cell count, 
C-reactive protein, pulmonary imaging improvement indicators and 
complete antipyresis time on Day 1, 3, 5 and 14 after administration. 
In-hospital time,clinical cure ration and mortality are also analysed. 
The secondary efficiency indicators are subject to descriptive 
statistical analysis according to the data type. 
 
(5) Safety analysis 
SS data sets are used for safety analysis. 
1) Adverse events are coded according to the MedDRA. 
2) The occurrence of adverse events/reactions, serious 
adverse events/reactions and adverse events/reactions 
resulting in drop out is summarized and analyzed in the 
form of a frequency table (number of cases, case, and 
incidence). 
3) The occurrence of varying severity orders of adverse 
events/reactions, serious adverse events/reactions and 
adverse events/reactions resulting in drop out is subject to 
descriptive statistical analysis in the form of a frequency 

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table (number of cases, case, and incidence) according to 
SOC and PT. 
4) A detailed list of various adverse events/reactions, serious 
adverse 
events/reactions 
and 
cases 
of 
adverse 
events/reactions resulting in drop out is made. 
5) Changes in the clinical significance determination of 
laboratory indicators, ECG and physical examination at 
each visit after administration and baseline test results are 
described in the form of crosstab. 
6) The laboratory indexes and vital signs examination are 
subject to descriptive statistical analysis according to trial 
grouping and visits. 
7) A detailed list of laboratory indexes, ECG, and clinically 
significant physical abnormalities. 
 
 
Expected 
study 
time 
Study start time: February 2020 
Study end time: February 2021 
 
 

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Flow chart of clinical trial 
Study stage 
Screenin
g period 
1 
Medication period 
follow-up 
observation 
period 
Early 
withdrawal 
2 
Day -2 ~ 
day 0 
(baselin
e) 
Day 1 
Day 3 
Day 7 
Day 10 
Day 14 
Day 14 
±1 
days 
Day 
28 ±2 
days 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Informed 
consent form 
× 
 
 
 
 
 
 
 
 
Demographic 
information 
× 
 
 
 
 
 
 
 
 
Medical data 
× 
× 
× 
× 
× 
× 
× 
× 
 
Vital signs 
× 
× 
× 
× 
× 
× 
× 
× 
× 
SOFA score 
× 
 
× 
× 
× 
× 
 
× 
 
Physical 
examination 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Review of 
inclusion/excl
usion criteria 
× 
× 
 
 
 
 
 
 
 
Blood routine 3 
× 
 
× 
× 
× 
× 
× 
× 
× 
Urine routine 4 
× 
 
× 
× 
× 
× 
× 
× 
× 
Blood 
biochemistry 5 
× 
 
× 
× 
× 
× 
× 
× 
× 
Coagulation 
function 6 
× 
 
× 
× 
× 
× 
 
 
× 
T cell subset 
and cytokines 
7 
× 
 
× 
× 
× 
× 
× 
× 
× 
C-reactive 
protein 
× 
 
× 
× 
× 
× 
 
 
× 
2019-nCOVRNA 
in throat swabs, 
urine and stool 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Chest imaging 
(CT) 
× 
 
 
× 
× 
× 
× 
× 
× 
12-lead ECG 
× 
 
 
× 
× 
× 
 
 
× 
Pregnancy 
test 8 
× 
 
 
 
 
 
 
× 
× 
Enrollment 
 
× 
 
 
 
 
 
 
 
Administration 
 
× 
× 
× 
× 
× 
 
 
 

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Study stage 
Screenin
g period 
1 
Medication period 
follow-up 
observation 
period 
Early 
withdrawal 
2 
Day -2 ~ 
day 0 
(baselin
e) 
Day 1 
Day 3 
Day 7 
Day 10 
Day 14 
Day 14 
±1 
days 
Day 
28 ±2 
days 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Record of 
clinical 
treatment 
scheme 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Trial drug 
dispensing 
 
× 
× 
× 
× 
× 
 
 
 
Trial drug 
recovery 
 
× 
× 
× 
× 
× 
 
 
× 
Combination 
therapy 
× 
× 
× 
× 
× 
× 
× 
 
 
Reserve 
throat swabs 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Reserve blood 
specimens 
(serum, plasma 
and cells) 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Reserve urine 
and stool 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Adverse event 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Notes: 
1. 
Visit 1 (screening period) and visit 2 (baseline) may be on the same day, and Day 0 is 
the first day of administration; 
2. 
To withdraw from the trial in advance, it is necessary to complete the last visit items; 
in case of AE at the end of the trial, follow-up should be conducted according to the "AE" 
requirements of the protocol; 
3. 
Blood routine examinations: including WBC, RBC, Hb, HCT, PLT, LY, LY%; 
4. 
Urine routine examinations: including WBC, RBC, Pro; 
5. 
Blood biochemical examinations: including ALT, AST, TBIL, ALP, GGT, Cr, BUN, Glu; 
6. 
Coagulation function: including PT, APTT, TT, FIB; 
7. 
T cell subset: counts and percentages of CD4+ and CD8+;