The current study is a multi-center, double arm, adjuvant, randomized control trial (RCT),
double-blind clinical trial, to analyze the differences in the usefulness and safety of
Exosome-MSC intravenous injection therapy in moderate-grade COVID-19 patients with
hyper-inflammation (Evans S.R, 2010).
This study used 2 groups (double arm) of study participants:
Treatment Group (Intervention Arm): received treatment in the form of standard therapy and
injection of Exosomes-MSC.
Control Group (Control Arm): received treatment in the form of standard therapy and injection
placebo.
The time interval for the implementation of the study protocol was 14 days. For each group
(Treatment and Control) the minimum target number of participating patients and according to
the inclusion criteria in this study were 30 people. The minimum total number of participants
with 2 groups (Treatment and Control) is 60 people. (Rohrig B., 2010)
Random sample selection was carried out nationally from patients who entered the treatment
room with a positive diagnosis of COVID-19 at the three Multi-Center Research Implementation
Hospitals (RSPAD Gatot Soebroto Jakarta, RSUP Dr. Sardjito Yogyakarta and RSUP M. Djamil
Padang) in the period 3 months after the issuance of Ethical Clearance and Approval for
Implementation of Clinical Trials from BPOM.
The sample size is calculated using the following formula:
n1 = n2 = 2(Za+Z1-β)^2/ Δ^2
n1: the number of participants in the Exosome-MSC group n2: the number of participants in the
control group Zα: standard deviation of type I error, 95% confidence interval (1.96) Zβ:
standard deviation of type II error, power 80% (0.84) SD: standard deviation of duration of
recovery on standard therapy (5.90). (Voinsky I, 2020)
Minimum expected difference in duration of healing (in days) when using Exosome-MSC compared
to standard therapy (5) From the above calculation, the results of the calculation are N1 =
N2 = 21.83 with rounding up each = 22 participants . To anticipate the adequacy of the number
of participants , each group was added 8 participants , 30 participants each in the
Exosome-MSC group and the control group so that the total number of participants was 60
participants.
Participants can be discontinued before the study is completed (drop-out) if they experience
significant side effects and/or adverse events, both treatment related and non treatment
related. Participants can also be discontinued before the study is completed (drop-out) if it
worsens to a severe degree. All Participants will be discontinued from the study when the
treatment and examination are completed according to the procedure.
Randomization of patients into the intervention group or control group was made for each
study site through the block 4 randomization technique. This process will be coordinated by
the Team who will carry out the Research Management/CRO function.
The double-blind procedure is a procedure to avoid bias of researchers and research
participants that will affect the results of data analysis. To apply this procedure, the
Exosome-MSC test material specimen in the Treatment Group was dissolved in 0.9% Nacl. The
dosage form will be disguised so that it is similar to Nacl 0.9% in the Control Group.
Research participants and local researchers implementing in hospitals do not have knowledge
about the status of the research group (arm). During the study, patients continued to take
their usual routine medications, such as antihypertensive drugs, antidiabetic drugs, calcium,
or folic acid. The treatment will be included as a confounding factor.
Research participants will be monitored closely. CLINICAL examinations are carried out EVERY
DAY, starting from the baseline (day 0) to day 14.
The clinical examination consists of:
body temperature,
oxygen saturation,
respiratory rate,
breath difficulties,
cough with phlegm,
RT-PCR results
standard therapy.received
allergic reactions,
secondary infection
side effects/ adverse events (AE) that are life threatening.
Remission score assessment based on 8 ordinal scales to determine Time to Clinical
Improvement (TTCI).
TTCI is the number of days until clinical improvement can be observed, as indicated by a
score of 1-3 out of 8 ordinal scales.
Laboratory examinations will be carried out on days 0, 1, 3, 7, 10 and 14 (unless they have
been discharged/recovered first) . On days 0 and 7 when the Exosomes-MSC injection therapy is
administered, laboratory examinations were performed before therapy.
Laboratory examinations consist of:
C-Reactive Protein,
ferritin,
D-Dimer,
LDH
Fibrinogen,
Routine blood, type count (including lymphocyte count)
PT and APTT
SGOT/SGPT,
urea/creatinine,
electrolyte K/Na/Cl,
Measures of intervention outcomes must be documented in a standardized Case Report Form (CRF)
for each patient participating in the study.
Adverse Events are any events, whether predicted or not, which can be related to the test
material or not, this includes worsening of the clinical condition previously owned by the
participant.
Serious Adverse Events (SAE), include
Dead
Life threatening Inpatient / Participant requires treatment as an inpatient
Additional length of stay *
Permanent / significant disability
Congenital abnormalities
Additional length of stay, defined as length of stay at any time. Hospitalization due to
routine administration of standard therapy is not included in this definition. If the
participant experiences an adverse event during the hospitalization period, the condition
must be reported as an adverse event.
All adverse events identified from the start of the study (day 0) to day 14 will be recorded
in the adverse event form in the case report form (CRF).
In the event of a Serious Adverse Events (SAE), researchers at the research site must report
it to Dermama Biotechnology Laboratorium within 24 hours after it is known as the initial
report, the report is addressed to: Dr. dr. Indah Hidajati Kampono, Sp.DV(K) Dermama
Biotechnology Laboratory Jl. Kelengkeng No. 8 Surakarta Phone/Fax Number: 0271-727007 E-mail:
Indahhidajati01@gmail.com Telephone/Mobile Number: +62 811-2632-086
Written reports of serious adverse events must be sent to the Ethics Committee within 3
calendar days and to Indonesian National Agency of Food and Drugs Control (BPOM) within 7
calendar days for SAE that are fatal or life threatening, and within 15 calendar days for
other SAE according to BPOM Regulation No. 21/201514.