This will be an investigator-initiated, parallel group, open-label, individually randomized, controlled clinical study. It will be conducted by Pt. B.D. Sharma Postgraduate Institute of Medical Sciences, Rohtak (Haryana). All the
study procedures will be carried out under the supervision of the expert
clinician. This pilot study is being undertaken to assess the efficacy and safety of oral Fixed Dose Combinations (FDCs) of Ledipasvir/Daclatasvir
with Sofosbuvir; in adults (aged ≥18 years) with SARS-CoV-2 /COVID-19
infection admitted at PGIMS, Rohtak.The study will be
done in accordance with the principles of the Declaration of Helsinki and the
International Conference on Harmonization–Good Clinical Practice guidelines.
The local and National guidelines for taking care of the COVID- patients will
patient will be recruited in the study as per
the following inclusion and exclusion criteria
Adult patients with
COVID-19 aged 18 years and above;
positive for SARS-CoV-2;
to give written informed consent.
Pregnancy or breast
aminotransferase or aspartate aminotransferase more than five times the upper
limit of normal;
Known severe renal
impairment (estimated glomerular filtration rate <30 mL/min per 1·73 m2) or
receipt of continuous renal replacement therapy, haemodialysis, or peritoneal
Enrolment into an
investigational treatment study for COVID-19 in the 30 days before screening.
child-bearing age (men and women) not agreeing to take effective contraceptive measures (including hormonal
contraception, barrier methods, or abstinence) during the study period and for
at least 7 days after the last study drug administration.
Any known hypersensitivity to the
Any patient belonging to Severe class
of COVID19 disease as per GOI guidelines (MoHFW)
a) The enrolled patient
selected as per the above inclusion and exclusion criteria will be given
detailed information about the purpose of the study and will be provided with
the patient information sheet, explaining the study procedures, risks, benefits,
responsibilities etc. After ensuring that the patient has understood about
the details of the study, a written informed consent will be obtained from each of the patients or their legal representatives if they are unable to provide consent.
b) All the patients
enrolled for the study will be subjected to relevant clinical and laboratory examination and their demographic details and
baseline parameters will be recorded as per case record form.
One hundered seventy five eligible patients will be randomly allocated
(web based randomization number generator), to one of the following three study
groups in the ratio of 1:2:2 (n= 35, 70, 70) .
I: Standard treatment as per hospital/MoHFW protocol
II- FDC of Ledipasvir (90mg) and Sofosbuvir (400mg) +
Treatment as per hospital/MoHFW protocol
for 14 days
III- FDC of Daclatasvir (60mg) and Sofosbuvir (400mg) +
Treatment as per hospital/MoHFW protocol for 14 days
Efficacy Assessment: All the patients will be actively assessed for various parameters of
efficacy at the baseline and for the study drug response at
various intervals for 14days and will be followed up for 30 days thereafter.
positivity in naso- and oro-pharyngeal samples will be tested on day 3, 7 and
14, both in qualitative and quantitative forms.
For sample size calculation, it was known that 20%
of patients of COVID19 with mild severity become negative on day 7 whereas the
incidence of negative RT-PCR on day 7 in the intervention group was assumed to
be 50%. Making an estimated hazard ratio of 2.5. We planned to enroll subjects
in a ratio of 1:2:2 in three groups (2 in intervention group for which there
were two groups and one for standard of care group). For final analysis of
negative RT PCR on day 7, we calculated that a total number of 145 patients
will provide 80% power to detect a hazard radio of 2.5 at a two sided
significance level of 0.05. Assuming an attrition rate of 20%, we planned to
recruit 175 cases for the trial with 35 subjects in the control group and 70
patients in each intervention group.
and Laboratory Monitoring
findings including history and physical examination, and laboratory and radiological investigation results will be entered into a
predesigned case record form.
Chest radiograph and ECG
will be taken at baseline and at regular intervals for monitoring of patient’s progress and to detect early cardiac rhythm changes. Patients with underlying cardiac conditions will be put on cardiac monitoring. All patients will be followed up till 30
days after discharge. Initial diagnosis
of SARS-CoV-2 infection will be made upon admission. Complete blood count, liver and
renal function tests, lactate dehydrogenase, creatine kinase, C-reactive protein, and erythrocyte sedimentation rate will be
regularly checked until
discharge. Virological measures will include
the proportions of patients with viral RNA detected and viral RNA load
(measured by quantitative RT-PCR).
of study drugs.