Efficacy of Sofosbuvir Plus Ledipasvir in Egyptian Patients With COVID-19 Compared to Standard Treatment

Currently there is no known effective therapy or vaccine for treatment of SARS-CoV-2, highlighting urgency around identifying effective therapies.

This study aiming to evaluate the anti-HCV medications efficacy "Sofosbuvir-Ledipasvir" in treatment of moderate cases with SARS-COV-2 infection, in comparison to the standard treatment (hydroxychloroquine, oseltamivir and azithromycin).

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Drug: Sofosbuvir plus Ledipasvir

Detailed Description

This randomized controlled clinical trial is a prospective, comparative, single blind, randomized study that was conducted on 250 patients, divided into two equal groups. The group I received Sofosbuvir plus Ledipasvir and Group II received Oseltamivir, hydroxychloroquine "HCQ" plus Azithromycin (the local medical committee of Almaza Fever Hospital guided standard treatment protocol for COVID-19).

Randomization (in RCT only)

Once enrolled in the study, patients randomly assigned to one of the following groups:

• Group I (SL group, n=125): patients received Sofosbuvir plus Ledipasvir.
• Group II (OCH group, n=125): patients received Oseltamivir plus HCQ & Azithromycin.

Randomization applied through computer-generated number and concealed using sequentially numbered, sealed opaque envelope.

Group I Patients assigned to this group (125 patients) were received Sofosbuvir plus Ledipasvir (FDA approved Anti-HCV drug since 2014, with Reference ID: 4081324), once daily for 15 to 21days as minimum and maximum duration of therapy, respectively.

Additional conservative medications were given including, third generation cephalosporines (Ceftriaxone 2 gm /24 hours) for 7 days, methylprednisolone 1 mg/kg/day for 7 days; and prophylactic low molecular weight heparin (enoxaparine) 40 mg/24 hours was given throughout hospitalization period.

Patients were evaluated as scheduled on day 0,5,10 & 15 (also, day 21 if extended duration) clinically, laboratory investigations including RT-PCR & C.T chest. RT-PCR with negative result was repeated after 24-48 hrs.

Medications stopped any time if there was any clinical, radiological or laboratory deterioration.

Group II

Patients in this group (125 patients) were received the local medical committee of Almaza Fever Hospital guided standard treatment protocol for COVID-19:

• Oseltamivir 150 mg q 12 hours for 10 days ;
• HCQ 400 q 12 hours for one day followed by 200mg q 12 hours for 9 days ; and
• Azithromycin 500mg once daily for 1 day , followed by 250mg once daily for 6 days.
• Additional conservative medications were also given. Patients were evaluated as scheduled on day 0, 5 & 11 clinically, laboratory Investigations including RT-PCR & C.T chest. RT-PCR with negative result was repeated after 24-48 hrs. Medication were stopped any time, if there was any clinical, radiological or laboratory deterioration.

2.3 Assessment tools

Basic investigations were applied for all patients on day 0 , repeated on days 5 ,10 & 15 or earlier regarding physician order , including :

• CBC, NLR "neutrophil lymphocyte ratio ".
• ESR.
• AST, ALT, creatinine; fasting blood glucose.
• ECG.
• C.T chest , pneumonia was assessed on admission using CT Severity Scoring System (CT-SSS) and CO-RADS ( Percentage per lobe with max of 5 points for each lobe and 25 points for both lungs ; Right Lung" RUL , RML & RLL " ; Left lung " LUL & LLL " ) (11)

Follow up CT chest was repeated on day 5, 10 and day15 or earlier according to physician's request. It was reported as progressive, regressive, stationary or resolved (progressive: crazy paving +↑CTSS ± consolidation; regressive: i.e. absorption (resolved crazy paving pattern +↓CTSS (12); Cured: complete resolution of pneumonic patches).

Other investigations were asked and repeated when needed including:

• LDH.
• TG.
• D. dimmer.
• S.Ferritin.
• Interleukin 6 level.
• Abdominal U.S.

COVID-19 RT-PCR test was done by extraction of the DNA of the virus by using either device (QIA cube or QIA symphony), it takes 70 minutes for every 12 sample on QIA cube or 5 hours for every 96 samples on the QIA symphony. Then the process was applied for the preparation and implementation of the RT-PCR step by using chemicals for detection of the COVID-19, which takes from one and half hour to two hours for 72 samples.

Discharge criteria

• Resolution of symptoms (Normal body temperature for at least 3 days and significantly improved respiratory symptoms).
• Radiological improvement of pneumonic pattern in CT chest.
• Documented virological clearance in 2 samples at least 24 hours apart.
• There was no co-morbidities or complications, which require hospitalization.
• SpO2 > 93 % without assisted oxygen inhalation.
• Discharge approved by multi-disciplinary medical team.

• Study Type: Interventional
• Enrollment (Actual): 250
• Phase: Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt
    • Almaza Military Fever Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Pneumonic patients with SARS-COV-2 infection confirmed to be positive by RT-PCR; and demonstrated moderate cases criteria (fever "measured temperature of at least 38 °C", lower respiratory symptoms "cough, shortness of breath" and imaging-confirmed pneumonia").
• Female patients enrolled in the study should have no planned pregnancy for 6 months, after participating in the study, with administration of proper contraceptive measures within 30 days from the first therapeutic dose of the investigational drugs.
• Patients agreed to sign an informed consent to participate in the current study and that they would not participate in other clinical trials within 30 days from the last administration of the study drugs.

Exclusion Criteria:

• Severe COVID-19 patients who met one of the following conditions: (1) Respiratory rate (RR) ≥ 30 times / min; (2) SaO2 / SpO2 ≤ 93% in resting state; (3) arterial partial pressure of oxygen (PaO2) / concentration of oxygen (FiO2) ≤ 300 mmHg
• Critical COVID-19 patients with one of the following conditions: (1) respiratory failure and need mechanical ventilation; (2) shock; (3) other organ failure combined with ICU treatment; severe liver disease (such as child Pugh score ≥ C, AST > 5 times upper limit);
• Patients with contraindications specified for sofosbuvir- ledipasvir; the pregnancy test of female subjects during the screening period was positive, the researchers judged that the patient was not suitable to participate in this clinical study due to devastating co-morbid diseases (e.g. de-compensated liver disease, congested heart failure, chronic kidney disease, malignant or hematological disease under therapy or 3 months ago) and patients received antiviral eradication therapy for hepatitis C or B viruses within the previous 6 months.
• Patients with chloroquine contra-indications: QTc > 500 m/sec, myasthenia gravis, porphyria, retinal pathology, epilepsy, G6PD deficiency, allergy to 4-aminoquinolone, chronic heart, kidney or liver disease, and arrhythmias.
• Any patient demonstrates worsening of symptoms, radiological progression with virologically persistence within at least 5 days of the therapeutic evaluation period of the study after exclusion of cytokine storm was considered as a clinical failure and was shifted to the other management protocol.
• Treatment was terminated at any time by a multidisciplinary team if a serious side effect occurred, which was attributed to the medications used ,e.g. cardiac arrhythmia, deteriorated liver or kidney function or unfortunately patient died .

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: • Group I (Sofosbuvir plus Ledipasvir); Patients assigned to this group (125 patients) were received Sofosbuvir plus Ledipasvir, once daily for 15 to 21 days as minimum and maximum duration of therapy, respectively.	Drug: Sofosbuvir plus Ledipasvir; Sofosbuvir plus Ledipasvir, once daily for 15 to 21days; Oseltamivir 150 mg q 12 hours for 10 days ;; HCQ 400 q 12 hours for one day followed by 200mg q 12 hours for 9 days ; and; Azithromycin 500mg once daily for 1 day , followed by 250mg once daily for 6 days.; Other Names: Oseltamivir plus Hydroxychloroquine & Azithromycin
Active Comparator: Group II (Oseltamivir plus HCQ & Azithromycin); Patients in this group (125 patients) were received the local medical committee of Almaza Fever Hospital guided standard treatment protocol for COVID-19: Oseltamivir 150 mg q 12 hours for 10 days ;; HCQ 400 q 12 hours for one day followed by 200mg q 12 hours for 9 days ; and; Azithromycin 500mg once daily for 1 day , followed by 250mg once daily for 6 days.; Additional conservative medications were also given. Patients were evaluated as scheduled on day 0, 5 & 11 clinically	Drug: Sofosbuvir plus Ledipasvir; Sofosbuvir plus Ledipasvir, once daily for 15 to 21days; Oseltamivir 150 mg q 12 hours for 10 days ;; HCQ 400 q 12 hours for one day followed by 200mg q 12 hours for 9 days ; and; Azithromycin 500mg once daily for 1 day , followed by 250mg once daily for 6 days.; Other Names: Oseltamivir plus Hydroxychloroquine & Azithromycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Therapeutic success (cured)	Cured: Documented virological clearance in 2 samples at least 24 hours apart.	21 days
28 days in hospital mortality	any incidence of deaths for any participant within 28 days from starting the treatments	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of clinical failure of treatments	participants who failed to achieve documented virological clearance in 2 samples at least 24 hours apart.	21 Days
Length of hospital stay	days of length of hospital staying in isolation till documented virological clearance in 2 samples at least 24 hours apart.	Through study completion, an average of 14 weeks
Incidence of side effects	Incidence of any side effects known to be related to the medication administrated either in group 1 or 2	21 days

Collaborators and Investigators

• Sponsor: Almaza Military Fever Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2020
• Primary Completion (Actual): July 8, 2020
• Study Completion (Actual): July 23, 2020

Study Registration Dates

• First Submitted: August 26, 2020
• First Submitted That Met QC Criteria: August 27, 2020
• First Posted (Actual): August 28, 2020

Study Record Updates

• Last Update Posted (Actual): August 28, 2020
• Last Update Submitted That Met QC Criteria: August 27, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Covid-19; Hydroxychloroquine; SARS-COV-2; Sofosbuvir- Ledipasvir
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Sofosbuvir; Azithromycin; Hydroxychloroquine; Ledipasvir; Oseltamivir
• Other Study ID Numbers: 14

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No