Clinical trial NCT04461340: Efficacy and Safety of Sirolimus in COVID-19 Infection
Official title: Efficacy and Safety of Sirolimus for Treating COVID-19 Infection
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: COVID 19
Keywords: sirolimus
COVID 19
Lead sponsor: Alexandria University
Sponsor class: OTHER
First posted: 2020-07-08
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: single-blinded randomized clinical trial in which participants will be randomly assigned to one of the study groups using block randomization with a ratio of 1:1.
Primary purpose: TREATMENT

Brief summary: This research is planned to illustrate the efficacy and safety of sirolimus as an adjuvant agent to the standard treatment protocol against COVID-19 infection

Detailed description: In early December 2019, several pneumonia cases of unknown origin were observed in Wuhan (China). A novel enveloped RNA β coronavirus was isolated and named severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2). The new virus rapidly spread across China and worldwide. On March 11th 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a pandemic. As of 1July 2020, COVID-19 has been confirmed in 10,357,662 individuals globally with deaths reaching 508,055 with a morality of 5.37%. Egypt has 68,311 confirmed cases and 2935 deaths.

The virus mainly spreads through respiratory droplets from infected patients. The clinical spectrum of COVID-19 infection ranges from asymptomatic forms to severe pneumonia requiring hospitalization and isolation in critical care units with the need of mechanical ventilation due to acute respiratory distress syndrome (ARDS). Main symptoms include fever, fatigue and dry cough. Common laboratory findings include lymphopenia and elevated lactate dehydrogenase levels. Platelet count is usually normal or mildly decreased. C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are usually increased while procalcitonin levels are normal and elevation of procalcitonin usually indicates secondary bacterial infection. Ferritin, D-dimer, and creatine kinase elevation is associated with severe disease. Chest computed tomographic scans show a typical pattern of bilateral patchy shadows or ground glass opacity.

Severe COVID-19 conditions are usually due to an aggressive inflammatory response known as "cytokine storm" that is characterized by the release of a large amount of pro-inflammatory cytokines. Lung injury, multiorgan failure, and unfavorable prognosis of severe COVID-19 infection have been attributed mainly to the cytokine storm state.

Many proinflammatory cytokines elevate in COVID-19 patients including interleukin (IL)-1, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α and interferon( IFN)-Ȣ stimulating immune cells to invade sites of infection causing endothelial dysfunction, vascular damage, alveolar damage and ARDS. Cytokine storm has been reported in several viral infections including influenza H5N1 virus, influenza H1N1 virus, and the two coronaviruses highly related to COVID-19; "SARS-CoV" and "MERSCoV".

Currently, there is no vaccine and/or specific therapeutic drugs targeting the SARS-CoV-2. Hence, it remains a major challenge to decide what potential therapeutic regimens to prevent and treat severe COVID-19 infections. Effective vaccines are essential to combat against the extremely contagious SARS-CoV-2. Until we have specific vaccines or therapeutic drugs targeting SARS-CoV-2, "repurposed" drugs have been used to treat COVID-19 patients. At present, treatment of SARS-CoV-2 infection are mainly repurposing the available therapeutic drugs and based on symptomatic conditions. Considering ARDS, followed by secondary infections, antibiotics, antiviral therapy, systemic corticosteroids, and anti-inflammatory drugs (including anti-arthritis drugs) are often used in the treatment regimens. Neuraminidase inhibitors, RNA synthesis inhibitors, convalescent plasma, and traditional herbal medicines have also been utilized in the treatment of COVID 19. Nevertheless, the efficacy of these treatment regimens remains to be verified by appropriately designed clinical trials. Sirolimus, also known as rapamycin, is an immunosuppressant that is used to prevent organ transplant rejection by inhibiting mammalian target of rapamycin (mTOR) kinase. mTOR plays a key role in viral replication. In an in vitro experiment, sirolimus has been shown to affect PI3K/AKT/mTOR pathway which inhibited MERS-CoV activity. Studies of patients hospitalized with influenza can further shed light on the antiviral effect of sirolimus. In a randomized clinical trial conducted on 38 patients with confirmed H1N1 pneumonia and on mechanical ventilator support, a group treated with corticosteroids and 2 mg/day of sirolimus for 14 days (N=19) showed significantly better clinical outcomes compared with the group treated with corticosteroids only, including shorter median duration of ventilator used. Delayed oseltamivir plus sirolimus treatment in pH1N1-infected mouse model further suggested a significant association between the sirolimus treatment and improved outcomes. At least one in silico study identified sirolimus as one of the 16 potential candidates for treating COVID-19 patients based on data from other human coronavirus infections using network-based drug repurposing model.

Eligibility criteria: Inclusion Criteria:

* Adults (˃18 years) COVID-19 positive patients (confirmed by PCR).
* Moderate infection ( pneumonia ± leucopenia or lymphopenia ).

Exclusion Criteria:

* Severe or life threatening COVID infection: Severe disease is defined as: dyspnea, respiratory frequency ≥ 30/min, blood oxygen saturation ≤ 93%, partial pressure of arterial oxygen to fraction of inspired oxygen ratio \< 300, and/or lung infiltrates \> 50% within 24 to 48 hours. Life threatening disease is defined as: respiratory failure, septic shock, and/or multiple organ dysfunction or failure .
* Pregnant or lactating females.
* Participation in any investigational clinical study, other than observational, within the past 30 days; or plans to participate in such a study at any time from the day of enrollment until 30 days post-treatment in the current study.
* Allergy or hypersensitivity to sirolimus.
* Taking immunosuppressive drugs.
* Glomerular filtration rate (GFR) \< 30 ml/min by CKD-EPI equation.
* liver cirrhosis .
* Decompensated heart failure.
* known active tuberculosis (TB) or history of incompletely treated TB.
* Uncontrolled systemic bacterial or fungal infections.
* Drugs that may affect sirolimus level: antifungals, diltiazem, verapamil, nicardipine, phenytoin, phenobarbital, rifampicin, carbamazepine.

Primary outcomes:
measure: Time to clinical recovery
timeFrame: 14-28 days
measure: Viral clearance
timeFrame: 14 days
Secondary outcomes:
measure: radiological lung extension
timeFrame: 14 days
measure: drug adverse events
timeFrame: 28 days
measure: 28 day mortality
timeFrame: 28 day
measure: intensive care unit (ICU) admission rate
timeFrame: 28 days
measure: Duration of hospital stay
timeFrame: 28 days
Other outcomes:
Locations:
city: Alexandria
country: Egypt
facility: Faculty of Medicine, Alexandria university, Egypt
Study officials:
affiliation: lecturer
name: Mohamed Mamdouh Elsayed, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Associate professor
name: Ayman I Baess, MD
role: STUDY_CHAIR
affiliation: professor
name: Heba M El weshahi, MD
role: STUDY_CHAIR
affiliation: professor
name: Nermine H Zakaria, MD
role: STUDY_CHAIR
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