COVID-19
Conditions
Keywords
COVID-19
Brief summary
This is a a randomized double blind placebo controlled Phase 2 trial with a 12 patient lead-in to evaluate safety, prior to full enrollment to an additional 28 patients (for a total of 40 patients) to assess efficacy of decitabine in the treatment of critically ill patients with COVID-ARDS. The patients will be randomized in a 1:1 ratio to receive standard of care plus Decitabine or standard of care plus saline based placebo. The primary objective is to determine safety and efficacy of decitabine for COVID-19 ARDS based on clinical improvement on a 6-point clinical scale.
Detailed description
This is a randomized double blind placebo controlled Phase 2 trial with a 12 patient lead-in to evaluate safety, prior to full enrollment to an additional 28 patients (for a total of 40 patients) to assess efficacy of decitabine in the treatment of critically ill patients with COVID-ARDS. The patients will be randomized in a 1:1 ratio to receive standard of care plus Decitabine or standard of care plus saline based placebo. Eligible patients will receive decitabine 10 mg/m2 daily for 5 days, 1 cycle only. This is a dose that is half the FDA approved dose for myelodysplastic syndrome (MDS), and using a single cycle. If less than 2 of the first 6 (treatment arm) patients experience an unacceptable toxicity, defined as any treatment related grade III or higher adverse events, as per section 5.7, within 15 days of initiation of treatment, the drug is safe to continue. If the investigators observe more than 33% patients with unacceptable toxicity, the investigators will pause the accrual pending safety evaluation. After validating safety, the investigators will enroll additional 28 patients towards the primary efficacy endpoint. The investigators will monitor safety throughout the trial by monitoring clinical hematologic, chemistry, vital signs, respiratory parameters, medications, and clinical changes daily as per the schedule of procedures. Bio samples from peripheral blood mononuclear cell (PBMC) and Mini Bronchoalveolar lavage (BAL) will be collected and stored for secondary analysis and mini BAL will only be collected as an optional sub-study for patient consented to a separate study protocol either at time-point of for-cause clinically indicated bronchoscopy, or for subjects consented to a separate Bronchoalveolar lavage (BAL) interventional study, under the auspices of that protocol. For research bio specimens required after study drug initiation, a window period of +/-24 hours while inpatient, and +/- 4 days for outpatient monitoring will be permitted. These objectives will allow for the planning of subsequent phase 3 studies, and strengthen implementation of a multi-center randomized trial should this study confirm safety, and suggest efficacy of therapy.
Interventions
DRUGDecitabine
Study duration is 6 weeks after the last dose of study drug. Number of study visits is dependent on Length of hospitalization of study participant. Study visits are scheduled on days 0-7, 11, 15, 29, and may occur via telemedicine or inpatient assessment or outpatient assessment in COVID recovered participants. Decitabine will be administered via Intravenous Administration 10/mg/m\^2/day Dosage: 10mg/m\^2/day IV day x 5 days (1 cycle only)
OTHERPlacebo Saline
Saline based placebo will be administered via Intravenous injection. Dosage Regimen: 10mg/m\^2/day IV day x 5 days (1 cycle only)
Sponsors
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
This is a randomized double blind placebo controlled Phase 2 trial with a 12 patient lead-in to evaluate safety, prior to full enrollment to an additional 28 patients (for a total of 40 patients) to assess efficacy of decitabine in the treatment of critically ill patients with COVID-ARDS. The patients will be randomized in a 1:1 ratio to receive standard of care plus Decitabine or standard of care plus saline based placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. ≥18 years 2. Use of Intermittent Mechanical Ventilation, non-invasive mechanical ventilation (NIMV) or High Flow Nasal Cannula. 3. Have ARDS or Acute Lung Injury physiology confirmed by Pao2/Fio2 ratio of \< 300 4. Severe Acute Respiratory Distress Syndrome (SARS) - Coronavirus (CoV-2) determined by lab polymerase chain reaction assay in either upper or lower respiratory tract sampling (e.g. bronchoalveolar lavage or nasopharyngeal swab) 5. If childbearing age: agree to practice effective birth control from screening until at least 180 days after last dose
Exclusion criteria
1. Hematologic cytopenias: Absolute Neutrophil Count (ANC) \<1500/mm3, Hgb\<7.0 and/or platelets \<100,000/mm3 2. Subjects receiving or enrolled in clinical trial for other investigational treatment for SARS- 2-CoV. 3. Active malignancy, solid tumors, and current or recent chemotherapy 4. Concomitant use of nonbiologic immunosuppressants (e.g. Janus Kinase (JAK) inhibitors, Bruton's Tyrosine Kinase (BTK) inhibitors) 5. Active HIV viremia, or any other uncontrolled secondary infection. 6. Concurrent immunomodulating biologics or use of Palifermin, Dipyrone, Deferiprone 7. Subjects with severe sepsis with vasopressors or extrapulmonary organ failure: 8. Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) /alkaline phosphatase (ALK) Phos ≥3x upper limit of normal (ULN) and Total Bilirubin (TBILI) ≥2x ULN; or Creatinine clearance \<30 mL/min 9. Pregnant women or women who are breastfeeding 10. Any Condition, per opinion of PI that would affect subject safety and/or compliance 11. Prior hypersensitivity to decitabine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients who are alive and free of respiratory failure at day 28 | From the day of randomization to day 28 | The proportion of patients who are alive and free of respiratory failure at day 28 since start of randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in oxygenation index | Daily, up to 6 weeks | Oxygenation index is used to assess severity of hypoxic respiratory failure. (OI = mean airway pressure (MAP) × Fraction of inspired oxygen (FiO2) × 100÷ partial pressure of oxygen (PaO2). This will be measured daily while subject is on mechanical ventilation up to 6 weeks. |
| Change in fraction of inspired oxygen | Up to day 29 | Fraction of inspired oxygen in the oxygen delivery system during hospital stay. Measured at 8 am daily during hospital stay and then weekly until day 29. |
| Overall survival | Up to 6 weeks | Patients status of alive versus death at completion of study follow up period, i.e. 6 weeks from start. |
| Length of stay in hospital | Till hospital discharge, up to 6 weeks | Duration of days from baseline to hospital discharge. |
| Ventilator free days | Up to 6 weeks | For subjects who received mechanical ventilation, total number of days from baseline to end of study at 6 weeks that subject was not on mechanical or non invasive mechanical ventilation. |
| Safety as assessed by adverse events | Up to 6 weeks | Safety assessments using adverse events will be monitored daily while inpatient and weekly through end of study at week 6 once discharged from hospital. They will be monitored and graded using Common Terminology Criteria Adverse Events version 5.0. |
| Percentage of patients with National Early Warning Score 2 of 3 or more | Weekly while patient is in hospital, up to 6 weeks | Determines the degree of illness of a patient and prompts critical care intervention. This composite score includes Respiratory Rate, Temperature, oxygen Saturation, Blood Pressure, Oxygen inspired and cognitive status. This will be measured at baseline and weekly while patient is in hospital. |
| All-cause mortality at 28 days since randomization | Daily upto day 28 | Total number of death at 28 days since day of randomization |
| Percentage of change of clinical score based on World Health Organization 9-point scale at day 10 from randomization | Daily from randomization to day 10 | Determine clinical score from randomization date to day 10 |
| Percentage of change of clinical score based on World Health Organization (WHO 9) COVID progression scale | Weekly while patient is in hospital, up to 6 weeks | Time from randomization to an at least 2-point decrease in clinical score based on WHO 9-point scale |
| Time to Polymerase chain reaction (PCR) negativity | Up to 6 weeks | If viremic at starting date of decitabine - time from baseline to 1st recorded negative COVID nucleic acid amplification (NAT) based assay, measured in days. |
Countries
United States
Outcome results
None listed