Factorial Randomized Trial of Rendesivir and Baricitinib... | NCT04832880

ID	Type	Description	Link
2020-001854-23	EudraCT Number

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Control arm (dexamethasone arm)	Experimental	IV dexamethasone 6 mg for 10 days	Drug: Dexamethasone
Remdesivir arm	Experimental	IV dexamethasone 6 mg for 10 days + remdesivir IV 200 mg on day 1, followed by 100 mg die until day 10	Drug: Remdesivir Drug: Dexamethasone
Baricitinib arm	Experimental	IV dexamethasone 6 mg for 10 days + baricitinib 4 mg die for 10 days. For patients aged > 75 years or estimated GFR < 60 ml/min*1.73m2, baricitinib dose is reduced to 2 mg for 10 days.	Drug: Baricitinib Oral Tablet [Olumiant] Drug: Dexamethasone
Remdesivir + baricitinib arm	Experimental	IV dexamethasone 6 mg for 10 days + remdesivir IV 200 mg on day 1, followed by 100 mg die until day 10 + baricitinib 4 mg die for 10 days. For patients aged > 75 years or estimated GFR < 60 ml/min*1.73m2, baricitinib dose is reduced to 2 mg for 10 days.	Drug: Baricitinib Oral Tablet [Olumiant] Drug: Remdesivir Drug: Dexamethasone

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Baricitinib Oral Tablet [Olumiant]	Drug	Baricitinib 4 mg die (2 mg for patients aged > 75 years) for 10 days.	Baricitinib arm Remdesivir + baricitinib arm

Measure	Description	Time Frame
Prevention of very severe respiratory failure or mortality	Composite outcome: Development of very severe respiratory failure (PaO2/FiO2 <150 mmHg) or mortality	Day1-Day 28

Measure	Description	Time Frame
Prevention of mortality	Proportion of dead patients	Day 7
Prevention of mortality	Proportion of dead patients	Day 14

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Adults aged > 18 years able to provide a valid informed consent to the study
Documented COVID-19 by direct testing (positive PCR), with lung infiltrates at imaging (Chest-X ray or CT) and requirement of oxygen supplementation
Less than 10 days form symptoms onset
Cytokine storm, using the criteria developed at Temple University (all of the three below criteria):
- CRP > 46 mg/l
- Ferritin > 250 ng/ml
- One variable of each of the three clusters below
  - Cluster 1
    - Albumin < 2.8 g/dl
    - Lymphocytes <10.2 % of WBC
    - Absolute neutrophil count > 11400/mm3
  - Cluster 2
    - ALT > 60 U/L
    - AST > 87 U/L
    - D-dimers > 4930 µg/l fibrinogen-equivalent-units (FEU).
    - LDH >416 U/L
    - High sensitivity troponin > 1.09 ng/ml
  - Cluster 3
    - Anion Gap at arterial blood gas < 6.8 mM
    - Chloride > 106 mM
    - Potassium > 4.9 mM
    - BUN:creatinine ratio > 29
PaO2/FiO2 200-400 mmHg, while in oxygen therapy or continuous positive airway pressure (C-PAP)
For women of childbearing potential and men: agreement to use contraception in the case of heterosexual intercourses before day 28 with a failure rate < 1% per year (bilateral tubal ligation, male sterilisation, hormonal contraceptives inhibiting ovulation, hormone-release or copper intrauterine devices). For men enrolled in the study, condom use is allowed.

Exclusion criteria:

Orotracheal intubation or ECMO support
Active solid / hematologic cancer (including invasive non-melanoma skin cancer)
Hypersensitivity or contra-indications to one of the investigational agents (including history of deep vein thrombosis / pulmonary thromboembolism within 12 weeks prior to screening)
Other active concurrent viral, fungal or bacterial infections (including active tuberculosis/latent TB treated for less than 4 weeks, HIV and HCV/HBV infections)
Pregnancy/breastfeeding
Incapability to provide a valid informed consent (including age < 18 years old)
Heart failure with NYHA >= 2 or any acute cardiac or vascular event requiring therapy in the previous 12 months
Chronic renal failure (baseline GFR < 45 ml/min*1.73m2)
Liver cirrhosis moderate / severe (Child-Pugh B or C)
Chronic respiratory failure requiring O2 therapy or ventilation therapy at home
Blood neutrophils <1000/mcL, platelet <50000/mcL, Hb levels <80 g/l
ALT/AST > 5 times UNL
Use of any biologic agent or small molecule inhibitor and other investigational drugs in the previous 4 weeks or 5 half-lives (whichever is longer). Specific cut-offs for wash-out are required for the following therapies:
- B-cell targeted therapies: 24 weeks or 5 half-lives (whichever is longer)
- TNF-inhibitors: 2 weeks or 5 half-lives (whichever is longer)
- JAK-inhibitors: 1 week or 5 half-lives (whichever is longer)
Use of other immunosuppressive agents in the last 3 months (chronic use of topical steroids and systemic steroids with a dose ≤5 mg of prednisone equivalents is allowed)
Use of any other investigational therapy for COVID-19 (including IV immunoglobulins, convalescent COVID-19 plasma or monoclonal antibodies)
Impossibility to discontinue Strong inhibitors of OAT3 (such as probenecid) at study entry
Any other condition judged by the local investigator as a contra-indication to eligibility
Subjects who have received live vaccines within 4 weeks before the study or are planned to receive live vaccine in the first months after study enrolment.

Name	Role	Phone	Extension	Email
Enrico Tombetti, MD, PhD	Contact	3289098793	+39	enrico.tombetti@unimi.it
Massimo Galli, Prof	Contact	3358058990	+39	massimo.galli@unimi.it

ID	Term
D011024	Pneumonia, Viral
D011014	Pneumonia
D012141	Respiratory Tract Infections
D007239	Infections
D014777	Virus Diseases
D018352	Coronavirus Infections
D003333	Coronaviridae Infections
D030341	Nidovirales Infections
D012327	RNA Virus Infections
D008171	Lung Diseases
D012140	Respiratory Tract Diseases

ID	Term
D011246	Pregnadienetriols
D011245	Pregnadienes
D011278	Pregnanes
D013256	Steroids
D000072473	Fused-Ring Compounds
D011083	Polycyclic Compounds
D013259	Steroids, Fluorinated

ID	Term
C000596027	baricitinib
C000606551	remdesivir
D003907	Dexamethasone