Factorial Randomized Trial of Rendesivir and Baricitinib Plus Dexamethasone for COVID-19 (the AMMURAVID Trial)

ASST Fatebenefratelli Sacco

Status and phase: Unknown; Phase 3

Conditions: Covid19

Treatments: Drug: Dexamethasone; Drug: Baricitinib Oral Tablet [Olumiant]; Drug: Remdesivir

Study type: Interventional

Funder types: Other

Identifiers

NCT04832880

2020-001854-23 (EudraCT Number)

The AMMURAVID trial

Details and patient eligibility

About

Background:

In the current worldwide medical emergency, a rapid identification of effective therapeutic strategy is crucial. So far, therapy with dexamethasone, remdesivir and baricitinib have been associated with evidence of impact on the clinical impact on COVID-19, but the effect of baricitinib and remdesivir in combination with dexamethasone.

The AAMMURAVID trial is endorced and supported by the Italian Regulatory agency (AIFA-Agenzia Italiana del Farmaco)

Enrollment: 4,000 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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4,000 participants in 4 patient groups

Control arm (dexamethasone arm)

Experimental group

Description:

IV dexamethasone 6 mg for 10 days

Treatment:

Drug: Dexamethasone

Remdesivir arm

Experimental group

Description:

IV dexamethasone 6 mg for 10 days + remdesivir IV 200 mg on day 1, followed by 100 mg die until day 10

Treatment:

Drug: Remdesivir

Drug: Dexamethasone

Baricitinib arm

Experimental group

Description:

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.

Treatment:

Drug: Dexamethasone

Drug: Baricitinib Oral Tablet [Olumiant]

Remdesivir + baricitinib arm

Experimental group

Description:

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.

Treatment:

Drug: Remdesivir

Drug: Dexamethasone

Drug: Baricitinib Oral Tablet [Olumiant]