COVID-19, Emerging Infectious Disease
Conditions
Brief summary
EU SolidAct is a randomized, multifactorial, adaptive platform trial for COVID-19 and emerging infectious diseases and pandemics. The purpose of this study is to evaluate the effect of a range of interventions to improve outcome of patients admitted to hospital with COVID-19. The platform is designed for running phase 2 and phase 3 trials, and with modular data capture (end point/safety data, biobanking, add-on studies) depending on the capacity of participating sites. The study consists of two parts with different primary end points depending on disease stage: EU SolidAct part A includes hospitalized patients with moderate disease, whereas EU SolidAct part B includes hospitalized patients with severe and critical disease.
Detailed description
There is an urgent need for developing an adaptive pan-European research platform for rapid and coordinated investigation of new candidate drugs during ongoing pandemics. EU-SolidAct is an Adaptive Platform Trial master protocol developed for evaluating drug interventions in hospitalized patients with COVID-19. While this master protocol is developed for therapeutic interventions in hospitalized patients, it could also form the basis for trial protocols on other interventions and/or in non-hospitalized populations. The protocol is additionally developed to facilitate a joint European response to the challenge of evaluating interventions during future epidemics. The described disease states and endpoints may need to be adapted to the epidemic in question. EU-SolidAct is a European, multicentre, randomized, parallel, phase 2 and 3 platform trial on drug interventions, both new and repurposed, single or in combination, in hospitalized adult patients with moderate or severe COVID-19, as defined by the WHO Working Group on the Clinical Characterisation and Management of COVID-191. Participants with moderate disease (WHO score 4-5) will be eligible for EU-SolidAct Part A, whereas participants with severe/critical disease (WHO score 6-9) will be eligible for EU-SolidAct Part B. This might include participants progressing from Part A. In Part A of phase 3 confirmatory trials, the primary objective is to determine the effect of therapeutic interventions on occurrence of disease progression, from moderate disease to severe/critical disease or death within 14 days. In Part B, the primary objective is to determine the effect of therapeutic interventions on occurrence of death within 60 days. In phase 2 the default objective for both parts is to explore the effect of the therapeutic intervention on respiratory dysfunction at day 5. Other objectives, e.g. effect on virological outcomes may be considered based on the treatment mode of action. In phase 3 trials, both superiority and non-inferiority hypotheses may be evaluated. In phase 2 trials, only superiority hypotheses will be evaluated. In addition to single treatments, combination of treatments could also be assessed through factorial design. EU-SolidAct is designed to be adaptive and to enable inclusion of hospitals in Europe and beyond, regardless of epidemic waves and available resources. This requires the master protocol to be modular, ranging from a core set of outcomes to more advanced data capture. Hospitals will access the study on different pre-set levels, ranging from a core set of clinical endpoints and safety measures, to a more advanced level with biobanking and possibilities for add-on studies
Interventions
DRUGBaricitinib
4 mg baricitinib (2 tablets of 2 mg) once daily
DRUGPlacebo
4 mg placebo (2 tablets of 2 mg) once daily
Sponsors
Institut National de la Santé Et de la Recherche Médicale, France
Epidemiological and Clinical Research Information Network
Oslo University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Corresponding placebo tablets
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\*\*EU SOLIDACT PLATFORM INCLUSION CRITERIA\*\*: Participants are eligible to be included in the study only if all the following general inclusion (GI) criteria apply: * GI1. ≥ 18 years of age * GI2. Laboratory-confirmed SARS-CoV-2 infection (new infection or reinfection) as determined by PCR not more than 14 days old. * GI3. Admitted to hospital * GI4. Informed consent by the participant or legally authorized representative * GI5A (SolidAct part A): Moderate disease state defined as hospitalised patients without oxygen therapy or oxygen by mask or nasal prongs needed, or * GI5B (SolidAct part B): Severe/critical disease state defined as fulfilling at least one of the following criteria: 1. SpO2\<90% on room air, or 2. SpO2 90-94% with a downwards trend and/or signs of respiratory distress\*, or 3. Need of oxygen by NIV (CPAP, BIPAP), high flow or non-rebreather mask, or 4. Need of mechanical ventilation/ECMO * persistently increased respiratory rate, use of accessory muscles, inability to complete full sentences. Clinical judgement must be applied to determine whether a low oxygen saturation is indicative of disease progression or severity or is habitual for a given patient (i.e., with underlying chronic lung disease). NIV=non-invasive ventilation. CPAP= Continuous Positive Airway Pressure, BPAP= Bi-level Positive Airway Pressure, ECMO = extracorporeal membrane oxygenation. Additional inclusion criteria are given in the intervention-specific sub-protocols. Note: these are based on the same criteria as in the WHO living guidelines recommending corticosteroid treatment for severe and critical COVID-195. In addition, the following specific inclusion criteria apply: SI-01. Immunocompromised patients defined as the presence of at least one of the following conditions9: 1. Hematological malignancy or pre-malignancy, except acute leukemia or history of lymphoma 2. Organ transplant recipients, except recipients of bone marrow or solid organ transplant last 6 months, or with transplant rejection last 6 months 3. HIV positive with CD4 count \< 350 cells and on stable antiretroviral therapy 4. Primary immunodeficiency 5. Rheumatoid arthritis, lupus, vasculitis, inflammatory bowel disease or other autoimmune disorder for which a patient is being treated with systemic immunosuppressive medication 6. Other specified cause, such as history of cancer, cancer treatment or other condition that in the opinion of the investigator could cause impaired host immunity SI-02. Elevation of 2 or more inflammatory markers above the following cutoffs: * Ferritin \> 700 ug/l * LDH \> 400 U/L * CRP \> 75 mg/L Note: Carefully check
Exclusion criteria
SE-01, SE-20 and SE-21 (immunosuppressive therapy), SE-22 (medical condition), SE-13 (neutropenia) and SE-14 (lymphopenia) for eligibility criteria. Immunocompromised patients should receive appropriate SoC, including anti-SARS-CoV2 monoclonal antibodies or emerging antiviral treatment, if available and indicated by current treatment guidelines at time of inclusion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of death within 60 days (primary end point, EU SolidAct part B) | 60 days | The primary outcome for phase 3 trials in EU SolidAct part B is occurrence of death within 60 days |
| SpO2/FiO2-ratio at day 5 (primary end point, phase 2 trials) | 5 days | In phase 2 exploratory trials, the default primary objective for both part A and B is to explore the effect of the intervention on respiratory dysfunction assessed by SpO2/FiO2-ratio at day 5 |
| Occurrence of disease progression within 14 days (primary end point, EU SolidAct part A) | 14 days | The primary outcome for phase 3 trials in EU SolidAct part A is occurrence of disease progression, defined as a progression of disease state from moderate (WHO score 4-5) to severe/critical (WHO score 6-9) or death (WHO score 10) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to first hospital discharge (shared secondary end point for part A and B) | 90 days | Time from randomization to first hospital discharge within 90 days |
| Occurrence of disease progression within 28 days (shared secondary end point for part A and B) | 28 days | Occurrence of disease progression, defined as a progression of disease state from moderate (WHO score 4-5) to severe/critical/death (WHO score 6-10) or from severe/critical (WHO score 6-9) to death |
| Time to sustained recovery (shared secondary end point for part A and B) | 90 days | Time from randomization to sustained recovery, defined as being discharged from the index hospitalization, followed by being alive and at home for 14 consecutive days within 90 days |
| Disease state at Day 15 and Day 29 (shared secondary end point for part A and B) | 28 days | Disease state on a 5-point scale defined as: 1. Mild (WHO score 1-3) or better, 2. Moderate (WHO score 4-5), 3. Severe (WHO score 6), 4. Critical (WHO score 7-9) or 5. Death at Day 15 and 29 |
| Time from randomization to recovery (shared secondary end point for part A and B) | 90 days | Time from randomization to recovery defined as no need for oxygen |
| SpO2/FiO2-ratio at Day 3, 5 and 8 (shared secondary end point for part A and B) | 8 days | Respiratory dysfunction assessed by SpO2/FiO2-ratio at Day 3, 5 and 8 |
| Viral clearance during hospitalization (shared secondary end point for part A and B) | Days 1, 3, 5, 8 and 15 | Viral clearance as assessed by SARS-CoV-2 PCR in naso/oropharyngeal specimens collected at Days 1, 3, 5, 8 and 15 (± 1 day, except baseline) if still hospitalized |
| Occurrence of serious adverse events within 90 days (shared secondary end point for part A and B) | 90 days | Occurrence of serious adverse events leading to study treatment discontinuation or death |
| Patient related outcomes at day 90 (shared secondary end point for part A and B) | 90 days | The Oslo COVID-19 QLQ-PW80 subscale scores at Day 90 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in procalcitonin from baseline | Days 1, 3, 5, 8, 15 and 22 | Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized |
| Changes in neutrophils from baseline | Days 1, 3, 5, 8, 15 and 22 | Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized |
| Changes in lymphocytes from baseline | Days 1, 3, 5, 8, 15 and 22 | Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized |
| Changes in White Blood Cell Count from baseline | Days 1, 3, 5, 8, 15 and 22 | Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized |
| Changes in Lactate dehydrogenase from baseline | Days 1, 3, 5, 8, 15 and 22 | Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized |
| Changes in Ferritin from baseline | Days 1, 3, 5, 8, 15 and 22 | Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized |
| Changes in C-reactive protein from baseline | Days 1, 3, 5, 8, 15 and 22 | Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized |
| Changes in D-dimer from baseline | Days 1, 3, 5, 8, 15 and 22 | Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized |
Countries
Austria, Belgium, Czechia, France, Germany, Greece, Hungary, Ireland, Italy, Luxembourg, Norway, Portugal, Slovakia, Spain, Turkey (Türkiye)
Outcome results
None listed