EU SolidAct: An Adaptive Pandemic and Emerging Infection Platform Trial

COVID-19 Clinical Trial

— Bari-SolidAct  

Official title:

European DisCoVeRy for Solidarity: An Adaptive Pandemic and Emerging Infection Platform Trial

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04891133
• Other study ID #: EU SolidAct
• Secondary ID: 2022-500385-99-0
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: June 3, 2021
• Est. completion date: January 23, 2023

Study information

• Verified date: February 2023
• Source: Oslo University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 290
• Est. completion date: January 23, 2023
• Est. primary completion date: December 15, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

**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. EXCLUSION CRITERIA: Participants are excluded from the study if any of the following general exclusion criteria

(GE) apply:

• GE1. Anticipated transfer to another non-trial hospital within 72 hours
• Additional exclusion criteria, including prohibited medication, confounding trials and details on contraception and pregnancy are given in the intervention-specific sub-protocols
• SE-01. Patients receiving Janus kinase (JAK) inhibitors (including baricitinib) for any indication at screening.
• SE-20. Have received tocilizumab or sarilumab for any indication 4 weeks prior to screening. Note: Tocilizumab as rescue therapy will be allowed in patients with clinical progression after inclusion, see section 6.8 concomitant medication. If tocilizumab or other immunosuppressive rescue therapy is started, IMP should be discontinued.
• SE-21. Patients with recent changes in immunosuppressive therapy that could interfere with the potential effect of baricitinib. Note: An assessment of the total level of immunosuppression, hematological parameters (SE-13 and SE-14), drug half-lives, drug-drug interactions, and underlying medical conditions (SE-22) must be performed as part of the risk/benefit evaluation.
• Recipients of bone marrow transplant or solid organ transplant last 6 months, or with transplant rejection last 6 months, should not be included.
• Organ transplant recipients receiving triple immunosuppression can only be included if the anti-metabolite (mycophenolic acid or mTOR inhibitor) has been temporarily discontinued per clinical practice10. IMP should be discontinued once triple immunosuppression is restarted.
• SE-22. Any medical condition that in the opinion of the investigator poses an inacceptable risk of serious infection or aggravation of the medical condition by participating in the trial. Note: Patients with acute leukemia or history of lymphoma should not be included. Cancer patients under active treatment, HIV positive individuals with detectable HIV-RNA, or other patient group associated with high risk of serious infection or aggravation of the medical condition should only be included if, in the judgement of the investigator, the potential benefit outweighs the potential risk.
• SE-03. Have received dexamethasone 6 mg daily (or alternative regimens with equivalent of corticosteroids) for more than 4 days prior to screening as part of SoC for severe/critical COVID-19
• SE-04. Had COVID-related symptoms > 21 days or hospitalized > 7 days.
• SE-05. Strong inhibitors of organic anion transporter 3 [OAT3] (e.g., probenecid) that cannot be discontinued at study entry.
• SE-07. Have received any live vaccine within 4 weeks before screening, or intend to receive a live vaccine during the study (until day 90 (+/- 14 days)). Note: Use of non-live (inactivated) vaccinations, including COVID-19 vaccinations, is allowed for all participants.
• SE-08. Are using or will use extracorporeal blood purification (EBP) device to remove proinflammatory cytokines from the blood such as a cytokine absorption or filtering device, for example, CytoSorb®.
• SE-09. Have diagnosis of current active tuberculosis (TB) or, if known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening tests required).
• SE-10. Suspected serious, active bacterial, fungal, viral, or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product.
• SE-12. Have a history of venous thromboembolism (VTE) (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) within 12 weeks prior to randomization or have a history of recurrent (>1) VTE (DVT/PE).
• SE-13. Neutropenia (absolute neutrophil count <1000 cells/microliters).
• SE-14. Lymphopenia (absolute lymphocyte count <200 cells/microliters).
• SE-15. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 times ULN.
• SE-16. Subjects with estimated glomerular filtration rate (eGFR) (Modification of Diet in Renal Disease [MDRD]) <30 millilitre/minute/1.73 meters squared are excluded.
• SE-17. Known hypersensitivity to baricitinib or any of its excipients.
• SE-18. Are pregnant or breastfeeding, or intend to become pregnant or breastfeed during the study. Note: Women of child bearing potential (WOCBP) can only be included based on a negative pregnancy test and WOCBP must comply with requirements regarding highly effective contraception. Refer to section 10.1 for contraception requirements.
• SE-19 Participation in any therapeutic clinical trials investigating immunomodulators for COVID-19

Related Conditions & MeSH terms

• Communicable Diseases
• Communicable Diseases, Emerging
• COVID-19
• Emerging Infectious Disease
• Infections

Intervention

Drug:
• Baricitinib
4 mg baricitinib (2 tablets of 2 mg) once daily
• Placebo
4 mg placebo (2 tablets of 2 mg) once daily

Locations

Country	Name	City	State
Austria	Medical University of Innsbruck (University Hospital for Neurosurgery)	Innsbruck
Austria	Medical Unversity of Innsbruck (Joint Institute for Emergency Medicine and Critical Care)	Innsbruck
Austria	Medical Unversity of Innsbruck (University Hospital for Anaesthesia and Intensive Care)	Innsbruck
Belgium	Cliniques Universitaires Saint-Luc	Brussels
Belgium	Erasme Hospital	Brussels
Belgium	UZ Brussel	Brussels
Czechia	St Anne University Hospital	Brno
France	CHU Amiens Picardie (ICU)	Amiens
France	CHU Amiens Picardie (ID)	Amiens
France	CHU de Bordeaux / Hopital Pellegrin (ICU)	Bordeaux
France	CHU de Bordeaux / Hopital Pellegrin (ID)	Bordeaux
France	Louis Mourier (ID)	Colombes
France	Lous Mourier (ICU)	Colombes
France	CHU François Mitterrand	Dijon
France	CHU Lille - Hopital Roger Salengro -Pôle Rèanimaition	Lille
France	Hopital de la Croix - Rousse - HCL (ICU)	Lyon
France	Hopital de la Croix - Rousse - HCL (ID)	Lyon
France	GHRMSA Hopital Emile Muller (ICU)	Mulhouse
France	GHRMSA Hopital Emile Muller (IM)	Mulhouse
France	Hôpital Bichat - Claude Bernard (ICU)	Paris
France	Hôpital Bichat - Claude Bernard (ID)	Paris
France	Hôpital Saint-Antoine (ICU)	Paris
France	Hôpital Saint-Antoine (ID)	Paris
Germany	Gesundheit Nord gGmbH (GeNo)	Bremen
Germany	Technische Universität München (TUM) - Klinikum rechts der Isar	München
Greece	Attikon University Hospital	Athens
Greece	Evangelismos Hospital	Athens
Hungary	University of Debrecen (Clinic for Infectology)	Debrecen
Hungary	University of Pécs	Pécs
Hungary	University of Szeged (Pandemic Clinics)	Szeged
Ireland	Cork University Hospital	Cork
Ireland	Beaumont Hospital, Dublin	Dublin
Ireland	Mater Misericordiae University Hospital	Dublin
Ireland	St James's Hospital, Dublin	Dublin
Ireland	St Vincent's University Hospital	Dublin
Ireland	Tallaght University Hospital	Dublin
Ireland	University Hospital Galway	Galway
Ireland	University Hospital Limerick	Limerick
Italy	Ospedale Santa Maria Annunziata, Malattie Infettive	Bagno A Ripoli
Italy	ASST - Spedali Civili di Brescia - University of Brescia	Brescia
Italy	ATS Sardegna - PO SS Trinità, U.O.C. Malattie Infettive	Cagliari
Italy	Azienda Opsedaliera Universitaria Mater Domini, U.O. Malattie Infettive e Tropicali	Catanzaro
Italy	ASL Frosinone - Ospedale Fabrizio Spaziani, U.O.C. Medicina Interna	Frosinone
Italy	Ospedale S.M. Goretti di Latina, U.O.C. Malattie Infettive	Latina
Italy	Ospedale Mater Salutis di Legnago, U.O.C. di Pneumologia	Legnano
Italy	Ospedale Mater Salutis di Legnago, U.O.S. di Malattie Infettive	Legnano
Italy	ASST Santi Paolo e Carlo, S.C. Malattie Infettive	Milano
Italy	Azienda Ospedaliera Universitaria Vanvitelli, U.O.C. Malattie Infettive	Napoli
Italy	AOU Policlinico "P. Giaccone", U.O.C. Malattie Infettive	Palermo
Italy	Azienda Ospedaliera Ospedali Riuniti Marche Nord, U.O.C. Malattie Infettive	Pesaro
Italy	ASL Taranto - Ospedale Oncologico San Giuseppe Moscati, U.O.C. Pneumologia	Taranto
Italy	AOU Città della Salute e Scienza Presidio Molinette	Torino
Italy	Azienda Sanitaria Universitaria Giuliano Isontina (ASU GI), S.C. Malattie Infettive	Trieste
Italy	Azienda Ospedaliera Universitaria Integrata di Verona, U.O.C. Malattie Infettive e Tropicali	Verona
Italy	IRCCS Ospedale Sacro Cuore Don Calabria, U.O.S. Malattie Infettive e Tropicali	Verona
Luxembourg	Centre Hospitalier de Luxembourg	Luxembourg
Norway	Drammen (Vestre Viken) Hospital	Drammen
Norway	Østfold sykehuset i Kalnes	Grålum
Norway	Akershus Universitetssykehus	Lørenskog
Norway	Lovisenberg Diaconal Hospital	Oslo
Norway	OUS Ullevål	Oslo
Norway	Bærum Hospital	Sandvika
Norway	Stavanger University Hospital	Stavanger
Norway	Vestfold Hospital	Tønsberg
Norway	University Hospital North Norway	Tromsø
Norway	St. Olavs Hospital	Trondheim
Portugal	CHMT - Centro Hospitalar do Médio Tejo- Hospital de Abrantes	Abrantes
Portugal	CHUC - Centro Hospitalar e Universitário de Coimbra	Coimbra
Portugal	CHUA-Faro - Centro Hospitalar Universitário do Algarve	Faro
Portugal	CHLC-HCC - Hospital Curry Cabral, Centro Hospitalar Universitário Lisboa Central	Lisboa
Portugal	CHLN - Centro Hospitalar Universitário Lisboa Norte	Lisboa
Portugal	CHLO - Centro Hospitalar de Lisboa Ocidental - HEM and HSFX	Lisbon
Portugal	CHSJ - São João Hospital Center	Lisbon
Portugal	HBA - Hospital Beatriz Ângelo	Loures
Slovakia	University Hospital Bratislava, Kramare	Bratislava
Slovakia	University Hospital Martin	Martin
Slovakia	Nsp Trebisov, Svet Zdravia a.s.	Trebišov
Slovakia	Faculty Hospital Trencin	Trencín
Slovakia	University Hospital Trnava	Trnava
Spain	Hospital Universitario Reina Sofia	Córdoba
Spain	Hospital Universitario de Jaen	Jaén
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Virgen de la Victoria	Málaga
Spain	Hospital Costa del Sol	Marbella
Spain	Hospital Universitario Virgen de Valme	Sevilla
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitario Virgen Macarena	Sevilla
Turkey	Ankara Üniversitesi Tip Fakültesi, Enfeksiyon Hastaliklari ve Klinik Mikrobiyoloji Anabilim Dali	Ankara
Turkey	Hacettepe Üniversitesi Tip Fakültesi, Infeksiyon Hastaliklari ve Klinik Mikrobiyoloji Anabilim Dali (Site 1)	Ankara
Turkey	Hacettepe Üniversitesi Tip Fakültesi, Infeksiyon Hastaliklari ve Klinik Mikrobiyoloji Anabilim Dali (Site 2)	Ankara
Turkey	Istanbul Üniversitesi Istanbul Tip Fakültesi, Enfeksiyon Hastaliklari ve Klinik Mikrobiyoloji Anabilim Dali	Istanbul
Turkey	Dokuz Eylül Üniversitesi Tip Fakültesi Enfeksiyon Hastaliklari ve Klinik Mikrobiyoloji Anabilim Dali	Izmir

Sponsors (3)

Lead Sponsor	Collaborator
Oslo University Hospital	Epidemiological and Clinical Research Information Network, Institut National de la Santé Et de la Recherche Médicale, France

Countries where clinical trial is conducted

Austria,  Belgium,  Czechia,  France,  Germany,  Greece,  Hungary,  Ireland,  Italy,  Luxembourg,  Norway,  Portugal,  Slovakia,  Spain,  Turkey, 

References & Publications (1)

Troseid M, Arribas JR, Assoumou L, Holten AR, Poissy J, Terzic V, Mazzaferri F, Bano JR, Eustace J, Hites M, Joannidis M, Paiva JA, Reuter J, Puntmann I, Patrick-Brown TDJH, Westerheim E, Nezvalova-Henriksen K, Beniguel L, Dahl TB, Bouscambert M, Halanova — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in C-reactive protein from baseline	Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized	Days 1, 3, 5, 8, 15 and 22
Other	Changes in Ferritin from baseline	Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized	Days 1, 3, 5, 8, 15 and 22
Other	Changes in Lactate dehydrogenase from baseline	Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized	Days 1, 3, 5, 8, 15 and 22
Other	Changes in D-dimer from baseline	Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized	Days 1, 3, 5, 8, 15 and 22
Other	Changes in procalcitonin from baseline	Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized	Days 1, 3, 5, 8, 15 and 22
Other	Changes in neutrophils from baseline	Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized	Days 1, 3, 5, 8, 15 and 22
Other	Changes in lymphocytes from baseline	Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized	Days 1, 3, 5, 8, 15 and 22
Other	Changes in White Blood Cell Count from baseline	Analyzed in blood samples collected at Days 1, 3, 5, 8, 15 and 22 (± 1 day) if still hospitalized	Days 1, 3, 5, 8, 15 and 22
Primary	Occurrence of death within 60 days (primary end point, EU SolidAct part B)	The primary outcome for phase 3 trials in EU SolidAct part B is occurrence of death within 60 days	60 days
Primary	Occurrence of disease progression within 14 days (primary end point, EU SolidAct part A)	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)	14 days
Primary	SpO2/FiO2-ratio at day 5 (primary end point, phase 2 trials)	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	5 days
Secondary	Occurrence of disease progression within 28 days (shared secondary end point for part A and B)	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	28 days
Secondary	Time to sustained recovery (shared secondary end point for part A and B)	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	90 days
Secondary	Time to first hospital discharge (shared secondary end point for part A and B)	Time from randomization to first hospital discharge within 90 days	90 days
Secondary	Disease state at Day 15 and Day 29 (shared secondary end point for part A and B)	Disease state on a 5-point scale defined as: Mild (WHO score 1-3) or better,; Moderate (WHO score 4-5),; Severe (WHO score 6),; Critical (WHO score 7-9) or; Death at Day 15 and 29	28 days
Secondary	Time from randomization to recovery (shared secondary end point for part A and B)	Time from randomization to recovery defined as no need for oxygen	90 days
Secondary	SpO2/FiO2-ratio at Day 3, 5 and 8 (shared secondary end point for part A and B)	Respiratory dysfunction assessed by SpO2/FiO2-ratio at Day 3, 5 and 8	8 days
Secondary	Viral clearance during hospitalization (shared secondary end point for part A and B)	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	Days 1, 3, 5, 8 and 15
Secondary	Occurrence of serious adverse events within 90 days (shared secondary end point for part A and B)	Occurrence of serious adverse events leading to study treatment discontinuation or death	90 days
Secondary	Patient related outcomes at day 90 (shared secondary end point for part A and B)	The Oslo COVID-19 QLQ-PW80 subscale scores at Day 90	90 days