Clinical trial NCT05926505: Safety and Efficacy of Anakinra Treatment for Patients With Post Acute Covid Syndrome
Official title: Safety and Efficacy of Anakinra Treatment for Patients With Persistent Respiratory Symptoms Post Acute Covid and Immune System Activation: the Precision Double-blind, Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Post-Acute COVID-19 Syndrome
Post-Acute COVID-19
Long COVID
Keywords: COVID-19
Long COVID
Post-Acute COVID-19
Anakinra
PRECISION
NCT05926505
Lead sponsor: Hellenic Institute for the Study of Sepsis
Sponsor class: OTHER
First posted: 2023-07-03
Enrollment: 182
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The PRECISION is a proof-of-concept, phase II randomized clinical trial aiming to evaluate the efficacy and safety of anakinra in patients with Post-Acute COVID Syndrome (PACS) of the pro-inflammatory respiratory phenotype. Improvement is measured by a composite endpoint, namely, the "Score of PACS progression reversal"

Detailed description: People with COVID-19 might have sustained post-infection sequelae, known as Post-Acute Covid Syndrome (PACS). A recent consensus definition by an international panel of 265 patients, clinicians, researchers, and WHO staff suggests that post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, and cognitive dysfunction and generally have an impact on everyday functioning.

The role of immune dysregulation in PACS is indirectly supported from the findings of the SAVE-MORE randomized clinical trial, in which patients with moderate and severe COVID-19, were 1:2 randomized to treatment with placebo or anakinra once daily for 10 days. The primary endpoint was the distribution of the frequencies of patients in the 11 points of the WHO clinical progression scale (CPS) by day 28. Patients' follow-up until day 90 showed significant reduction of the incidence of PACS; this was 24.4% among placebo-treated patients and 15.7% among patients treated with anakinra.

After the end of the SAVE-MORE trial, the understanding of the immune activation of PACS and the development of tools for the evaluation of patients have become the main aims of the Hellenic Institute for the study of sepsis (HISS) group. More precisely, patients with medical history of COVID-19 pneumonia during three separate time periods and matched comparators for age, sex, comorbidities, and state of vaccination were followed up and evaluated for PACS. Main findings can be summarized as follows:

1. For at least one year after acute COVID-19 there is considerable immune dysregulation involving both the innate and the adaptive responses.
2. Patients with PACS may be classified into four main phenotype clusters: fatigue involving 70.8%, respiratory cluster involving 33.2%, systemic symptoms involving 17.7% and other symptoms involving 26.1%.
3. The risk for progression into PACS was significantly lower among patients treated with anakinra in the acute stage (odds ratio 0.59, p: 0.017) showing a role of IL-1 for the progression into PACS.
4. Patients with fatigue bring distinct immunotype compared to the respiratory cluster.
5. IP-10 (interferon-gamma-induced protein-10) at levels more than 250 pg/ml has sensitivity 99.3%, specificity 90.9%, positive predictive value (PPV) 97.9% and negative predictive value (NPV) 97.6% for the diagnosis of the post acute COVID immune dysregulation.

PRECISION is a proof-of-concept, randomized clinical trial (RCT) aiming to evaluate the efficacy and safety of anakinra in patients with PACS in improving the clinical and immunological state over 4 to 8 weeks as measured by a composite endpoint, namely, the "Score of PACS progression reversal".

Eligibility criteria: Inclusion Criteria:

1. Age equal to or above 18 years
2. Male or female gender
3. In the case of women of childbearing age and men, an adequate method of contraception should be used during the study. Contraception should be maintained for at least a period of 3 months after the discontinuation of treatment. As an adequate method of contraception, it is suggested: -male or female condom with or without spermicide -contraceptive cap, a diaphragm or contraceptive sponge with a spermicide Prior to admission to the study, a pregnancy test will be performed to exclude pregnancy to women of childbearing age.
4. Written informed consent provided by the patient. For subjects without decision-making capacity, informed consent must be obtained from a legally designated representative following the national legislation in the Member State where the trial is planned.
5. History of confirmed COVID-19 infection the last 90 days or more
6. Symptoms compatible with PACS (defined as at least one positive answer to the questionnaire for restriction of daily activities) lasting for more than 2 months
7. Serum levels of IP-10 more than 250 pg/ml
8. Presence of ONE of the following two clinical conditions: Condition 1: Impaired Lung Function tests (defined as: DLCOcor \<76% AND TLC and/or FVC lower than 80% of predicted) Condition 2: At least a total radiology score in HRCT more than 20 OR walking of a distance less than 500m in the 6-minute walk test

If patients meet the criteria for both Conditions 1 and 2, they will be considered for randomization and evaluation for the primary endpoint as in Condition 1.

Exclusion Criteria:

1. Age below 18 years
2. Denial for written informed consent
3. Any stage IV malignancy
4. Any primary immunodeficiency
5. Less than 1,500 neutrophils/mm3
6. Known hypersensitivity to anakinra
7. Known lung fibrosis prior to COVID-19
8. Medical history of pulmonary hypertension or chronic heart failure
9. Known chronic obstructive pulmonary disease GOLD stage 3 or 4 prior to COVID-19
10. Known active tuberculosis (under treatment) or latent tuberculosis (by positive tuberculin test)
11. Oral or IV intake of corticosteroids at a daily dose equal or greater than 0.4 mg/kg prednisone for a period greater than the last 15 days.
12. Any anti-cytokine biological treatment the last one month
13. Severe hepatic failure defined as Child-Pugh stage of 3
14. End-stage renal failure necessitating hemofiltration or peritoneal hemodialysis
15. Pregnancy or lactation. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study
16. Participation in any other interventional trial

Primary outcomes:
measure: Score of PACS progression reversal
timeFrame: Through study completion,an average of 2 years
Secondary outcomes:
measure: The frequency of the Score of PACS progression reversal between patients receiving 8 weeks anakinra treatment compared to patients receiving 4 weeks anakinra treatment (+4 weeks of placebo).
timeFrame: Through study completion,an average of 2 years
measure: Changes of concentration of cytokines produced by stimulated PBMCs at week 4 between the two arms of treatment.
timeFrame: Through study completion,an average of 2 years
measure: Change of each component of the score for the primary outcome at week 4 between the two arms of treatment.
timeFrame: Through study completion,an average of 2 years
measure: At least 10% decrease of the pulmonary artery pressure at week 4 between the two arms of treatment.
timeFrame: Through study completion,an average of 2 years
measure: At least 10% increase of LV ejection fraction (if abnormal at baseline) at week 4 between the two arms of treatment.
timeFrame: Through study completion,an average of 2 years
Other outcomes:
Locations:
city: Jena
country: Germany
facility: Out-patient long-COVID department, Jena University Hospital
city: Patra
country: Greece
facility: Out-patient long-COVID department, Patras University General Hospital
state: Achaia
city: Athens
country: Greece
facility: Out-patient long-COVID department III, Evangelismos Athens General Hospital
state: Attiki
city: Athens
country: Greece
facility: Out-patient long-COVID department I, Sotiria Athens Hospital of Chest Diseases
state: Attiki
city: Athens
country: Greece
facility: Out-patient long-COVID department II, Sotiria Athens Hospital of Chest Diseases
state: Attiki
city: Athens
country: Greece
facility: Out-patient long-COVID department IV, Sotiria Athens Hospital of Chest Diseases
state: Attiki
city: Athens
country: Greece
facility: Out-patient long-COVID department, Laiko General Hospital
state: Attiki
city: Chaïdári
country: Greece
facility: 2nd Department of Propedeutic Medicine, ATTIKON University General Hospital
state: Attiki
city: Chaïdári
country: Greece
facility: 4th Department of Internal Medicine, ATTIKON University General Hospital
state: Attiki
city: Alexandroupoli
country: Greece
facility: Out-patient long-COVID department, Alexandroupolis University General Hospital
city: Athens
country: Greece
facility: Out-patient long-COVID department X, Sotiria Athens Hospital of Chest Diseases
city: Ioannina
country: Greece
facility: Out-patient long-COVID department, Ioannina University General Hospital
city: Larissa
country: Greece
facility: Out-patient long-COVID department, University Hospital of Larissa
city: Magoúla
country: Greece
facility: Out-patient long-COVID department II, Thriasio General Hospital of Elefsina
city: Magoúla
country: Greece
facility: Out-patient long-COVID department I, Thriasio General Hospital of Elefsina
city: Piraeus
country: Greece
facility: Out-patient long-COVID department, Tzaneion Piraeus General Hospital
city: Thessaloníki
country: Greece
facility: Out-patient long-COVID department, AHEPA Hospital of Thessaloniki
city: Genova
country: Italy
facility: Infectious Diseases Clinic, Ospedale Policlinico San Martino IRCCS and Department of Health Sciences, University of Genova, Genoa, Italy
city: Jesolo
country: Italy
facility: Department of Internal Medicine, Hospital of Jesolo, Italy
city: Milan
country: Italy
facility: Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS Ospedale San Raffaele & Vita-Salute San Raffaele University, Milan, Italy
city: Modena
country: Italy
facility: Infectious Diseases Clinic, University of Modena, Italy
city: Rome
country: Italy
facility: Dipartimento Scienze di Laboratorio e Infettivologiche - Fondazione Policlinico Gemelli IRCCS, Roma Italy
city: Rome
country: Italy
facility: ID Respiratory Unit, Spallanzani Institute of Rome, Italy
city: Barcelona
country: Spain
facility: Department of Pulmonary Medicine, Barcelona University Hospital
Study officials:
affiliation: Hellenic Institute for the Study of Sepsis
name: Evangelos Giamarelos-Bourboulis, MD,PhD
role: STUDY_CHAIR
References: