The PRECISION is a proof-of-concept, phase II randomized clinical trial aiming toevaluate the efficacy and safety of anakinra in patients with Post-Acute COVID Syndrome(PACS) of the pro-inflammatory respiratory phenotype. Improvement is measured by acomposite endpoint, namely, the "Score of PACS progression reversal"
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".
Drug: Placebo
Placebo is injected subcutaneously once daily for 4 weeks. After the period of 4 weeks,
patients allocated to arm 1 will be shifted to subcutaneous treatment with 100mg anakinra
once daily for 4 weeks.
Drug: Anakinra 149 MG/ML Prefilled Syringe [Kineret]
Anakinra is injected subcutaneously as 100 mg once daily for 4 weeks. After the first
period the patients will be randomized 1:1 to continue receiving subcutaneous treatment
with 100mg anakinra once daily for 4 weeks or placebo once daily for 4 weeks.
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
Out-patient long-COVID department, Jena University Hospital
Jena, Germany
Out-patient long-COVID department, Patras University General Hospital
Patra, Achaia, Greece
Out-patient long-COVID department III, Evangelismos Athens General Hospital
Athens, Attiki, Greece
Out-patient long-COVID department I, Sotiria Athens Hospital of Chest Diseases
Athens, Attiki, Greece
Out-patient long-COVID department II, Sotiria Athens Hospital of Chest Diseases
Athens, Attiki, Greece
Out-patient long-COVID department IV, Sotiria Athens Hospital of Chest Diseases
Athens, Attiki, Greece
Out-patient long-COVID department, Laiko General Hospital
Athens, Attiki, Greece
2nd Department of Propedeutic Medicine, ATTIKON University General Hospital
Chaïdári, Attiki, Greece
4th Department of Internal Medicine, ATTIKON University General Hospital
Chaïdári, Attiki, Greece
Out-patient long-COVID department, Alexandroupolis University General Hospital
Alexandroupoli, Greece
Out-patient long-COVID department X, Sotiria Athens Hospital of Chest Diseases
Athens, Greece
Out-patient long-COVID department, Ioannina University General Hospital
Ioannina, Greece
Out-patient long-COVID department, University Hospital of Larissa
Larissa, Greece
Out-patient long-COVID department II, Thriasio General Hospital of Elefsina
Magoúla, Greece
Out-patient long-COVID department I, Thriasio General Hospital of Elefsina
Magoúla, Greece
Out-patient long-COVID department, Tzaneion Piraeus General Hospital
Piraeus, Greece
Out-patient long-COVID department, AHEPA Hospital of Thessaloniki
Thessaloníki, Greece
Infectious Diseases Clinic, Ospedale Policlinico San Martino IRCCS and Department of Health Sciences, University of Genova, Genoa, Italy
Genova, Italy
Department of Internal Medicine, Hospital of Jesolo, Italy
Jesolo, Italy
Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS Ospedale San Raffaele & Vita-Salute San Raffaele University, Milan, Italy
Milan, Italy
Infectious Diseases Clinic, University of Modena, Italy
Modena, Italy
Dipartimento Scienze di Laboratorio e Infettivologiche - Fondazione Policlinico Gemelli IRCCS, Roma Italy
Rome, Italy
ID Respiratory Unit, Spallanzani Institute of Rome, Italy
Rome, Italy
Department of Pulmonary Medicine, Barcelona University Hospital
Barcelona, Spain
Evangelos Giamarelos-Bourboulis, MD,PhD
00302105831994
egiamarel@med.uoa.gr
Evangelos Giamarelos-Bourboulis, MD,PhD, Study Chair
Hellenic Institute for the Study of Sepsis