Infectious Pneumonia, Severe COVID-19
Conditions
Keywords
COVID-19, SARS-CoV-2, Infectious pneumonia acquired in the community (CAP)
Brief summary
Primary objective: \- To compare the efficacy of reparixin vs. placebo in the proportion of patients dead or requiring IMV (or ECMO) by Day 28. Key secondary objectives: * To compare the efficacy of reparixin vs placebo in all-cause mortality at day 180. * To compare the efficacy of reparixin vs placebo in proportion of patients alive and discharged at day 28 * To compare the efficacy of reparixin vs placebo in ventilatory-free days at day 28. * To compare the efficacy of reparixin vs placebo in proportion of patients with IMV (or ECMO) by day 28. * To compare the efficacy of reparixin vs placebo in length of primary hospital stay. Other efficacy objectives \- To compare the efficacy of reparixin vs placebo on several disease severity/progression measures including recovery, ventilatory free days and mortality. Safety objectives: \- To evaluate safety and tolerability of oral reparixin versus placebo in the specific clinical setting.
Detailed description
Multinational, multicentre, randomized, double-blind, placebo-controlled, parallel-group, phase III trial. This study was conducted at 101 sites across 7 countries (Argentina, Australia, Austria, Germany, Italy, Turkey, and the United States \[US\]) that enrolled 414 male and female patients \> 18 years of age, hospitalized for CAP (including COVID-19). Please note that of these 101 sites, only 74 had enrolled patients and, hence, have been reported on CT.gov. The maximum study duration for a participant was 180 days, which included screening (day -1 or 1), treatment (up to day 21), and follow-up period (up to day 180). Of the 414 patients enrolled, 409 (98.8%) were randomized 1:1 to receive investigational products (oral reparixin \[N = 205\] or matched placebo \[N = 204\], three times a day (TID), for up to 21 days. Randomization was stratified according to disease severity and site. Actually, 394 participants (96.3%)(oral reparixin \[N = 201\] or matched placebo \[N = 193\]) received at least 1 dose of the investigational product and hence were included in the FAS population. All the patients received the Standard of Care (SoC) based on their clinical need, including COVID-19 and CAP medications, as per local standard therapy at the trial site and in line with international guidelines. Of the randomized population (N = 409), 186 participants (45.5%) completed the study; 223 (54.5%) discontinued the study prematurely. The primary outcome was evaluated at day 28, while the secondary outcomes were scheduled to be evaluated from day 3 to day 180. An independent external data monitoring committee (DMC) oversaw the study and evaluated unblinded interim data for efficacy, futility, and safety. The interim efficacy analysis met the pre-specified criteria for futility and the DMC recommended early termination of the study. Based on the recommendation of the DMC, Dompé decided to terminate the study earlier than planned. The decision was not related to any safety concerns. Due to the early study termination and not reaching the planned enrollment target, the outcome measure analyses were conducted for descriptive purposes only.
Interventions
DRUGReparixin
Reparixin 600 mg tablets, administered orally at the dose of 1200 mg TID (2 tablets TID) as add-on therapy to standard of care up to 21 days. IMP was taken with a glass of water (about 250 mL) and a light meal or snack, as it was preferable that reparixin was taken with food. However, If the patient was unwilling or unable to administer oral tablets, investigator could decide a nasogastric tube as an alternative route.
OTHERPlacebo
Administered orally three times a day (TID) as add-on therapy to standard of care (SoC) up to 21 days. Placebo was taken with a glass of water (about 250 mL) and a light meal or snack, as it was preferable that placebo was taken with food. However, if the patient was unwilling or unable to administer oral tablets, investigator could decide a nasogastric tube as an alternative route.
Sponsors
Dompé Farmaceutici S.p.A
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
The appearance, including packaging and labelling, of the investigational product tablets (reparixin and placebo) were identical in appearance such that the actual treatment could not be identified. The investigational product identity remained unknown to participants, site staff, CRO and Dompé personnel until after the study was completed and the database was unblinded (5 February 2025).
Intervention model description
male and female patients \>18 years, hospitalised for COVID-19, were assigned (1:1) to receive either oral reparixin (treatment group) or matched placebo (control group) three times a day (TID) for up to 21 days.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Informed consent signed 2. Male and female ≥18 years old; 3. Patients hospitalized for clinically suspected CAP, defined as the occurrence of (within 48h from hospital admission): 1. at least 1 of the following signs/symptoms: dyspnea, cough, purulent sputum, crackles (rales) and/or rhonchi 2. body temperature \> 38°C or \<36°C (before or during admission) or leucocytosis (\> local ULN) 3. new/increased pulmonary infiltrate(s) by chest imaging 4. Need for non-invasive supplemental oxygen (NIAID-OS 5-6); 5. SpO2 \<92% at room air, or PaO2/FiO2 (or SpO2/FiO2) \<300; 6. Females of child-bearing potential and with an active sexual life must not wish to get pregnant within 30 days after the end of the study and must be using at least one of the following reliable methods of contraception: 1. Hormonal contraception, systemic, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit until 30 days after the last IMP dose 2. A non-hormonal intrauterine device \[IUD\] or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit until 30 days after the last IMP dose 3. A male sexual partner who agrees to use a male condom with spermicide 4. A sterile sexual partner Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. For all female subjects, with child-bearing potential, pregnancy test result must be negative before first drug intake.
Exclusion criteria
1. Treatment with IMV or ECMO (NIAID-OS 7); 2. Hepatic dysfunction: ALT or AST \> 5 ULN; history of chronic hepatic disease (defined with Child-Pugh score B or C); 3. Renal dysfunction: estimated glomerular filtration rate (eGFR, MDRD) \<50 mL/min/1.73 m2, or need for haemodialysis or hemofiltration; 4. Current use of \>2 immunosuppressive medications or immunosuppression status (AIDS, aplastic anaemia, asplenia, systemic chemotherapy within the past 3 months, neutropenia (ANC \< local LLN), solid organ or bone marrow transplant recipients) 5. Treatment with prohibited medication within 5 half-lives, and inability to stop during treatment period; 6. Anticipated discharge from the hospital or transfer to another hospital within 72 hours of screening 7. History of: 1. intolerance or hypersensitivity to ibuprofen to more than one medication belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib (hypersensitivity to sulphanilamide antibiotics alone, e.g. sulfamethoxazole does not qualify for exclusion) 2. lactase deficiency, galactosemia or glucose-galactose malabsorption 3. gastrointestinal bleeding or perforation due to previous NSAIDs therapy or recurrent peptic ulcer/haemorrhage 4. allergy to reparixin or any component of the IMP formulation 8. Active bleeding or bleeding diathesis (excluding menses), prior intracranial haemorrhage 9. Participation in other interventional clinical trials 10. Clinical condition not compatible with oral administration of the study drug 11. Pregnancy: 1. positive or missing pregnancy test before first drug intake or day 1; 2. pregnant or lactating women; 3. women of childbearing potential and fertile men who do not agree to use at least one primary form of contraception for the duration of the study 12. Current hospital stay \>72h 13. Complicated CAP-associated conditions, such as fungal pulmonary infection, tuberculosis infection, abscess, empyema, significant bilateral pleural effusion, massive pulmonary embolism
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Dead or Requiring Invasive Mechanical Ventilation (IMV) or Extracorporeal Membrane Oxygenation (ECMO) by Day 28 [NIAID-OS 7]. | Day 28 | The primary endpoint was based on NIAID-OS ordinal scale (National Institute of Allergy and Infectious Disease) with score OS 7 which means patients "hospitalized, on invasive mechanical ventilation or ECMO". The scores on this scale of Disease severity range from OS 1 (best outcome) to OS 8 (worst outcome). NIAID-OS (National Institute of Allergy and Infectious Disease Ordinal Scale) SCORE Descriptor: * OS 1 Not hospitalized, no limitations on activities; * OS 2 Not hospitalized, limitation on activities and/or requiring home O2; * OS 3 Hospitalized, no supplemental O2 - no longer requires ongoing medical care; * OS 4 Hospitalized, no supplemental O2 - requiring ongoing medical care; * OS 5 Hospitalized, requiring supplemental O2; * OS 6 Hospitalized, on non-invasive ventilation or high-flow oxygen devices; * OS 7 Hospitalized, on invasive mechanical ventilation or ECMO; * OS 8 Death; |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality by Day 180 | Day 180 | Key secondary endpoint. All-cause mortality is a measurement of the total number of deaths from any cause within a specific population over a defined period. It is a broad metric used in medical research and public health to assess overall population health, identify risk factors for premature death, and evaluate the effectiveness of interventions. The number of participants (in the form of unadjusted proportion) who met the endpoint is reported. |
| Proportion of Patients Alive and Discharged From the Hospital by Day 28 | Day 28 | Key secondary endpoint. The number of participants alive or discharged, expressed in the form of unadjusted proportion, who met the endpoint at the final analysis at day 28 is provided. |
| Ventilatory-free Days (VFD) by Day 28 | Day 28 | Key secondary endpoint. Number of days from Day 0 to Day 28 when the patient was alive and free of invasive ventilation is reported. In case of multiple periods of IMV during the first 28 days, the total duration of ventilation considered all periods of ventilation during the index admission. Patients who died within 28 days or who still were on invasive ventilation after 28 days were scored 0 VFDs. |
| Proportion of Patients With IMV (or ECMO) by Day 28 | Day 28 | Key secondary endpoint.The number of participants, expressed in the form of unadjusted proportion, who met the endpoint at the final analysis is reported. |
| Length of Primary Hospital Stay (in Days) | Day 180 | Key secondary endpoint. The duration of primary hospital stay, expressed in days, are reported. This parameter is included in the set of final evaluation, which comprises: no. of days of hospitalization, etiologic agents (if identified), ICU admission and total days in ICU, occurrence, and duration of IMV and/or ECMO, if any. |
| Clinical Failure by Day 3 and Day 7 | Day 3 and Day 7 | Clinical failure was defined as the occurrence of IMV/ECMO or vasopressor, or death. IMV= invasive mechanical ventilation. ECMO=extracorporeal membrane oxygenation. |
| 28-day ICU-free Days | Day 28 | ICU-free days = days of hospitalization out of the Intensive Care Unit. Death within Day 28 was handled as an unfavorable event and ICU-free days were set at 0. |
| Days Free of IMV or ECMO (Number of Days With NIAID-OS 1-6) by Day 28 | Day 28 | These parameters are expressed as number of days with NIAID-OS score not equal to 7 or 8, where NIAID-OS is the National Institute of Allergy and Infectious Disease Ordinal Scale; a scale ranging from 1 to 8, where the lower the score, the better the outcome. The IMV/ECMO-free days at Day 28 were analyzed according to MI approach and ANOVA model. Death due to progression of the respiratory disease within Day 28 was handled as an unfavorable event and IMV/ECMO-free days at Day 28 was set at 0. |
| Duration of Antibiotic Therapy (Days) by Day 28 | Day 28 | A descriptive summary of duration of antibiotic therapy (days) at day 28 for the FAS is reported. |
| Hospital Free Days | Day 28 | Results for hospital-free days at day 28 in the FAS are presented through an unadjusted descriptive summary. |
| Proportion of Patients Recovered | days 3, 7, 14, 21, 28, and hospital discharge (Up to Day 41) | Results for the proportion of participants recovered at fixed timepoints in the FAS are presented. Recovering was defined as a downward shift from screening of ≤2 points on the NIAID-OS or live discharge from hospital. Unadjusted proportion is reported. |
| Proportion of Patients Worsening | days 3, 7, 14, 21, 28, and hospital discharge (Up to Day 41) | Results for the proportion of participants worsening at fixed timepoints in the FAS are presented. Worsening was expressed as upward shift from screening of at least \>1 point of the NIAID-OS or if patient died before X Visit Day. An unadjusted proportion is reported. |
| Change From Baseline in the Arterial Partial Pressure of Oxygen (PaO2) | days 3, 7, 14, 21, 28, and hospital discharge (Up to Day 41) | Descriptive statistics for the change from baseline in arterial partial pressure of oxygen (PaO2) at fixed timepoints are reported. |
| Change From Baseline in Pulse Oximetry (SpO2) | days 3, 7, 14, 21, 28, and hospital discharge (Up to Day 41) | Descriptive statistics for the change from baseline in pulse oximetry, measured as peripheral arterial oxygen saturation (SpO2), at fixed timepoints are reported. |
| Change From Baseline in Inspired Oxygen (FiO2) Levels | days 3, 7, 14, 21, 28, and hospital discharge (Up to Day 41) | FiO2 is a parameter of lung function representing the fraction of oxygen in the inspired air, ranging from 0.21 (room air) to 1.00 (100% oxygen). The endpoint assesses the change from baseline in FiO2 levels at predefined timepoints during the study. |
| Change From Baseline in PaO2/FiO2 Ratio | days 3, 7, 14, 21, 28, and hospital discharge (Up to Day 41) | The PaO2/FiO2 ratio is a parameter of lung function that reflects the efficiency of oxygen transfer from the lungs to the blood. It is calculated as the ratio between the arterial partial pressure of oxygen (PaO2, measured in mmHg) and the fraction of inspired oxygen (FiO2, expressed as a fraction ranging from 0.21 to 1.00). This endpoint assesses the change from baseline in the PaO2/FiO2 ratio at predefined timepoints during the study. |
| Change From Baseline in SpO2/FiO2 Ratio | Days 3, 7, 14, 21, and 28 | The SpO2/FiO2 ratio is a noninvasive indicator of lung function and oxygenation efficiency, calculated as the ratio between peripheral oxygen saturation (SpO2, expressed as a percentage) and the fraction of inspired oxygen (FiO2, expressed as a fraction ranging from 0.21 to 1.00). This endpoint assesses the change from baseline in the SpO2/FiO2 ratio at predefined timepoints during the study. |
| All-cause Mortality | Days 28, 60 and 90 | Results for all-cause mortality rates in the FAS are reported, at day 28, day 60, and day 90. Analysis was based on logistic regression model with Multiple Imputation using retrieve dropouts with proportion of patients died up to Day 28 as dependent variable, treatment, disease severity at baseline (NIAID-OS \<=5 vs. NIAID-OS 6), age class (\<65, \>= 65 years), sex and presence of concomitant disease at baseline as qualitative independent variables. |
| Hospital Re-admission by Day 90 and 180 | Days 90 and 180 | Hospital Re-admission by Day 90 and 180 in the FAS is presented. The number of participants is expressed as unadjusted proportion. |
| Time to Discharge or to a NEWS (National Early Warning Score) of ≤ 2 (for 24 Hours), Whichever Occurs First | Day 28 | The median time to discharge or to a NEWS (National Early Warning Score) of ≤ 2 (for 24 hours), whichever occurs first, was expressed using a "time to event" approach, and measured in days. NIAID-OS, National Early Warning Score (NEWS) was evaluated daily until day 28 (or hospital discharge). In a scored system standardizing the assessment of acute-illness severity in the NHS, NEWS includes Blood Pressure (BP), Heart Rate (HR), Respiratory Rate (RR), body temperature, level of consciousness (A, V, P, U), peripheral arterial oxygen saturation (SpO2) and supplemental oxygen. Time to discharge or to a NEWS of \<= 2 (for 24 hours) = Min(Date of discharge, Date of NEWS of \<= 2 (for 24 hours)) - Day 1 date + 1. Date of NEWS of \<= 2 (for 24 hours): Given two consecutive days with NEWS of \<= 2, the date of the first assessment has been considered. |
| Change in Quality of Life Using EuroQol-5-dimensions-5 Levels (EQ-5D-5L) Questionnaire From Hospital Discharge to Day 90 and Day 180 | Days 90±7 and 180±14 | The EQ-5D-5L asks patients to indicate whether they have no, slight, moderate, severe, extreme problems on each of 5 dimensions of health: mobility; self-care; usual activities; pain/discomfort; anxiety/depression.The count of patients of each level (1 - no problems, 2 - slight problems, 3 - moderate problems, 4 - severe problems, 5 - extreme problems) for each of the 5 dimensions were reported. The higher the score for each dimension (range 1-5), the worse the outcome. |
| Duration of IMV and/or ECMO by Days 90 and 180 | Days 90 and 180 | The summary of IMV/ECMO duration by day 90 and day 180 for the FAS is presented. The duration of IMV/ECMO use by day 90 was calculated as the total number of days between day 1 and the last available assessment day (≥ day 83) during which the participant was either receiving IMV/ECMO or had a NIAID-OS score of 7. Participants with less than 83 days of follow-up were considered non-evaluable for this endpoint. Similarly, the duration of IMV/ECMO by day 180 was calculated using the same methodology. |
| Proportion of Participants Requiring ICU Admission by Days 90 and 180 | Days 90 and 180 | Unadjusted proportion of ICU admission is reported as number and percentage of participants requiring ICU admission by day 90 and day 180. |
| Hospital Length of Stay by Days 90 and 180 | Days 90 and 180 | Results for hospital length of stay (days) by day 90 and 180 in the FAS are reported. |
| Occurrence of Infections by Days 90 and 180 | Days 90 and 180 | Occurrence of infections was expressed as the unadjusted proportion of participants with at least one infection by days 90 and 180 in the FAS. |
| ICU Length of Stay by Days 90 and 180 | Days 90 and 180 | Results for the Intensive Care Unit length of stay (days) by day 90 and day 180 in the FAS are reported. |
| Number of Patients With at Least One Treatment-emergent Adverse Event (TEAE) | Throughout the study till Day 180 (± 14) or end of treatment | A TEAE is defined as any adverse event reported in the study having a possible, probable, or highly probable relationship to investigational product. A serious AE is defined as any untoward medical occurrence that at any dose: * results in death. * is life-threatening (i.e. the patient was at risk of death at the time of the event. It does not refer to an event which hypothetically might have caused death if it were more severe), * requires inpatient hospitalization or prolongation of existing hospitalization, * results in persistent or significant disability/incapacity, * is a congenital anomaly/birth defect * is a medically significant or important medical condition, i.e. an important medical event that based upon appropriate medical judgment, may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed above. |
Countries
Argentina, Australia, Austria, Germany, Italy, Turkey (Türkiye), United States
Contacts
PRINCIPAL_INVESTIGATORGiovanni Landoni, MD
IRCCS Ospedale San Raffaele Centro di Ricerca Anestesia e Rianimazione
Participant flow
Recruitment details
A total of 444 participants were screened and 414 were enrolled; 409 (98.8%) were randomized 1:1 to receive investigational products (reparixin \[N = 205\] or placebo \[N = 204\]). A total of 186 participants (45.5%) completed the study; 223 (54.5%) discontinued the study prematurely.
Pre-assignment details
The pre-planned interim analyses for efficacy and safety were carried out, per protocol, for evaluation by the DMC when the first 250 participants had reached day 28 or died or experienced IMV or ECMO by day 28. The p-value from the interim analysis of the primary endpoint met the pre-specified criteria for futility. In accordance with DMC, Dompé decided to terminate the study early (not for safety reasons), resulting in a lower-than-planned no. of participants enrolled
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 231 Participants |
| Age, Categorical Between 18 and 65 years | 163 Participants |
| Age, Continuous | 65.1 years STANDARD_DEVIATION 15.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 39 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 154 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 32 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 344 Participants |
| Region of Enrollment Argentina | 57 participants |
| Region of Enrollment Australia | 3 participants |
| Region of Enrollment Austria | 35 participants |
| Region of Enrollment Germany | 8 participants |
| Region of Enrollment Italy | 90 participants |
| Region of Enrollment Turkey | 40 participants |
| Region of Enrollment United States | 159 participants |
| Sex: Female, Male Female | 76 Participants |
| Sex: Female, Male Male | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 16 / 205 | 19 / 204 |
| other Total, other adverse events | 129 / 200 | 127 / 194 |
| serious Total, serious adverse events | 46 / 200 | 56 / 194 |
Outcome results
None listed