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Reparixin in COVID-19 Pneumonia - Efficacy and Safety

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ClinicalTrials.gov Identifier: NCT04794803
Recruitment Status : Terminated (The sponsor has decided to start with a separate protocol for phase 3 and therefore this study was terminated with only phase 2.)
First Posted : March 12, 2021
Last Update Posted : March 16, 2021
Sponsor:
Information provided by (Responsible Party):
Dompé Farmaceutici S.p.A

Brief Summary:
  • Phase 2 Study Objectives: efficacy and safety of of Reparixin treatment as compared to the control arm in adult patients with severe COVID-19 pneumonia
  • Phase 3 Study Objectives: efficacy and safety of Reparixin treatment as compared to the control arm in adult patients with moderate or severe COVID-19 pneumonia

Condition or disease Intervention/treatment Phase
Severe Pneumonia Drug: Reparixin Drug: Standard of care Phase 2 Phase 3

Detailed Description:

This clinical trial is an adaptive phase 2/3, randomized, controlled multicenter study on the efficacy and safety of Reparixin in the treatment of hospitalized patients with COVID-19 pneumonia. 48 patients are planned to be enrolled in Phase 2 and an estimated total of 111 patients are planned to be enrolled up to the end of Phase 3, with a randomization 2:1 Reparixin vs Control (Standard of care).

In the phase 2 segment of this study, patients are randomized 2:1 to Reparixin oral tablets 1200 mg (Group 1, active treatment) or standard of care (Group 2, control arm). In case of worsening (e.g. need of ICU and/or mechanical ventilation) after the first 24hrs, patients are offered a rescue medication with no restriction from the sponsor and fully based on their physicians' judgement.

In the phase 3 segment of this study, it is planned that patients are randomized 2:1 to Reparixin or standard of care. The Phase 3 design will be reassessed and decided based on the results of the Phase 2.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 55 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study on the Efficacy and Safety of Reparixin in the Treatment of Hospitalized Patients With COVID-19 Pneumonia
Actual Study Start Date : May 5, 2020
Actual Primary Completion Date : November 30, 2020
Actual Study Completion Date : February 2, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pneumonia

Arm Intervention/treatment
Experimental: Reparixin
Reparixin oral tablets 1200 mg TID for 7 days
Drug: Reparixin
Reparixin will be administered via oral tablets 1200 mg TID for 7 days. In case of improvement, treatment can be prolonged at discretion of the investigator up to a maximum of 21 days of treatment in total or live discharge from the hospital, whichever comes first.
Other Name: Repertaxin L-lysine salt

Active Comparator: Standard of care
Standard of care
Drug: Standard of care
Standard of care
Other Name: Control




Primary Outcome Measures :
  1. Phase 2 primary endpoint - Composite endpoint of clinical events [ Time Frame: Baseline ]
    The patient requires at least one of the following: supplemental oxygen requirement, mechanical ventilation use, admission to Intensive Care Unit (ICU), and use of a rescue medication for any reason

  2. Phase 2 primary endpoint - Composite endpoint of clinical events [ Time Frame: day 1 ]
    The patient requires at least one of the following: supplemental oxygen requirement, mechanical ventilation use, admission to Intensive Care Unit (ICU), and use of a rescue medication for any reason

  3. Phase 2 primary endpoint - Composite endpoint of clinical events [ Time Frame: day 2 ]
    The patient requires at least one of the following: supplemental oxygen requirement, mechanical ventilation use, admission to Intensive Care Unit (ICU), and use of a rescue medication for any reason

  4. Phase 2 primary endpoint - Composite endpoint of clinical events [ Time Frame: week 1 ]
    The patient requires at least one of the following: supplemental oxygen requirement, mechanical ventilation use, admission to Intensive Care Unit (ICU), and use of a rescue medication for any reason

  5. Phase 2 primary endpoint - Composite endpoint of clinical events [ Time Frame: day 21(end of treatment) ]
    The patient requires at least one of the following: supplemental oxygen requirement, mechanical ventilation use, admission to Intensive Care Unit (ICU), and use of a rescue medication for any reason

  6. Phase 2 primary endpoint - Composite endpoint of clinical events [ Time Frame: Follow-up (FU) (7±3 days after treatment period) ]
    The patient requires at least one of the following: supplemental oxygen requirement, mechanical ventilation use, admission to Intensive Care Unit (ICU), and use of a rescue medication for any reason

  7. Phase 3 Primary Endpoint: Composite endpoint of death and of severe clinical events [ Time Frame: Baseline ]
    The patient dies or requires mechanical ventilation use and/or admission to ICU

  8. Phase 3 Primary Endpoint: Composite endpoint of death and of severe clinical events [ Time Frame: day 1 ]
    The patient dies or requires mechanical ventilation use and/or admission to ICU

  9. Phase 3 Primary Endpoint: Composite endpoint of death and of severe clinical events [ Time Frame: day 2 ]
    The patient dies or requires mechanical ventilation use and/or admission to ICU

  10. Phase 3 Primary Endpoint: Composite endpoint of death and of severe clinical events [ Time Frame: week 1 ]
    The patient dies or requires mechanical ventilation use and/or admission to ICU

  11. Phase 3 Primary Endpoint: Composite endpoint of death and of severe clinical events [ Time Frame: day 21(end of treatment) ]
    The patient dies or requires mechanical ventilation use and/or admission to ICU

  12. Phase 3 Primary Endpoint: Composite endpoint of death and of severe clinical events [ Time Frame: Follow-up (FU) (7±3 days after treatment period) ]
    The patient dies or requires mechanical ventilation use and/or admission to ICU


Secondary Outcome Measures :
  1. Phase 2/3 Secondary Endpoint: Changes in clinical severity score (as recommended by the World Health Organization -WHO- for COVID studies) [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (7±3 days after treatment period) ]

    The time to clinical improvement of two points from the time of randomization on a seven-category ordinal scale or live discharge from the hospital, whichever comes first. The seven-category ordinal scale consists of the following:

    1) not hospitalized, with resumption of normal activities; 2) not hospitalized, but unable to resume normal activities; 3) hospitalized, not requiring supplemental oxygen; 4) hospitalized, requiring supplemental oxygen; 5) hospitalized, requiring high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6) hospitalized, requiring ECMO, invasive mechanical ventilation, or both; and 7) death.


  2. Phase 2/3 Secondary Endpoint: Dyspnea severity [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]
    The severity of dyspnea is measured through the Liker scale. The Liker scale is used as follows: the patient grades his current breathing compared to when he first started the drug (from -3 to 3). "0" = no change, "1" =minimally better, "2" =moderately better, "3" =markedly better, "-1" =minimally worse, "-2" =moderately worse, "-3" =markedly worse.

  3. Phase 2/3 Secondary Endpoint: Dyspnea severity [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]
    The severity of dyspnea is measured also through the VAS scale. The VAS scale is used as follows: the patient draws a horizontal line on an axial graph (from 0 to 100) to show the degree of how he feels about breathing. The number "0" equals the worst breathing the patient has ever felt and the number "100" equals the best he has ever felt.

  4. Phase 2/3 Secondary Endpoint: duration of supplemental oxygen treatment [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]
    Duration of oxygen administration (hours) = Administration end date/time - Administration start date/time / 60.

  5. Phase 2/3 Secondary Endpoint: quantity of supplemental oxygen treatment [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]
    Cumulative quantity of oxygen treatment (L) = Sum of all Quantity (L) in CONCOMITANT OXYGEN TREATMENT form, from randomization to time point of interest.

  6. Phase 2/3 Secondary Endpoint: Incidence of mechanical ventilation use [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]
    Proportion along with the 95% confidence interval (Clopper-Pearson's formula) of subjects requiring mechanical ventilation are calculated and compared.

  7. Phase 2/3 Secondary Endpoint: duration of mechanical ventilation use [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]

    Cumulative duration of mechanical ventilation (hours) = Sum of duration of mechanical ventilation (hours) in mechanical ventilation form, from randomization to time point of interest.

    Duration of mechanical ventilation (hours) = End date/time - Start date/time / 60


  8. Phase 2/3 Secondary Endpoint: Incidence of intensive care unit (ICU) admission need [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]
    Proportion along with the 95% confidence interval (Clopper-Pearson's formula) of subjects requiring ICU admission are calculated and compared.

  9. Phase 2/3 Secondary Endpoint: Lung damage extension changes from baseline [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]
    Lung damage extentions is assessed by Chest CT or Rx

  10. Phase 2/3 Secondary Endpoint: Change from baseline in lung exudation degree [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]
    Lung exudation degree is assessed by Chest CT or Rx

  11. Phase 2/3 Secondary Endpoint: PaO2 [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]

    PaO2 measures the pressure of oxygen dissolved in the blood and how well oxygen is able to move from the airspace of the lungs into the blood.

    Normally, PaO2 is between 75 and 100 mmHg (at sea level). Lower levels indicate an unsufficient amount of oxygen flowing from the alveoli to the blood.


  12. Phase 2/3 Secondary Endpoint: SpO2 [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]
    SpO2 measures the amount of oxygen-carrying hemoglobin in the blood relative to the amount of hemoglobin not carrying oxygen. Acceptable normal ranges for patients without pulmonary pathology are from 95 to 99 percent.

  13. Phase 2/3 Secondary Endpoint: Partial arterioral oxygen pressure (PaO2) to fraction of inspiration O2 (FiO2) ratio [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]
    PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage) also known as the Horowitz index, the Carrico index, and (most conveniently) the P/F ratio at sea level, the normal PaO2/FiO2 ratio is ~ 400-500 mmHg (~55-65 kPa).

  14. Phase 2/3 Secondary Endpoint: C-reactive protein (CRP) [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]
    For a standard CRP test, a normal reading is less than 10 milligram per liter (mg/L). Levels between 10 mg/L and 100 mg/L are moderately elevated and are usually due to more significant inflammation from an infectious or non-infectious cause. Inflammatory status is documented by C-reactive protein (CRP) ≥ 100mg/L.

  15. Phase 2/3 Secondary Endpoint: Hs-CRP [ Time Frame: Baseline, day 1, day 2, week 1, day 21(end of treatment), follow-up (FU) (7±3 days after treatment period) ]
    The hs-CRP test detects lower levels of CRP in the bloodstream (0.5-10 mg/L), whereas the CRP test measures levels in a higher range (10-1,000 mg/L).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Phase 2 Inclusion Criteria:

    1. Age 18 to 90.
    2. Confirmed COVID-19 diagnosis
    3. At least one of the following: # Respiratory distress, RR ≥ 30 breaths/min without oxygen; # Partial arterial oxygen pressure (PaO2) / Fraction of inspiration O2 (FiO2) >100 <300mmHg

    (1mmHg = 0.133kPa). 4. Chest imaging confirms lung involvement and inflammation. 5. Inflammatory status as documented by at least one of the following: Lactate dehydrogenase (LDH) > normal range, C-reactive protein (CRP) ≥ 100mg/L or IL-6 ≥ 40pg/mL, serum ferritin ≥ 900ng/mL, XDP >20mcg/mL.

  • Phase 3 Inclusion Criteria: Same as above; other criteria TBD based on Phase 2 outcomes.

Exclusion Criteria:

• Phase 2/3 Exclusion Criteria:

  1. Cannot obtain informed consent.
  2. Severe hepatic dysfunction (Child Pugh score ≥ C, or AST> 5 times the upper limit); Severe renal dysfunction (estimated glomerular filtration rate ≤ 30mL / min / 1.73 m2) or receive continuous renal replacement therapy, hemodialysis, or peritoneal dialysis.
  3. Patients with hypersensitivity to ibuprofen or to more than one non steroidal anti-inflammatory drug or to more than one medication belonging to the class of sulfonamides (e.g. sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib; hypersensitivity to sulphanilamide antibiotics alone, e.g. sulfamethoxazole, does not qualify for exclusion)
  4. Severe, active bleeding such as hemoptysis, gastrointestinal bleeding, central nervous system bleeding, and nosebleeds within 1 month before enrollment.
  5. Pregnant and lactating women and those planning to get pregnant.
  6. Participated in other interventional clinical trials with investigational medicinal products, not considered suitable for this study by the researchers.
  7. At the time of enrollment, patients not in a clinical condition compatible with the oral administration of the study drug.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04794803


Locations
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Brazil
Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina de São Paulo
São Paulo, Brazil, 05403-900
Italy
Ospedale San Paolo
Milan, Lombardy, Italy, 20100
Ospedale San Raffaele
Milan, Lombardy, Italy, 20100
Ospedale di Varese
Varese, Lombardy, Italy
Sponsors and Collaborators
Dompé Farmaceutici S.p.A
Investigators
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Principal Investigator: Lorenzo Piemonti, MD PhD Ospedale San Raffaele
Principal Investigator: Alberto Zangrillo, MD PhD Ospedale San Raffaele
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Responsible Party: Dompé Farmaceutici S.p.A
ClinicalTrials.gov Identifier: NCT04794803    
Other Study ID Numbers: REPAVID-19
2020-001645-40 ( EudraCT Number )
First Posted: March 12, 2021    Key Record Dates
Last Update Posted: March 16, 2021
Last Verified: March 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dompé Farmaceutici S.p.A:
COVID-19
Additional relevant MeSH terms:
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COVID-19
Pneumonia
Respiratory Tract Infections
Infections
Pneumonia, Viral
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases