Study of LAU-7b for the Treatment of Coronavirus Disease 2019 (COVID-19) Disease in Adults

Phase 3TerminatedNCT04417257

Laurent Pharmaceuticals Inc.351 enrolled

Overview

A randomized, double-blind, placebo-controlled Phase 2/3 Study of LAU-7b against confirmed COVID-19 Disease in hospitalized patients at a higher risk of complications.

RESOLUTION is a multicenter, randomized, double-blind, placebo-controlled Phase 2/3 study of LAU-7b for the treatment of COVID-19 Disease in participants at a higher risk than the general COVID-19 Disease population to develop complications while hospitalized. The goal of the study is to evaluate the efficacy of LAU-7b therapy + standard-of-care relative to placebo + standard-of-care in participants with COVID-19 Disease with confirmed SARS-CoV-2 infection. SARS is "severe acute respiratory syndrome". CoV is " Coronavirus". The purpose of the treatment with LAU-7b is to prevent the worsening of the health of hospitalized participants including aggravation such as recourse to mechanical ventilation and death. The means are the direct effects of LAU-7b on the resolution of inflammation, interference with viral proliferation and protection from excessive pro-inflammatory response.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

351

Conditions

COVID-19 Disease

Interventions

LAU-7bDRUG

LAU-7b will be administered orally once-a-day with the main meal of the day, if possible, for a total of up to 14 days.

Placebo oral capsuleDRUG

Placebo will be administered orally once-a-day with the main meal of the day, if possible, for a total of up to 14 days.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Participant exhibited symptoms \[Extension Phase 3 study only: (including at least one lower respiratory symptom such as shortness of breath or dyspnea)\] of COVID-19 disease at screening and/or since the start of their hospitalization (may have included treated symptoms) 2. Participant was 18 years and older, of either gender 3. Participant must have had at least one of the following factors/co-morbidities: 1. Controlled or uncontrolled diabetes 2. Pre-existing cardiovascular disease, including hypertension 3. Pre-existing respiratory disease such as chronic obstructive pulmonary disease(COPD), asthma, emphysema 4. Active \[Extension Phase 3 study only: or a former smoker\] with 20 pack-years of smoking history 5. Obesity as depicted by BMI ≥30 kg/m2 6. Laboratory tests indicative of a higher risk of COVID-19-related complications, such as troponin \>1.5 the upper limit of normal (ULN), \[Extension Phase 3 study only: D-dimer \>3.0 ULN\] and/or C reactive protein (CRP) \>1.5 ULN 7. Aged 70 years and older who, based on the judgment of the investigator, was at a higher risk of developing complications 4. Participant had a documented positive test for the SARS-CoV-2 virus \[Pilot Phase 2 study only: or was suspected to be positive and with a test result pending\]. \[Extension Phase 3 study only: Co-infection with other viral respiratory infections was allowed and had to be documented in medical history\] 5. Participant was under observation by, or admitted to, a controlled facility or hospital \[Extension Phase 3 study only: for no more than 48 hours (72 hours from amendment 3 onwards) before screening, including any prior stay in another hospital\] to receive standard of care (SoC) for COVID-19 disease 6. \[Pilot Phase 2 study only: Participant's hs was 3, 4, or 5 on the WHO ordinal scale and not previously a "6"\] \[Extension Phase 3 study only: 3 or 4 on the World Health Organization (WHO) ordinal scale and not previously a "5 or a 6"\] 7. If female, participant was either post-menopausal (one year or greater without menses), surgically sterile, or, for female subjects of child-bearing potential who were capable of conception had to be practicing a highly effective method of birth control (acceptable methods included intrauterine device, complete abstinence, spermicide + barrier, male partner surgical sterilization, or hormonal contraception) during the study and through 30 days after the last dose of the study medication. Periodical abstinence was not classified as an effective method of birth control. A pregnancy test had to be negative at the Screening Visit 8. Participant had the ability to understand and give informed consent, which could have been verbal with a witness, according to local requirements 9. Participant was deemed capable of adequate compliance including attending scheduled visits for the duration of the study 10. Participant was able to swallow the study drug capsules Exclusion Criteria: 1. Pregnancy or breastfeeding 2. Health condition deemed to possibly interfere with the study endpoints and/or the safety of the participants. For example, the following conditions were considered contraindicated for participation in the study, but this was not an exhaustive list. In case of doubt, the investigator was to consult with the Sponsor's medical representative: 1. Presence of inherited retinitis pigmentosa 2. Presence or history of liver failure (Child-Pugh B or C) 3. Presence or history of stage 4 severe chronic kidney disease or dialysis requirement 4. Febrile neutropenia 5. \[Pilot Phase 2 study: Presence of active cancer treated with systemic chemotherapy or radiotherapy\]\[Extension Phase 3 study: Presence of end-stage cancer\] 3. Known history of a severe allergy or sensitivity to retinoids, or with known allergies to excipients in the oral capsule formulation used in the study 4. Participation in another drug clinical trial within 30 days (or a minimum of 5 t½) prior to screening, except ongoing participation in non-interventional studies 5. Calculated creatinine clearance (CrCl), using the Cockroft-Gault equation for example \[Pilot Phase 2 study: \<60 mL/min\] \[Extension Phase 3 study: \<30 mL/min)\] 6. Presence of total bilirubin \>1.5 x ULN (in the absence of demonstrated Gilbert's syndrome), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \>2.5 x ULN 7. \[Extension Phase 3 study only: Subject expected to be transferred to ICU or die in the next 24 hours\]

Locations (29)

Outcomes

Primary Outcomes

Primary Outcome for Phase 2: Proportion of Participants Alive and Free of Respiratory Failure by Day 29 (Ordinal Scale Scores 1-4, Inclusively)

This will be assessed through health status scoring using the WHO 7-point Ordinal Scale, a higher score is worse than a low score. 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or extra-corporeal membrane oxygenation 7. Death

Time frame: On Day 29

Primary Outcome for Phase 3: Proportion of Participants Requiring Mechanical Ventilation (Includes Extra-corporeal Membrane Oxygenation - ECMO) AND/OR Deceased (All Causes) by Day 60 (Ordinal Scale Scores 1-4, Inclusively)

Time frame: By Day 60

Secondary Outcomes

The Safety of LAU-7b Therapy, Overview.

This will be assessed through monitoring of treatment emergent adverse events and serious adverse events, vital signs including oxygen saturation and body temperature, symptom-directed physical examinations and safety laboratory tests.

Time frame: From baseline to Day 60

The Safety of LAU-7b Therapy, Display of TEAEs With Incidence Equal or Greater Than 10% in Either Treatment Group

Data from ClinicalTrials.gov

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Chandler Regional Medical Center / Mercy Gilbert Medical Center

Chandler, Arizona, United States

Hoag Memorial Hospital Presbyterian

Newport Beach, California, United States

University of California Davis Medical Center

Sacramento, California, United States

Nuvance Health - Danbury Hospital

Danbury, Connecticut, United States

MedStar Washington Hospital Center

Washington D.C., District of Columbia, United States

Baptist Medical Center Beaches

Jacksonville Beach, Florida, United States

St Lukes Hospital

Boise, Idaho, United States

NorthShore University Health System - Swedish Hospital

Chicago, Illinois, United States

NorthShore University Health System - Glenbrook Hospital

Glenview, Illinois, United States

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States

...and 19 more locations

Time frame: From baseline to Day 60

Health Status of the Participant on the 7-point Ordinal Scale on Days 14 and 29, Compared Between Active and Placebo Groups.

The health status was graded using the World Health Organization 7-point Ordinal Scale, a higher score is worse than a low score. 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or extra-corporeal membrane oxygenation 7. Death

Time frame: On Days 14 and 29

For Phase 2 Portion: Rate of All-causes Death by Day 29, Depicted by a Change From Baseline in the Ordinal Scale Score to Category 7

This was assessed with Day 29 (and Day 60, presented separately) Health Status grading using the World Health Organization 7-point Ordinal Scale, a higher score is worse than a low score. 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or extra-corporeal membrane oxygenation 7. Death

Time frame: On Day 29

For Phase 3 Portion: Rate of All-causes Death by Day 29, Depicted by a Change From Baseline in the Ordinal Scale Score to Category 7

Time frame: On Day 29

For Phase 2 Portion: Rate of All-causes Death By Day 60, Depicted by a Change From Baseline in the Ordinal Scale Score to Category 7

This was assessed with Day 60 (and Day 29, presented separately) Health Status grading using the World Health Organization 7-point Ordinal Scale, a higher score is worse than a low score. 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or extra-corporeal membrane oxygenation 7. Death

Time frame: On Day 60

For Phase 3 Portion: Rate of All-causes Death By Day 60, Depicted by a Change From Baseline in the Ordinal Scale Score to Category 7

Time frame: On Day 60

Proportion of Participants Alive and Free of Respiratory Failure by Day 29 (Ordinal Scale Scores 1-4, Inclusively)

Time frame: Day 29

For Phase 2 Portion: Rate of COVID-19 Disease-related Aggravation, Depicted by a Change From Baseline in the Ordinal Scale Score of at Least One Category

This was assessed through daily health status scoring using the World Health Organization 7-point Ordinal Scale, a higher score is worse than a low score. 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or extra-corporeal membrane oxygenation 7. Death

Time frame: From baseline to Day 60

For Phase 3 Portion: Rate of COVID-19 Disease-related Aggravation, Depicted by a Change From Baseline in the Ordinal Scale Score of at Least One Category

Time frame: From baseline to Day 60

For Phase 2 Only: Rate of COVID-19 Disease-related Transfer to Intensive Care Unit, Depicted by a Change From Baseline in the Ordinal Scale Score to Categories 5 or 6.

Time frame: From baseline to Day 60

For Phase 2 Only: Rate of COVID-19 Disease-related Transfer to Mechanical Ventilation, Depicted by a Change From Baseline in the Ordinal Scale Score to Category 6

Time frame: From baseline to Day 60

For Phase 2 Only: Mean Change From Baseline of the Ordinal Scale Patient Health Status as a Function of Assessment Time.

This was assessed through daily health status scoring using the World Health Organization 7-point Ordinal Scale (below), a higher score is worse than a low score. Outcome measure data are counts of participants with a given change from baseline in number of categories, by treatment group. The mean change from baseline is compared between treatment groups. 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or extra-corporeal membrane oxygenation 7. Death

Time frame: From baseline to Day 60

For Phase 2 Only: Time to a Participant's Improvement of at Least One Category on the Ordinal Scale Health Status.

This was assessed through daily health status scoring using the World Health Organization 7-point Ordinal Scale (below), a higher score is worse than a low score. If health status was not improved (remains stable or aggravates) by Day 60, it was censored at Day 60. 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or extra-corporeal membrane oxygenation 7. Death

Time frame: From baseline to Day 60

For Phase 2 Portion: Time to Recovery, Defined as the Time to Reach Categories 2 or 1 on the Ordinal Scale Participant Health Status (First Occurrence if More Than Once).

This was assessed through daily health status scoring using the World Health Organization 7-point Ordinal Scale (below), a higher score is worse than a low score. If health status did not reach categories 2 or 1 by Day 60, it was censored at Day 60. 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or extra-corporeal membrane oxygenation 7. Death

Time frame: From baseline to Day 60

For Phase 3 Portion: Time to Recovery, Defined as the Time to Reach Categories 2 or 1 on the Ordinal Scale Participant Health Status (First Occurrence if More Than Once).

This was assessed through daily health status scoring using the World Health Organization 7-point Ordinal Scale (below), a higher score is worse than a low score. If health status did not reach categories 2 or 1 by Day 60, it was censored at Day 60. 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or extra-corporeal membrane oxygenation 7. Death

Time frame: From baseline to Day 60

For Phase 2 Only: Time to Mechanical Ventilation, Defined Here as Time to Reach Category 6 on the Ordinal Scale Participant Health Status.

This was assessed through daily health status scoring using the World Health Organization 7-point Ordinal Scale (below), a higher score is worse than a low score. If category 6 was skipped and the subject died (category 7), it was considered an event. Subjects with missing observations were censored at their last available assessment if they did not need mechanical ventilation while on study. 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or extra-corporeal membrane oxygenation 7. Death

Time frame: From baseline to Day 60

For Phase 2 Only: Time to Death, Defined Here as a Time to Reach Category 7 on the Ordinal Scale Participant Health Status, Censored to Day 60 if it Happens Later Than Day 60

This was assessed through daily health status scoring using the World Health Organization 7-point Ordinal Scale (below), a higher score is worse than a low score. It was censored to Day 60 if it happened later than Day 60, or at the last available visit where the subject was alive if no further ordinal scale health status. 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 6. Hospitalized, on invasive mechanical ventilation or extra-corporeal membrane oxygenation 7. Death

Time frame: From baseline to Day 60

For Phase 2 Portion: Duration of Hospitalization (Days) Within the Study Period Days 1-60

Monitoring of the hospitalization. In case of re-hospitalization within Day 60 for a given participant, the additional hospitalization time was included. Hospitalization for more than 60 days was considered 60 days in the calculation.

Time frame: From baseline to Day 60

For Phase 3 Portion: Duration of Hospitalization (Days) Within the Study Period Days 1-60

Time frame: From baseline to Day 60

For Phase 2 Only: Time to Attain an Undetectable Viral Load in Oropharyngeal Swabs.

Intent was to compare median time to undetectable viral load between treatment groups, through oropharyngeal swabs done at specified times while hospitalized. However, almost all sites were unable to obtain serial samples until discharge of participants. Therefore, with only a handful of results (reported herein), it was not possible to estimate the time to undetectable viral load.

Time frame: Until discharge of participants, up to Day 60

The Change From Baseline in the Score Obtained on the EuroQol Five-dimensions Five-level (EQ-5D-5L) Quality-of-life Survey

This will be assessed in person or remotely, in participants reaching Days 14, 29, 45 and 60 and able to fill the questionnaire. EQ-5D-5L value was calculated based on the EQ-5D-5L user guide, and a higher value indicated better health status. The upper anchor point, full health, was 1.0 and the minimum value was 0.0.

Time frame: On Days 1, 14, 29, 45 and 60