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    Summary
    EudraCT Number:2020-002369-32
    Sponsor's Protocol Code Number:100-303
    National Competent Authority:Romania - National Agency for Medicines and Medical Devices
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-06-19
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedRomania - National Agency for Medicines and Medical Devices
    A.2EudraCT number2020-002369-32
    A.3Full title of the trial
    Open-label, pharmacokinetic, pharmacodynamic, ascending dose safety lead-in followed by a single-center, placebo-controlled, double-blind, adaptive, safety and efficacy, pilot study of Trans Sodium Crocetinate (TSC) in SARS-CoV-2 infected subjects
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Open-label, pharmacokinetic, pharmacodynamic, ascending dose safety lead-in followed by a single-center, placebo-controlled, double-blind, adaptive, safety and efficacy, pilot study of Trans Sodium Crocetinate (TSC) in SARS-CoV-2 infected subjects
    A.4.1Sponsor's protocol code number100-303
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorDiffusion Pharmaceuticals Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDiffusion Pharmaceuticals Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDiffusion Pharmaceuticals Inc
    B.5.2Functional name of contact pointChairman and CEO
    B.5.3 Address:
    B.5.3.1Street Address1317 Carlton Avenue
    B.5.3.2Town/ cityCharlottesville, Virginia
    B.5.3.3Post code22902
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1434825-1834
    B.5.5Fax number+1434220-0722
    B.5.6E-mailDkalergis@diffusionpharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTrans Sodium Crocetinate Crocetinate
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN/A
    D.3.9.1CAS number 64603-92-5
    D.3.9.2Current sponsor codeTRANS SODIUM CROCETINATE
    D.3.9.3Other descriptive nameTRANS SODIUM CROCETINATE
    D.3.9.4EV Substance CodeSUB193723
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection/infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    COVID-19 infection
    E.1.1.1Medical condition in easily understood language
    COVID-19 infection
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level LLT
    E.1.2Classification code 10084401
    E.1.2Term COVID-19 respiratory infection
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Lead in Pk/PD:
    1. Determine the safety and tolerability of TSC when administered four times per day (every 6 hours) for up to 5 days for each of the four doses to be studied.
    Randomized Pilot:
    1. Determine the safety and efficacy of TSC administered at the optimum, safe and tolerable biologic dose four times per day (every 6 hours) for up to 15 days as compared to placebo
    E.2.2Secondary objectives of the trial
    Lead in Pk/PD:
    1.Determine the relative degree of improvement by TSC dose in blood oxygenation following treatment with TSC as measured by the SpO2:FiO2 (S:F) ratio via continuous pulse oximetry.
    2.PK/PD determine blood oxygenation by PaO2:FiO2 (P:F) ratio or S:F ratio following the TSC admin.
    3.Determine the optimum, safe and tolerable biologic dose of TSC among the four doses to be studied given four times per day (every 6 hours) for up to 5 days using the S:F ratio
    Randomized Pilot:
    1.Demonstrate that TSC is not associated with an increased occurrence of serious adverse events in COVID-19 patients. The study endpoint analysis will compare the frequency of SAEs in the TSC and placebo groups.
    2.Demonstrate that treatment with TSC is not associated with increases in any organ-specific classes of serious adverse events or increased mortality.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Hospitalized subjects with confirmed SARS-CoV-2 infection and hypoxemia, defined as SpO2 < 94% on room air or requiring supplemental oxygen
    2. Laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other commercial or public health assay in any specimen < 72 hours prior to enrollment.
    3. WHO ordinal scale score of 3, 4 or 5 at baseline
    4. Male or non-pregnant female adult ≥18 years of age at time of enrolment.
    5. Subject (or legally authorized representative) provides written informed consent prior to initiation of any study procedures.
    6. Understands and agrees to comply with planned study procedures.
    7. Agrees to the collection of venous blood per protocol.
    8. Illness of any duration
    9..Women of childbearing potential must have a negative blood pregnancy test at the screening/baseline visit (Day 1) and agree to use a double method of birth control through 30 days after the last dose of study drug
    E.4Principal exclusion criteria
    1. Intubated and mechanically ventilated at baseline
    2. Receiving extracorporeal membrane oxygenation (ECMO) at baseline
    3. Severe organ dysfunction (SOFA score > 10)
    4. Patient or LAR unable to provide written informed consent
    5. ALT/AST > 5 times the upper limit of normal.
    6. Stage 3 (EGFR by MDRD) severe chronic kidney disease or requiring dialysis (i.e. eGFR < 30)
    7. Pregnancy or breast feeding.
    8. Anticipated transfer to another hospital which is not a study site within 72 hours.
    9. Allergy to any study medication
    10. Moribund patient not expected to survive 24 hours
    E.5 End points
    E.5.1Primary end point(s)
    Lead-In PK/PD
    • Serious adverse events / Adverse events (Dose Limiting Toxicity)
    Randomized pilot
    • Time to recovery through Day 28, defined as time to achieve (and maintain through Day 28) a WHO ordinal severity scale score of 1, 2 or 3 with a minimum 1-point improvement from baseline
    E.5.1.1Timepoint(s) of evaluation of this end point
    Lead-In PK/PD Dose Selection: Serious adverse events/adverse events (following 5 days treatment)

    Randomized Pilot: day 29
    E.5.2Secondary end point(s)
    WHO Ordinal scale
    o Time to improvement of one category from admission on the ordinal scale
    o Subject clinical status on an ordinal scale at days 3, 5, 8, 11, 15 a nd 29
    o Mean change in the ranking on an ordinal scale from baseline to days 3, 5, 8, 11, 15 and 29
    National Early Warning Score (NEWS)
    o The time to discharge or to a NEWS of < 2 and maintained for 24 hurs, whichever occurs first
    o Change from baseline to days 3, 5, 8, 11, 15 and 29 in NEWS
    Oxygenation
    o Oxygen free days in the first 28 days (to day 29)
    o Incidence and duration of new oxygen use during the trial
    o Proportion on mechanical ventilation, ECMO, noninvasive ventilation and high-flow nasal cannula oxygen delivery and return to room air or baseline oxygen requirement
    o Time to return to room air or baseline oxygen requirement
    o Days on extracorporeal membrane oxygenation (ECMO)
    o Blood oxygenation by recorded continuous pulse oximetry (SpO2:FiO2 ratio)
    o Blood oxygenation by serial arterial blood gas measurements collected prior to the first dose of TSC and at 1 minute, 30 minutes, 1.5 hours, 3 hours and 6 hours post TSC administration by calculated PaO2:FiO2 ratios.
    o Durability of blood oxygenation via SpO2:FiO2 ratios
    Mechanical Ventilation
    o Ventilator free days in the first 28 days (to day 29)
    o Incidence and duration of new mechanical ventilation use during the trial
    Hospitalization
    o Hospital length of stay by Day 29
    o ICU length of stay by Day 29
    Mortality
    o 15-day mortality
    o 28-day mortality
    o All cause mortality at Day 29
    o In hospital mortality
    o Mortality at Day 60
    Other
    o Glasgow Coma Score
    o Sequential Organ Failure Assessment (SOFA) Score at baseline, 24 and 48 hours, Day 7, Day 15
    o Development of acute kidney injury (as defined by AKIN criteria)
    o 28-day new renal replacement therapy (RRT) free days (excluding patients on chronic HD)
    o Proportion of patients alive and free of respiratory failure by Day 28 defined as at least one of the following:
    o Endotracheal intubation and mechanical ventilation
    o Oxygen delivered by high-flow nasal cannula (heated, humidified oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen > 0.5)
    o Noninvasive positive pressure ventilation
    o Extracorporeal membrane oxygenation
    o Clinical diagnosis of respiratory failure with initiation of none of these measures only when clinical decision making is driven solely by resource limitation
    Safety
    o Cumulative incidence of serious adverse events (SAEs)to Day 60
    o Cumulative incidence of Grade 3 or 4 adverse events (AEs)to Day 60
    o Discontinuation or temporary suspension of study drug injections (for any reason)
    o Changes in white cell count, haemoglobin, platelets, creatinine glucose, total bilirubin, ALT and AST on days 1, 3, 5, 8, 11 (while hospitalized); and Day 15 and 29 ( if able to return to clinic or still hospitalized)
    E.5.2.1Timepoint(s) of evaluation of this end point
    WHO scale
    days 3, 5, 8, 11, 15 and 29
    NEWS
    days 3, 5, 8, 11, 15,29 in NEWS
    Oxygenation
    Oxygen free days in the first 28 days (to day 29)
    Blood oxygenation prior to 1st dose of TSC and at 1 min, 30 min, 1.5 , 3 and 6 hrs post TSC adm. by calculated PaO2:FiO2 ratios.
    -Ventilator free days in the first 28 days
    -Incidence and duration of new mechanical ventilation use during the trial
    Hospitalization
    -Hospital and ICU length of stay by Day 29
    Mortality
    -15-day/28-day/ mortality
    All cause mortality at Day 29
    In hospital mortality
    Mortality at Day 60
    Other
    - SOFA Score at baseline, 24 and 48 hours, Day 7and 15
    -28-day new RRT free days
    Safety
    Changes in wbc, hgb, plt, cr glucose, T bilirubin, ALT / AST from day 1 through day 15 and day 29
    AE, SAE to day 60
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Safety and Tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Pk,PD,Safety and Tolerability
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    lvls
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 24
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state224
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    none
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-07-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-03-17
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