IMU-838 and Oseltamivir in the Treatment of COVID-19
IMU-838 and Oseltamivir in the Treatment of COVID-19
To evaluate whether time-to-improvement is significantly better in IMU-838 plus Oseltamivir
 (IONIC Intervention) and standard care vs. Oseltamivir and standard care in adult subjects
 with coronavirus disease (COVID-19)
The IONIC Protocol describes an overarching trial design to provide reliable evidence on the
 efficacy of IMU-838 (vidofludimus calcium) when delivered in combination with an antiviral
 therapy (Oseltamivir) [IONIC Intervention] for confirmed or suspected COVID-19 infection in
 adult patients receiving usual standard of care.

 At present, there are no known treatments for COVID-19. Whilst, the anticipated scale of the
 epidemic is such that hospitals, and particularly intensive care facilities, may be massively
 overstretched. As described by a few models of pandemic spread, up to 50% of the adult
 population may fall sick over a period of 8-12 weeks, of whom around 10% may require
 hospitalisation. This figure could imply nearly 2 million hospital admissions. Considering
 this scenario, therapies which may only have a moderate impact on survival or on hospital
 resources could be worthwhile.

 Critically, the present trial design has been developed with consideration of the front-line
 hospital staff working within an overstretched care system in these unprecedented times. To
 minimise their burden the protocol is deliberately flexible so that it is suitable for a wide
 range of settings, allowing:

 -  a broad range of patients to be enrolled (patient pathway, disease stage or mode of
 diagnosis)

 -  Additional sub-studies may be added to provide more detailed information on side effects
 or sub-categorisation of patient types but these are not the primary objective and are
 not required for participation.

 -  To be able to include more sites: the investigators will initiate the trial as a single
 centre (UHCW) and more sites invited to participate according to the emerging evidence

 -  The investigator have included 'Exploratory and Secondary objectives' in the protocol
 however, in consideration of the circumstances the research activities will emulate
 investigations performed as per standard care/routines care to minimise any burden on
 the delivery teams.

 This is a Phase 2b, randomised, parallel-group, open-label study to assess the efficacy and
 safety of an oral dose of IMU-838 (22.5 mg twice daily [45 mg/day]) plus Oseltamivir (75mg
 twice daily [150mg/day]) (IONIC Intervetion) or Oseltamivir alone (75mg twice daily) in
 hospitalised patients with COVID-19.
Inclusion Criteria:

 -  1. Male or non-pregnant female patients at least 18 years old 2. Severe Acute
 Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection, either:

 -  Confirmed cases: prospective participants who test positive to a validated
 specific SARS-CoV-2 nucleic acid test or has the virus identified by electron
 microscopy or viral culture, as per local trust policy ≤ 7 days before
 randomisation.

 -  Probable/Suspected case: prospective participants who may have been in contact
 with a confirmed case of COVID-19, AND have mild to severe COVID-19 clinical
 symptoms AND radio-graphic evidence* of pulmonary infiltrates consistent with
 COVID-19 disease 3. Moderate to severe COVID-19 requiring hospitalisation defined
 as: a) Clinical status category 3-5 (inclusive) on the 7-point clinical status
 category scale as proposed by the World Health Organisation (WHO) master
 protocol: I. Category 3: hospitalized, no oxygen therapy II. Category 4:
 hospitalized, oxygen by mask or nasal prongs III. Category 5: hospitalized,
 non-invasive ventilation or high-flow oxygen *where routinely available, no tests
 will be requested for research purpose

 Exclusion Criteria

 Therapy Exclusion Criteria:

 Use of the following concomitant medications is prohibited at Screening Visit and
 throughout the duration of the trial:

 1. Use of Oseltamivir for more than 48 hrs prior to the first treatment dose

 2. Use of antiviral drugs (e.g. nucleoside analogue reverse-transcriptase inhibitors,
 protease inhibitors, etc.)

 3. History of long-term or concurrent use of mycophenolate mofetil, methotrexate
 exceeding 17.5 mg weekly

 4. Chloroquine or hydroxychloroquine

 5. Any medication known to significantly increase urinary elimination of uric acid, in
 particular lesinurad as well as uricosuric drugs such as probenecid

 6. Treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin,
 bosutinib, sorafinib, enasidenib, erlotinib, regorafenib, pazopanib and nilotinib

 7. Any drug significantly restricting water diuresis, in particular vasopressin and
 vasopressin analogues

 8. Use of rosuvastatin at daily doses higher than 10 mg

 Medical History of Concomitant Disease Exclusion Criteria

 -  Allergic or hypersensitivity to the IMU-838, Oseltamivir, or any of the ingredients

 -  Pregnant or breastfeeding or with intention to become pregnant during the study

 -  Participants who cannot take trial medication orally at presentation

 -  Undergoing active chemotherapy or radiotherapy.

 -  If the attending clinician believes that there is a specific contra-indication to the
 IONIC intervention.

 -  Patient has a medical or concomitant disease history preventing them from
 participating

 -  Critical patients whose expected survival time < 48-72 hours

 -  Evidence of pancytopenia or immunosuppression

 -  Any contraindication to Oseltamivir or standard of care

 Presence of the following laboratory values at Screening Exclusion Criteria

 -  Platelet count <100,000/mm³ (<100 x 109/L)

 -  Total bilirubin > 2 x ULN or ALT or GGT > 5 x ULN

 -  Elevated indirect (unconjugated) bilirubin >1.2 x ULN (i.e. >1.1 mg/dL)

 -  Serum uric acid levels at Screening Visit >1.2 x ULN (for women >6.8 mg/dL, for men
 >8.4 mg/dL)

 -  Renal impairment defined as estimated glomerular filtration rate ≤45 mL/min/1.73m²

 -  Decompensated liver cirrhosis (Child-Pugh score B and C)

 -  History or presence of serious or acute heart disease such as uncontrolled cardiac
 dysrhythmia or arrhythmia, uncontrolled angina pectoris, cardiomyopathy, or
 uncontrolled congestive heart failure (New York Heart Association [NYHA] class 3 or 4)

 -  Cardiac disease resulting in marked limitation of physical activity. Patients are
 comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea,
 or anginal pain. NYHA class 4: Cardiac disease resulting in inability to carry on any
 physical activity without discomfort. Symptoms of heart failure or the anginal
 syndrome may be present even at rest. If any physical activity is undertaken,
 discomfort is increased.

 -  History or presence of any major medical or psychiatric illness (such as severe
 depression, psychosis, bipolar disorder), history of suicide attempt, or current
 suicidal ideation, if any of those conditions in the opinion of the investigator could
 create undue risk to the patient or could affect adherence with the trial protocol

 COVID-19 related exclusion criteria

 • Participation in any other interventional clinical trial for an experimental treatment
 for COVID-19