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.
Drug: IMU-838
IMU-838 twice daily at 22.5mg doses for 14 days
Other Name: Intervention Arm
Drug: Oseltamivir
Oseltamivir twice daily at 75mg doses for 14 days
Other Name: Control arm
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
University Hospital Coventry and Warwickshire NHS Trust
Coventry, West Midlands, United Kingdom