| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Infection with the new Coronavirus |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10051905 |
| E.1.2 | Term | Coronavirus infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of IMU-838 plus investigator's choice of standard of care therapy (SoC) vs placebo plus SoC in the treatment of coronavirus disease 2019 (COVID-19) based on the need for invasive ventilation (INV) up to 28 days |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of IMU-838 (+SoC) vs placebo (+SoC) in the treatment of COVID-19 based on survival without respiratory failure, the duration of hospitalization in intensive care unit (ICU) and all-cause mortality up to 28 days
- To evaluate the efficacy of IMU-838 (+SoC) vs placebo (+SoC) in the treatment of COVID-19 based on a variety of further variables and time points (e.g., clinical status, renal impairment, oxygenation, hospitalization, concomitant vasoactive treatments, clinical recovery)
- To evaluate trough plasma levels of IMU-838
- To evaluate safety and tolerability of IMU-838
- To explore blood levels of disease markers
- To explore viral titers, measures of viral virulence and inflammatory markers |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients at least 18 years old (may only be extended to
include children 12 years or older after MA1 following approval of a protocol amendment)
2. Admitted to the hospital or other medical in-patient treatment facility for treatment of COVID-19
The hospitalization needs to be for medical reasons (treatment of COVID-19 disease) and cannot be for social reasons or due to housing insecurity.
3. SARS-CoV-2 infection confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) test in a nasopharyngeal, oropharyngeal or respiratory sample at ≤4 days before randomization
4. Moderate COVID-19 disease defined as fulfilling clinical status category 3 or 4 on the WHO 9-point ordinal scale [21]:
o Category 3: Hospitalized (see note above for US only), virus-positive, no oxygen therapy with the following condition:
− The hospitalization needs to be for medical reasons (treatment of COVID-19 disease) and cannot be for social reasons or due to housing insecurity
o Category 4: Hospitalized, virus-positive, oxygen by mask or nasal prongs (excluding high-flow oxygen therapy) with the following condition:
− Peripheral capillary oxyhemoglobin saturation (SpO2) >92% at maximum of 6 liters oxygen flow per minute
− Stable respiratory rate ≤30 breaths/min at maximum of 6 liters oxygen flow per minute
5. Presence of at least 1 symptom characteristic for COVID-19 disease i.e., fever, cough or respiratory distress
6. Willingness and ability to comply with the protocol
7. Written informed consent given prior to any trial-related procedure
8. For women of childbearing potential: Application of a highly effective method of birth control (failure rate less than 1% per year when used consistently and correctly) together with a barrier method between trial consent and 30 days after the last intake of the IMP.
Highly effective forms of birth control are those with a failure rate less than 1% per year and include:
o oral, intravaginal, or transdermal combined (estrogen and progestogen containing) hormonal contraceptives associated with inhibition of ovulation
o oral, injectable, or implantable progestogen-only hormonal contraceptives associated with inhibition of ovulation
o intrauterine device or intrauterine hormone-releasing system
o bilateral tubal occlusion
o vasectomized partner (i.e., the patient’s male partner underwent effective surgical sterilization before the female patient entered the clinical trial and is the sole sexual partner of the female patient during the clinical trial)
o sexual abstinence (acceptable only if it is the patient’s usual form of birth control/lifestyle choice; periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are no acceptable methods of contraception)
Barrier methods of contraception include:
o Condom
o Occlusive cap (diaphragm or cervical/vault caps) with spermicidal gel/film/cream/suppository
9. Male patients must agree not to father a child or to donate sperm starting at Screening, throughout the clinical trial and for 30 days after the last intake of the IMP. Male patients must also
o abstain from sexual intercourse with a female partner (acceptable only if it is the patient’s usual form of birth control/lifestyle choice), or
o use adequate barrier contraception during treatment with the IMP and until at least 30 days after the last intake of the IMP, and
o if they have a female partner of childbearing potential, the partner should use a highly effective contraceptive method as outlined in inclusion criterion 8
o if they have a pregnant partner, they must use condoms while taking the IMP to avoid exposure of the fetus to the IMP |
|
| E.4 | Principal exclusion criteria |
Underlying disease-related exclusion criteria
1. Involvement in the trial is not in the patient’s best interest according to the investigator’s decision, including the presence of any condition that would, in the assessment of the investigator, not allow the protocol to be followed safely
2. Presence of respiratory failure, shock, and/or combined failure of other organs that requires ICU monitoring in the near foreseeable future
3. Critical patients whose expected survival time <48-72 hours
4. Presence of the following laboratory values at screening:
o White blood cell count (WBC) <1.0 x 109/L
o Platelet count <100,000/mm³ (<100 x 109/L)
o Total bilirubin>2 x ULN
o Alanine aminotransferase (ALT) or gamma glutamyl transferase (GGT) >5 x ULN
5. Participation in any other interventional clinical trial
6. Hospitalization primarily for reasons other than COVID-19 (including primarily for concomitant conditions during ongoing SARS-CoV-2 infection)
7. Anticipated transport to a different hospital or institution, in particular when such transport is anticipated for pending ECMO or RRT treatment
8. Clinical suspicion of a bacterial superinfection at Screening
IMP-related exclusion criteria
9. Patients who cannot take drugs orally
10. Allergic or hypersensitive to the IMP or any of the ingredients
11. Use of the following concomitant medications is prohibited from Screening to end of treatment with IMP in this trial (up to Day 14) if not indicated otherwise in this protocol:
o Concurrent use of any mycophenolate mofetil or of methotrexate exceeding 17.5 mg weekly
o Any medication known to significantly increase urinary elimination of uric acid, in particular lesinurad (Zurampic™) as well as uricosuric drugs such as probenecid
o Current treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin, bosutinib, sorafenib, enasidenib, erlotinib, regorafenib, pazopanib and nilotinib
o Any drug significantly restricting water diuresis, in particular vasopressin and vasopressin analogs
o Use of rosuvastatin at daily doses higher than 10 mg
o Arbidol and Colchicine
o Any use of other DHODH inhibitors, including teriflunomide (Aubagio™) or leflunomide (Arava™)
o Chloroquine and Hydroxychloroquine during the entire trial, unless taken for indicated use before entering the trial
12.Patients with clinically relevant conditions leading to hyperuricemia
13. Use of any investigational product within 8 weeks or 5x the respective half-life before the date of informed consent, whichever is longer, and throughout the duration of the trial
General exclusion criteria
14. Patients who have a “do not intubate” or “do not resuscitate” order (unless the patient waives in writing this order and will allow intubation for the duration of the trial period)
15. Patients with pre-existing end-stage liver disease (Child Pugh B and C score)
16.Patients with known Gilbert syndrome (unless their indirect
[unconjugated] bilirubin level is confirmed to be <1.2 x ULN, i.e. <1.1 mg/dL)
17.Patients with known acute or clinically relevant chronic renal failure,
patients currently on dialysis, as well as patients with an estimated
glomerular filtration rate value <30 mL/min/1.73 m² body surface area
according to the Chronic Kidney Disease Epidemiology Collaboration
equation for adults (or the Schwartz bedside equation for children and
adolescents, if applicable)
18. 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)
19. Legal incapacity, limited legal capacity, or any other condition that makes the patient unable to provide consent for the trial
20. Pregnant or breastfeeding
21. An employee of an investigator or Sponsor or an immediate relative of an investigator or Sponsor
22. Patients institutionalized due to judicial order |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients without any need for INV until end-of-study (EoS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
•Proportion of patients surviving without respiratory failure (defined as
any need of ICU, INV, high-flow oxygen or extracorporeal membrane
oxygenation [ECMO*] until EoS)
• Duration of ICU treatment until EoS
• 28-day all-cause mortality
• Time to clinical improvement, defined as the time from first dose of investigational medicinal product (IMP) to an improvement of at least 2 points on the WHO 9-category ordinal scale1, or live discharge from hospital without oxygen supplementation, whichever comes first
• Duration of hospitalization
• Proportion of patients
- free of renal-replacement therapy (RRT)* until EoS
- free of (ECMO)* until EoS
• Proportion of patients
- free of INV until Days 6 and 14*
- free of RRT until Days 6 and 14*
- free of ECMO until Days 6 and 14*
- with improvement of at least 2 points (from randomization) on the 9-category WHO ordinal scale1 on Days 6, 14, and 28
- with auxiliary oxygen therapy* (including all types of oxygen therapy) until Days 6, 14, and 28
- with clinical recovery defined as
•Axillary temperature ≤36.6 Celsius degrees, or oral temperature ≤37.2
Celsius degrees, or rectal or tympanic temperature ≤37.8 Celsius degrees; and
•Respiratory frequency ≤24 times/min without oxygen inhalation; and
•Oxygen saturation ≥98% without oxygen inhalation
-With clinical improvement, defined as an improvement of at least 2 points on the WHO 9 category ordinal scale, or live discharge from hospital without oxygen supplementation, whichever comes first
• Change in daily clinical patient status on the WHO 9-category ordinal scale
• Duration of INV
• Duration of ECMO
• Duration of RRT
• Duration of auxiliary oxygen therapy (including all types of oxygen therapy)
• Duration of hospitalization for survivors
• The rate of ICU* admission on Days 6, 14, and 28
• Hospital-free days
• Time from IMP treatment initiation to death
• Time to first prescription of INV
• Time to first prescription of RRT
• Time to first prescription of ECMO
• Time to first prescription of INV, RRT, and ECMO
• Time to ICU admission
• Cumulative dose of vasoactive therapies (daily until Day 14) and days with vasoactive therapies (until Day 14)
• Time to clinical recovery
• Morning trough plasma levels of IMU-838 on Days 0, 1 through 6, 14, and 28
• Correlation of trough levels (quartiles) to selected clinical outcomes
• Adverse events (AEs) and serious AEs
• Vital signs
• Clinical laboratory parameters (blood chemistry, hematology, and urinalysis)
• Electrocardiogram (ECG) parameters
• Temperature
• D-dimer
• Lactate dehydrogenase (LDH)
• C-reactive protein
• Troponin I
• Procalcitonin
• Correlation of disease markers to selected clinical outcomes
• Severe Acute Respiratory Syndrome Coronavirus Virus (SARS-CoV-2) mean viral load - log10 copies in spontaneous sputum and nasopharyngeal swab samples
- Decrease of SARS-CoV-2 viral load
- Time course of SARS-CoV-2 viral load
• Qualitative virologic clearance in spontaneous sputum and nasopharyngeal swab samples (= 2 consecutive negative SARS-CoV-2 reverse transcriptase polymerase chain reaction tests at least 24 hours apart)
• Rate of conversion to a negative SARS-CoV-2 (qualitative) test on Days 6, 14 and 28
• Time to conversion to a negative SARS-CoV-2 (qualitative) test
Biomarkers
• Interleukin (IL)-17, IL-1ß, IL-6, interferongamma (IFNγ), tumor necrosis factor alpha
Serologic markers
• Immunoglobulin (Ig)A and IgG antibodiesagainst SARS-CoV-2
• Time to appearance of IgA and/or IgGantibodies
• Proportion of patients with IgA and/orIgG antibodies on Days 6, 14, and 28
*Patients who are assessed by the investigator to have a medical need of the respective treatment (i.e., INV, ECMO, RRT, ICU, hospitalization) but do not receive these treatments for other reasons will be counted for this endpoint. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Optional two part-study: Phase 2(Proof-of-Activity Phase, Part 1), Optional Phase 3 (Part 2) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bosnia and Herzegovina |
| Bulgaria |
| Germany |
| Greece |
| Hungary |
| Macedonia, the former Yugoslav Republic of |
| Moldova, Republic of |
| Romania |
| Russian Federation |
| Ukraine |
| United States |
|
| E.8.7 | Trial 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
|
| Last patient last visit in the entire trial |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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