COVID-19
Conditions
Brief summary
This trial is a randomized, double-blind, placebo-controlled, parallel-group, 2-arm, multicenter trial to evaluate the efficacy and safety of C21 versus placebo as add-on to standard of care (SoC) in adult subjects with COVID-19. The trial planned to enroll a total of maximum 300 randomized subjects, 150 per arm (oral C21 100 mg twice a day (BID) or placebo for 14 days) according to the 1:1 randomization.
Detailed description
The trial consists of 3 consecutive periods: a screening period of up to 48 hours, a 2-week investigational medicinal product (IMP) treatment period and a follow-up period of up to 7 weeks after last IMP intake. All subjects went through a series of efficacy, safety, and laboratory assessments. Safety laboratory tests and samples for future exploratory analysis were obtained at the screening visit. The trial duration for an individual subject was not exceeded 9 weeks.
Interventions
DRUGC21
C21
DRUGPlacebo
Placebo
Sponsors
Vicore Pharma AB
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years or the legal age of consent in the jurisdiction in which the trial was taking place at the time of signing the informed consent (Specific for India; Age ≥18 to ≤65 years at the time of signing the informed consent) 2. Hospitalized due to SARS-CoV-2 infection confirmed by a hospital-approved polymerase chain reaction (PCR) test, documented by either of the following: 1. PCR positive in sample collected \<72 hours prior to randomization (Visit 2); OR 2. PCR positive in sample collected ≥72 hours and ≤7 days prior to randomization, documented inability to obtain a repeat sample AND progressive disease suggestive of ongoing SARS-CoV-2 infection 3. A score of 5 or 6 on the 8-point ordinal scale: 1. Score 5: Hospitalized, requiring supplemental oxygen 2. Score 6: Hospitalized, on non-invasive ventilation or high-flow oxygen device 4. Contraceptive use by men and women of childbearing potential consistent with local regulations regarding the methods of contraception for those participating in clinical studies and according to Appendix 3 in the Protocol (see Section 10.3) 5. Written informed consent, consistent with International Council for Harmonization Good Clinical Practice Revision 2 and local laws, obtained before the initiation of any trial-related procedure 6. Capable of giving signed informed consent as described in Appendix 1 in the Protocol (see Section 10.1.3) which includes compliance with the requirements and restrictions listed in the informed consent form and in this Protocol Country specific: 7. Specific for India: For subjects with an ordinal scale score of 5, moderate to severe COVID-19 disease confirmed by at an SpO2≤93 % or a respiratory rate≥24/min on room air. Note: If a subject was on supplemental oxygen with SpO2\>93% and respiratory rate\<24/min, but desaturation to ≤93 % or increase of respiratory rate to ≥24/min on lower supplemental oxygen or room air is documented during screening, the inclusion criterion was considered to be met.
Exclusion criteria
1. Concurrent serious medical condition which in the opinion of the investigator constituted a risk or a contraindication for the participation in the trial or that could interfere with the trial objectives, conduct or evaluation 2. Known, active tuberculosis, active hepatitis B, C, or human immunodeficiency virus (HIV) infection (i.e., HIV with a CD4 count\<500 cells/mm³). 3. Moderate or severe impairment of hepatic function (e.g., Child-Pugh class B or C where alterations in the score components were not due to another underlying disease (see Section 8.4.5 in the Protocol)). 4. Severe renal impairment (i.e., estimated glomerular filtration rate (eGFR)≤30 ml/min/1.73m2) 5. COVID-19 symptom onset \>21 days prior to screening (Visit 1). 6. Hospitalized due to COVID-19 for \>72 hours at screening (Visit 1). 7. Invasive mechanical ventilation or ECMO within 72 hours of screening (Visit 1). 8. Expected need for invasive mechanical ventilation or ECMO in \<48 hours in the opinion of the investigator 9. Moderate to severe ARDS (e.g., same-day PaO2/FiO2 ≤200 mmHg; or SpO2/FiO2 ≤232 if arterial blood gas test is not available), if on non-invasive mechanical ventilation or high-flow oxygen. 10. Pregnant or breast-feeding female subjects 11. Any previous and concurrent experimental treatment for COVID-19 that was not considered local SoC. 12. Treatment with the medications listed below within 1 week prior to screening (Visit 1) or anticipated need for such medication during the participation in this trial: 1. Strong Cytochrome P450 (CYP) 3A4 inducers. 2. P-glycoprotein (P-gp) substrates with narrow therapeutic index. 3. High dose Breast Cancer Resistance Protein (BCRP) sensitive substrates. 4. Warfarin. 5. Sulphasalazine or rosuvastatin. 13. Current or previous participation in any other clinical trial where the subject had received a dose of IMP within 1 month or 5 half-lives of the IMP, whichever was longest, prior to screening (Visit 1). 14. Positive pregnancy test (see Section 8.4.6 in the Protocol). 15. Abnormal laboratory value at screening (Visit 1) indicating a potential risk for the subject if enrolled in the trial as evaluated by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality up to Day 60 | Day 1 to Day 60 | Proportion of subjects in the mITT (all randomised, including 5 subjects not treated) with death up to Day 60 follow-up |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Sustained Hospital Discharge up to Day 60 | Day 1 to Day 60 | Time to sustained hospital discharge from Day 1 to Day 60: Time to sustained hospital discharge was defined as the time to the date of discharge from the initial hospitalization or re-hospitalization due to COVID-19 after which the subject was not re-hospitalized for COVID-19 related reasons. |
| Supplemental Oxygen-free Days up to Day 29 | Day 1 to Day 29, maximum 28 Days | Supplemental oxygen-free days from Day 1 up to Day 29, observed range 0 to 28 days. Subjects with deaths imputed as -1 day according to SAP and FDA guidance. Outcome was identical in both groups for both median and range |
| Proportion of Subjects Free of Respiratory Failure, Defined as an 8-point Ordinal Scale Score ≤5, at Day 15 | Day 15 | Proportion of subjects free of respiratory failure, defined as an 8-point ordinal scale score ≤5, at Day 15. Missing data imputed by MI, proportion given are average over the imputations. |
| Proportion of Subjects Discharged From Hospital and Free of Supplemental Oxygen at Day 15 | Day 15 | Proportion of subjects discharged from hospital and free of supplemental oxygen at Day 15. Missing data imputed by MI, proportion given are average over the imputations. |
Countries
Argentina, Brazil, Colombia, Czechia, India, Philippines, Russia, South Africa, Ukraine, United States
Participant flow
Pre-assignment details
316 subjects were screened. Of those, 44 subjects were screening failures, 39 for failure to meet eligibility criteria, 3 due to withdrawal by the subject, and 2 for other reasons. The remaining 272 subjects were randomized. 5 of the randomized subjects did not receive treatment. The screening period was from signing of ICF until randomization.
Participants by arm
| Arm | Count |
|---|---|
| C21 Treatment Oral C21 treatment 100 mg twice daily for 14 days | 136 |
| Placebo Treatment Oral placebo treatment twice daily for 14 days | 136 |
| Total | 272 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up | Death | 4 | 3 |
| Follow-up | Withdrawal by Subject | 1 | 0 |
| Randomization | Withdrawal by Subject | 2 | 3 |
| Treatment Period | Adverse Event | 0 | 1 |
| Treatment Period | Death | 6 | 6 |
| Treatment Period | Discontinuation criteria of eGFR | 0 | 1 |
| Treatment Period | Lost to Follow-up | 1 | 0 |
| Treatment Period | Protocol Violation | 0 | 1 |
| Treatment Period | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | C21 Treatment | Placebo Treatment | Total |
|---|---|---|---|
| Age, Continuous | 53.5 years | 56.5 years | 55.0 years |
| Body mass index | 28.71 Kg/m^2 | 28.14 Kg/m^2 | 28.42 Kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 127 Participants | 127 Participants | 254 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 6 Participants |
| Height | 168.8 Cm | 167.6 Cm | 168.2 Cm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 43 Participants | 45 Participants | 88 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 90 Participants | 87 Participants | 177 Participants |
| Region of Enrollment Brazil | 4 participants | 5 participants | 9 participants |
| Region of Enrollment Colombia | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Czechia | 20 participants | 19 participants | 39 participants |
| Region of Enrollment India | 38 participants | 38 participants | 76 participants |
| Region of Enrollment Philippines | 3 participants | 5 participants | 8 participants |
| Region of Enrollment Russia | 9 participants | 7 participants | 16 participants |
| Region of Enrollment South Africa | 2 participants | 3 participants | 5 participants |
| Region of Enrollment Ukraine | 54 participants | 55 participants | 109 participants |
| Region of Enrollment United States | 4 participants | 4 participants | 8 participants |
| Sex: Female, Male Female | 57 Participants | 63 Participants | 120 Participants |
| Sex: Female, Male Male | 79 Participants | 73 Participants | 152 Participants |
| Weight | 81.89 Kg | 79.26 Kg | 80.58 Kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 136 | 10 / 136 |
| other Total, other adverse events | 22 / 134 | 24 / 133 |
| serious Total, serious adverse events | 15 / 134 | 13 / 133 |
Outcome results
Primary
All-cause Mortality up to Day 60
Proportion of subjects in the mITT (all randomised, including 5 subjects not treated) with death up to Day 60 follow-up
Time frame: Day 1 to Day 60
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| C21 Treatment | All-cause Mortality up to Day 60 | Censored | 126 Participants |
| C21 Treatment | All-cause Mortality up to Day 60 | Death | 10 Participants |
| Placebo Treatment | All-cause Mortality up to Day 60 | Death | 10 Participants |
| Placebo Treatment | All-cause Mortality up to Day 60 | Censored | 126 Participants |
p-value: 0.94995% CI: [0.4, 2.36]Log Rank
Secondary
Proportion of Subjects Discharged From Hospital and Free of Supplemental Oxygen at Day 15
Proportion of subjects discharged from hospital and free of supplemental oxygen at Day 15. Missing data imputed by MI, proportion given are average over the imputations.
Time frame: Day 15
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| C21 Treatment | Proportion of Subjects Discharged From Hospital and Free of Supplemental Oxygen at Day 15 | 0.676 proportion of responders |
| Placebo Treatment | Proportion of Subjects Discharged From Hospital and Free of Supplemental Oxygen at Day 15 | 0.679 proportion of responders |
p-value: 0.94895% CI: [-11.4, 10.6]Regression, Logistic
Secondary
Proportion of Subjects Free of Respiratory Failure, Defined as an 8-point Ordinal Scale Score ≤5, at Day 15
Proportion of subjects free of respiratory failure, defined as an 8-point ordinal scale score ≤5, at Day 15. Missing data imputed by MI, proportion given are average over the imputations.
Time frame: Day 15
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| C21 Treatment | Proportion of Subjects Free of Respiratory Failure, Defined as an 8-point Ordinal Scale Score ≤5, at Day 15 | 0.884 proportion of responders |
| Placebo Treatment | Proportion of Subjects Free of Respiratory Failure, Defined as an 8-point Ordinal Scale Score ≤5, at Day 15 | 0.901 proportion of responders |
p-value: 0.67195% CI: [-9.3, 6]Regression, Logistic
Secondary
Supplemental Oxygen-free Days up to Day 29
Supplemental oxygen-free days from Day 1 up to Day 29, observed range 0 to 28 days. Subjects with deaths imputed as -1 day according to SAP and FDA guidance. Outcome was identical in both groups for both median and range
Time frame: Day 1 to Day 29, maximum 28 Days
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| C21 Treatment | Supplemental Oxygen-free Days up to Day 29 | 23.0 Days |
| Placebo Treatment | Supplemental Oxygen-free Days up to Day 29 | 23.0 Days |
p-value: 0.42595% CI: [-1, 1]Wilcoxon (Mann-Whitney)
Secondary
Time to Sustained Hospital Discharge up to Day 60
Time to sustained hospital discharge from Day 1 to Day 60: Time to sustained hospital discharge was defined as the time to the date of discharge from the initial hospitalization or re-hospitalization due to COVID-19 after which the subject was not re-hospitalized for COVID-19 related reasons.
Time frame: Day 1 to Day 60
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| C21 Treatment | Time to Sustained Hospital Discharge up to Day 60 | 9.0 Days |
| Placebo Treatment | Time to Sustained Hospital Discharge up to Day 60 | 9.0 Days |
p-value: 0.30195% CI: [0.91, 1.52]Log Rank