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Clinical Trial Results:
A randomised, double-blind, placebo-controlled, phase 2 trial investigating the safety and efficacy of C21 in hospitalised subjects with COVID-19 infection not requiring mechanical ventilation

Summary
EudraCT number	2020-001502-38
Trial protocol	GB
Global end of trial date	13 Oct 2020

Results information
Results version number	v1(current)
This version publication date	30 Apr 2021
First version publication date	30 Apr 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

VP-C21-006

ISRCTN number

US NCT number

NCT04452435

WHO universal trial number (UTN)

Sponsor organisation name

Vicore Pharma AB

Sponsor organisation address

Kronhusgatan 11, Göteborg, Sweden, SE-411 05

Public contact

Anne Katrine Cohrt, Vicore Pharma AB, +45 2011 1391, anne-katrine.cohrt@vicorepharma.com

Scientific contact

Carl-Johan Dalsgaard, Vicore Pharma AB, +46 70 975 98 63, carl-johan.dalsgaard@vicorepharma.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

18 Dec 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

13 Oct 2020

Global end of trial reached?

Yes

Global end of trial date

13 Oct 2020

Was the trial ended prematurely?

Main objective of the trial

To investigate the efficacy of C21 200 mg daily dose (100 mg b.i.d.) on COVID-19 infection not requiring mechanical ventilation

Protection of trial subjects

None.

Background therapy

All subject received standard of care as background therapy.

Evidence for comparator

Actual start date of recruitment

27 May 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

India: 206

Worldwide total number of subjects

206

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

186

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The trial planned to enrol 150 subjects. The 106 subjects randomised were all recruited at sites in India. As the number of subjects randomised was considered sufficient to meet the statistical demands of the trial, enrolment was stopped prematurely. This ensured that trial results could be available in a timely manner.

Screening details

206 subjects were enrolled. 96 of the enrolled subjects were screening failures because inclusion criteria 4 (CRP ≥50 and ≤150 mg/L) was not met. 2 enrolled subjects decided to withdraw from the trial before randomisation. 2 subjects died before randomisation (pneumonia). The remaining 106 subjects were randomised to trial treatment

Number of subjects started

206

Number of subjects completed

106

Reason: Number of subjects

Adverse event, serious fatal: 2

Reason: Number of subjects

Consent withdrawn by subject: 2

Reason: Number of subjects

Screening failure: 96

Period 1 title

Overall period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer

Are arms mutually exclusive

Yes

Placebo treatment

Arm description

Oral placebo treatment twice daily for 7 days

Arm type

Placebo

Investigational medicinal product name

Reference treatment (placebo)

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg twice daily (BID) for 7 days

C21 treatment

Arm description

Oral C21 treatment of 100 mg twice daily for 7 days

Arm type

Experimental

Investigational medicinal product name

C21

Investigational medicinal product code

Other name

Compound 21, VP01

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg twice daily (BID) for 7 days

Number of subjects in period 1 ^[1]	Placebo treatment	C21 treatment
Started	55	51
Completed	42	45
Not completed	13	6
Adverse event, serious fatal	3	-
Consent withdrawn by subject	4	1
Discharged from hospital	4	4
Required non-invasive ventilation	1	1
Lost to follow-up	1	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 206 subjects were enrolled in the trial but only 106 subjects were randomised and were included in the overall or baseline period.

Baseline characteristics

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Reporting group title

Placebo treatment

Reporting group description

Oral placebo treatment twice daily for 7 days

Reporting group title

C21 treatment

Reporting group description

Oral C21 treatment of 100 mg twice daily for 7 days

Reporting group values	Placebo treatment	C21 treatment	Total
Number of subjects	55	51	106
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Age at screening
Units: years
arithmetic mean (full range (min-max))	51.1 (22 to 68)	54.3 (29 to 68)	-
Gender categorical
Units: Subjects
Female	13	13	26
Male	42	38	80
Supplemental oxygen use at baseline
Units: Subjects
Yes	32	29	61
No	23	22	45
Ethnicity
Units: Subjects
Hispanic or Latino	55	51	106
Not Hispano or Latino	0	0	0
Unknown or Not Reported	0	0	0
Race
Units: Subjects
Asian	55	51	106
CRP value (mg/L) at baseline
Units: Subjects
≤ Median	22	24	46
> Median	25	21	46
Missing	8	6	14
Height
Height at screening
Units: cm
arithmetic mean (full range (min-max))	166.0 (143 to 188)	166.1 (132 to 198)	-
Weight
Weight at screening
Units: kg
arithmetic mean (full range (min-max))	69.2 (47 to 112)	70.1 (46 to 116)	-
BMI
BMI at screening
Units: kg/m2
arithmetic mean (full range (min-max))	25.1 (20 to 34)	25.4 (15 to 41)	-

Subject analysis set title

Full analysis set

Subject analysis set type

Full analysis

Subject analysis set description

The full analysis set (FAS) consisted of all subjects who were randomized and received at least 1 dose of IMP and who had at least 1 post-baseline assessment of efficacy.

Subject analysis set title

Per protocol analysis set

Subject analysis set type

Per protocol

Subject analysis set description

The per-protocol analysis set (PPAS) was a subset of the FAS and consisted of all subjects without any major protocol deviations that were judged to compromise the analysis of the data.

Subject analysis sets values	Full analysis set	Per protocol analysis set
Number of subjects	106	98
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Age at screening
Units: years
arithmetic mean (full range (min-max))	52.6 (22 to 68)	52.8 (24 to 68)
Gender categorical
Units: Subjects
Female	26
Male	80
Supplemental oxygen use at baseline
Units: Subjects
Yes	61
No	45
Ethnicity
Units: Subjects
Hispanic or Latino	0
Not Hispano or Latino	106
Unknown or Not Reported	0
Race
Units: Subjects
Asian	106
CRP value (mg/L) at baseline
Units: Subjects
≤ Median		46
> Median		46
Missing		14
Height
Height at screening
Units: cm
arithmetic mean (full range (min-max))	166.1 (132 to 198)	166.7 (132 to 198)
Weight
Weight at screening
Units: kg
arithmetic mean (full range (min-max))	69.6 (46 to 116)	70.3 (46 to 116)
BMI
BMI at screening
Units: kg/m2
arithmetic mean (full range (min-max))	25.2 (15 to 41)	25.3 (15 to 41)

End points

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Reporting group title

Placebo treatment

Reporting group description

Oral placebo treatment twice daily for 7 days

Reporting group title

C21 treatment

Reporting group description

Oral C21 treatment of 100 mg twice daily for 7 days

Subject analysis set title

Full analysis set

Subject analysis set type

Full analysis

Subject analysis set description

The full analysis set (FAS) consisted of all subjects who were randomized and received at least 1 dose of IMP and who had at least 1 post-baseline assessment of efficacy.

Subject analysis set title

Per protocol analysis set

Subject analysis set type

Per protocol

Subject analysis set description

The per-protocol analysis set (PPAS) was a subset of the FAS and consisted of all subjects without any major protocol deviations that were judged to compromise the analysis of the data.

Primary: Change From Baseline in C-reactive Protein (CRP) After Treatment With C21 200 mg Daily Dose (100 mg b.i.d.)

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End point title

Change From Baseline in C-reactive Protein (CRP) After Treatment With C21 200 mg Daily Dose (100 mg b.i.d.)

End point description

Change in C-reactive protein (CRP) from baseline to the average of the last two assessments in the treatment period.

End point type

Primary

End point timeframe

Treatment period of 7 days

End point values	Placebo treatment	C21 treatment
Number of subjects analysed	46	45
Units: mg/L
least squares mean (confidence interval 90%)	0.22 (0.17 to 0.29)	0.19 (0.14 to 0.25)

Primary endpoint analysis

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[1]

P-value

= 0.4891 ^[2]

Method

ANCOVA

Confidence interval

Notes
[1] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
[2] - The ratio of adjusted treatment means was 0.85 (90% CI: 0.57, 1.26; p=0.4891), indicating that the null hypothesis could not be rejected.

Subgroup analysis - use of oxygen at baseline

Statistical analysis description

A subgroup analyses was performed in subjects with supplemental oxygen use at baseline. A total of 26 subjects in the C21 group and 27 in the placebo group were included in the analysis of change in CRP from baseline to the mean of the last 2 non-missing scheduled assessments during the treatment period by baseline supplemental oxygen use.

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[3]

P-value

= 0.0881 ^[4]

Method

ANCOVA

Confidence interval

Notes
[3] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
[4] - The ratio of adjusted treatment means was 0.59, the 90% CI did not span 1.0 (0.35, 0.98); and the p-value was less than 0.1 (p=0.0881) indicating a statistically significant difference between the groups.

Subgroup analysis - no oxygen use at baseline

Statistical analysis description

A total of 19 (86.4%) subjects with no supplemental oxygen use at baseline in the C21 group and 19 (82.6%) subjects in the placebo group were included in the analysis of change in CRP by baseline supplemental oxygen use.

Comparison groups

C21 treatment v Placebo treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.6285 ^[5]

Method

ANCOVA

Confidence interval

Notes
[5] - The ratio of adjusted treatment means was 1.20 (90% CI: 0.64, 2.26; p=0.6285), indicating no statistically significant difference between the groups.

Subgroup analysis - age ≤ median

Statistical analysis description

A total of 20 (87.0%) subjects of median age (54 years) or lower at baseline in the C21 group and 26 (83.9%) in the placebo group were included in the analysis of change in CRP from baseline to the mean of the last 2 non-missing scheduled assessments during the treatment period by baseline age category.

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.5978 ^[6]

Method

ANCOVA

Confidence interval

Notes
[6] - The ratio of adjusted treatment means was 0.85 (90% CI: 0.51, 1.42; p=0.5978), indicating no statistically significant difference between the treatment groups.

Subgroup analysis - age > median

Statistical analysis description

For subjects above median age (54 years) at baseline, a total of 25 (89.3%) subjects in the C21 group and 20 (83.3%) subjects in the placebo group were included in the analysis of change in CRP by baseline age category.

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.3109 ^[7]

Method

ANCOVA

Confidence interval

Notes
[7] - The ratio of adjusted treatment means was 0.70 (90% CI: 0.39, 1.26; p=0.3109), indicating no statistically significant difference between the treatment groups.

Subgroup analysis by sex - women

Statistical analysis description

A total of 12 (92.3%) women in the C21 group and 10 (76.9%) women in the placebo group were included in the analysis of change in CRP by sex.

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.0923 ^[8]

Method

ANCOVA

Confidence interval

Notes
[8] - The ratio of adjusted treatment means was 0.38, the 90% CI did not span 1.0 (90% CI: 0.14, 0.98) and the p-value was less than 0.1 (p=0.0923), indicating a statistically significant difference between the groups

Subgroup analysis by sex - men

Statistical analysis description

A total of 33 (86.8%) men in the C21 group and 36 (85.7%) men in the placebo group were included in the analysis of change in CRP from baseline to the mean of the last 2 non-missing scheduled assessments during the treatment period by sex.

Comparison groups

C21 treatment v Placebo treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.7134 ^[9]

Method

ANCOVA

Confidence interval

Notes
[9] - The ratio of adjusted treatment means was 1.10 (90% CI: 0.71, 1.71; p=0.7134), indicating no statistically significant difference between the treatments.

Subgroup analysis by baseline CRP value ≥ median

Statistical analysis description

A total of 22 (100.0%) subjects in the C21 group and 24 (100.0%) subjects in the placebo group with median CRP values or higher at baseline were included in the analysis.

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.9374 ^[10]

Method

ANCOVA

Confidence interval

Notes
[10] - The ratio of adjusted treatment means was 1.03 (90% CI: 0.58, 1.82; p=0.9374), 0.9374), indicating no statistically significant difference between the treatment groups.

Subgroup analysis by baseline CRP value < median

Statistical analysis description

A total of 24 (96.0%) subjects with CRP levels lower than median at baseline in the C21 group and 21 (100.0%) in the placebo group were included in the analysis of change in CRP from baseline to the mean of the last 2 non-missing scheduled assessments during the treatment period by baseline CRP category.

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.22444 ^[11]

Method

ANCOVA

Confidence interval

Notes
[11] - The ratio in adjusted treatment means was 0.68 (90% CI: 0.40, 1.15; p=0.2244), indicating no statistically significant difference between the treatment groups.

Secondary: Change from baseline in body temperature

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End point title

Change from baseline in body temperature

End point description

End point type

Secondary

End point timeframe

Treatment period of 7 days

End point values	Placebo treatment	C21 treatment
Number of subjects analysed	54	51
Units: °C
least squares mean (confidence interval 90%)	-0.34 (-0.47 to -0.21)	-0.11 (-0.25 to 0.02)

Secondary endpoint analysis - body temperature

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

equivalence ^[12]

P-value

= 0.0492 ^[13]

Method

ANCOVA

Confidence interval

Notes
[12] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%
[13] - The difference of 0.23°C in adjusted treatment means between the groups was statistically significant (90% CI: 0.04, 0.42; p=0.0492).

Secondary: Change from baseline in IL-6

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End point title

Change from baseline in IL-6

End point description

End point type

Secondary

End point timeframe

Treatment period of 7 days

End point values	Placebo treatment	C21 treatment
Number of subjects analysed	34	31
Units: pg/mL
least squares mean (confidence interval 90%)	0.73 (0.51 to 1.03)	0.73 (0.51 to 1.05)

Secondary endpoint analysis- IL-6

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[14]

P-value

= 0.9923 ^[15]

Method

ANCOVA

Confidence interval

Notes
[14] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
[15] - The ratio of adjusted treatment means was 1.00 (90% CI: 0.61, 1.66; p=0.9923), indicating no statistically significant difference between the treatment groups.

Secondary: Change from baseline in IL-10

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End point title

Change from baseline in IL-10

End point description

Change in IL-10 from baseline to the average of the last two assessments during the treatment period

End point type

Secondary

End point timeframe

Treatment period of 7 days

End point values	Placebo treatment	C21 treatment
Number of subjects analysed	39	37
Units: pg/mL
least squares mean (confidence interval 90%)	0.73 (0.60 to 0.89)	0.66 (0.54 to 0.80)

Secondary endpoint analysis - IL-10

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[16]

P-value

= 0.5355 ^[17]

Method

ANCOVA

Confidence interval

Notes
[16] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
[17] - The ratio of adjusted treatment means was 0.90 (90% CI: 0.68, 1.19; p=0.5355), indicating no statistically significant difference between the treatment groups.

Secondary: Change from baseline in TNF

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End point title

Change from baseline in TNF

End point description

Change in TNF from baseline to the average of the last two assessments during the treatment period.

End point type

Secondary

End point timeframe

Change in TNF from baseline to the average of the last two assessments during the treatment period.

End point values	Placebo treatment	C21 treatment
Number of subjects analysed	46	46
Units: pg/mL
least squares mean (confidence interval 90%)	1.01 (0.86 to 1.19)	0.91 (0.77 to 1.07)

Secondary endpoint analysis - TNF

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[18]

P-value

= 0.4738 ^[19]

Method

ANCOVA

Confidence interval

Notes
[18] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
[19] - The ratio of adjusted treatment means was 0.90 (90% CI: 0.72, 1.14; p=0.4738), indicating no statistically significant difference between the treatment groups.

Secondary: Change from baseline in CA125

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End point title

Change from baseline in CA125

End point description

Change in CA125 from baseline to the average of the last two assessments in the treatment period

End point type

Secondary

End point timeframe

Treatment period of 7 days

End point values	Placebo treatment	C21 treatment
Number of subjects analysed	48	46
Units: u/mL
least squares mean (confidence interval 90%)	1.16 (1.04 to 1.31)	1.17 (1.05 to 1.31)

Secondary endpoint analysis - CA125

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[20]

P-value

= 0.9418 ^[21]

Method

ANCOVA

Confidence interval

Notes
[20] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
[21] - The ratio of adjusted treatment means was 0.99 (90% CI: 0.84, 1.17; p=0.9418), indicating no statistically significant difference between the treatment groups.

Secondary: Change from baseline in ferritin

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End point title

Change from baseline in ferritin

End point description

Change in ferritin from baseline to the average of the last two assessments during the treatment period.

End point type

Secondary

End point timeframe

Treatment period of 7 days

End point values	Placebo treatment	C21 treatment
Number of subjects analysed	47	46
Units: ng/mL
least squares mean (confidence interval 90%)	0.74 (0.66 to 0.84)	0.75 (0.66 to 0.84)

Secondary endpoint analysis - ferritin

Comparison groups

C21 treatment v Placebo treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[22]

P-value

= 0.9733 ^[23]

Method

ANCOVA

Confidence interval

Notes
[22] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
[23] - The ratio of adjusted treatment means was 1.00 (90% CI: 0.85, 1.19; p=0.9733), indicating no statistically significant difference between the treatment groups.

Secondary: Number of subjects not in need of oxygen supply

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End point title

Number of subjects not in need of oxygen supply

End point description

Number of subjects not in need of oxygen supply at the end of treatment

End point type

Secondary

End point timeframe

Treatment period of 7 days

End point values	Placebo treatment	C21 treatment
Number of subjects analysed	55	51
Units: Subjects	30	37

Number of subjects not in need of oxygen

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

equivalence ^[24]

P-value

= 0.0568 ^[25]

Method

Regression, Logistic

Confidence interval

Notes
[24] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%
[25] - The odds ratio for C21 versus placebo was 2.20, the 90% CI did not span 1.0 (90% CI: 1.11, 4.35) and the p-value was less than 0.1 (p=0.0568), showing a statistically significant difference in favour of C21.

Secondary: Number of subjects not in need of mechanical invasive or non-invasive ventilation

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End point title

Number of subjects not in need of mechanical invasive or non-invasive ventilation

End point description

Number of subjects not in need of mechanical invasive or non-invasive ventilation during the treatment period.

End point type

Secondary

End point timeframe

Treatment period of 7 days

End point values	Placebo treatment	C21 treatment
Number of subjects analysed	55	51
Units: Subjects	53	50

Secondary endpoint analysis - ventilation

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

equivalence ^[26]

P-value

= 0.6088 ^[27]

Method

Regression, Logistic

Confidence interval

Notes
[26] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
[27] - The odds ratio for 21 versus placebo was 1.89, indicating no statistically significant difference between the treatment groups (90% CI: 0.25, 14.52; p=0.6088.

Secondary: Time to need of mechanical invasive or non-invasive ventilation

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End point title

Time to need of mechanical invasive or non-invasive ventilation

End point description

Time to need of mechanical invasive or non-invasive ventilation during treatment period.

End point type

Secondary

End point timeframe

Treatment period of 7 days

End point values	Placebo treatment	C21 treatment
Number of subjects analysed	2	1
Units: hours
arithmetic mean (full range (min-max))	77.925 (59.98 to 95.87)	60.0 (60.0 to 60.0)

Secondary endpoint analysis - time to ventilation

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

equivalence ^[28]

P-value

= 0.5757

Method

Logrank

Confidence interval

Notes
[28] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.

Secondary: Time on oxygen supply (for those not needing mechanical invasive or non-invasive ventilation)

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End point title

Time on oxygen supply (for those not needing mechanical invasive or non-invasive ventilation)

End point description

Time on oxygen supply during the treatment period (for those not needing mechanical invasive or non-invasive ventilation)

End point type

Secondary

End point timeframe

Treatment period of 7 days

End point values	Placebo treatment	C21 treatment
Number of subjects analysed	55	51
Units: Days
median (inter-quartile range (Q1-Q3))	5.0 (1.0 to 7.0)	5.0 (1.0 to 7.0)

Secondary endpoint analysis - time on oxygen

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

equivalence ^[29]

P-value

= 0.8588

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[29] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.

Secondary: Adverse Events

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End point title

Adverse Events

End point description

Adverse events were reported from signing of informed consent until end-of-trial visit and are described under adverse events.

End point type

Secondary

End point timeframe

From signing of informed consent until end-of-trial, 14-17 days

End point values	Placebo treatment	C21 treatment
Number of subjects analysed	55	51
Units: Adverse events and subjects	90	64

No statistical analyses for this end point

Post-hoc: Oxygen Supplementation at Day 14

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End point title

Oxygen Supplementation at Day 14

End point description

Number of subjects requiring oxygen supplementation at Day 14

End point type

Post-hoc

End point timeframe

Follow-up Day 14 (7 days after end-of-treatment)

End point values	Placebo treatment	C21 treatment
Number of subjects analysed	55	51
Units: Subjects	11	1

Post-hoc analysis - Day 14

Comparison groups

Placebo treatment v C21 treatment

Number of subjects included in analysis

106

Analysis specification

Post-hoc

Analysis type

equivalence ^[30]

P-value

= 0.003 ^[31]

Method

Chi-squared

Confidence interval

Notes
[30] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
[31] - The post hoc analysis showed that 1 (2.0%) subject in the C21 group and 11 (20.0%) subjects in the placebo group were in need of oxygen supplementation at Day 14, with a statistically significant difference between the treatment groups (p=0.003).

Adverse events

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Timeframe for reporting adverse events

From signing of informed consent until end-of-trial visit, 14-19 days.

Adverse event reporting additional description

At each visit, the subject was asked about AEs in an objective manner, e.g., “Have you experienced any problems since the last visit?”

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Placebo treatment

Reporting group description

Oral placebo treatment twice daily for 7 days

Reporting group title

C21 treatment

Reporting group description

Oral C21 treatment of 100 mg twice daily for 7 days

Serious adverse events	Placebo treatment	C21 treatment
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 55 (5.45%)	1 / 51 (1.96%)
number of deaths (all causes)	3	1
number of deaths resulting from adverse events	3	1
Cardiac disorders
Cardio-respiratory arrest
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 55 (1.82%)	1 / 51 (1.96%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Infections and infestations
COVID-19 pneumonia
alternative assessment type: Non-systematic
subjects affected / exposed	2 / 55 (3.64%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	Placebo treatment	C21 treatment
Total subjects affected by non serious adverse events
subjects affected / exposed	36 / 55 (65.45%)	30 / 51 (58.82%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	4 / 55 (7.27%)	3 / 51 (5.88%)
occurrences all number	5	3
Alpha tumour necrosis factor increased
subjects affected / exposed	3 / 55 (5.45%)	1 / 51 (1.96%)
occurrences all number	3	1
Aspartate aminotransferase increased
subjects affected / exposed	3 / 55 (5.45%)	6 / 51 (11.76%)
occurrences all number	4	6
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 55 (3.64%)	1 / 51 (1.96%)
occurrences all number	2	1
Blood calcium decreased
subjects affected / exposed	2 / 55 (3.64%)	1 / 51 (1.96%)
occurrences all number	2	1
Blood glucose increased
subjects affected / exposed	3 / 55 (5.45%)	5 / 51 (9.80%)
occurrences all number	3	7
Blood potassium increased
subjects affected / exposed	2 / 55 (3.64%)	1 / 51 (1.96%)
occurrences all number	2	1
Blood urea increased
subjects affected / exposed	2 / 55 (3.64%)	0 / 51 (0.00%)
occurrences all number	2	0
Carbohydrate antigen 125 increased
subjects affected / exposed	4 / 55 (7.27%)	0 / 51 (0.00%)
occurrences all number	4	0
Interleukin level increased
subjects affected / exposed	4 / 55 (7.27%)	4 / 51 (7.84%)
occurrences all number	4	6
Lymphocyte count decreased
subjects affected / exposed	3 / 55 (5.45%)	1 / 51 (1.96%)
occurrences all number	4	1
Neutrophil count increased
subjects affected / exposed	3 / 55 (5.45%)	1 / 51 (1.96%)
occurrences all number	5	1
Platelet count decreased
subjects affected / exposed	3 / 55 (5.45%)	1 / 51 (1.96%)
occurrences all number	3	1
Platelet count increased
subjects affected / exposed	2 / 55 (3.64%)	0 / 51 (0.00%)
occurrences all number	2	0
Serum ferritin increased
subjects affected / exposed	2 / 55 (3.64%)	5 / 51 (9.80%)
occurrences all number	2	5
White blood cell count increased
subjects affected / exposed	3 / 55 (5.45%)	0 / 51 (0.00%)
occurrences all number	4	0
Gastrointestinal disorders
Constipation
subjects affected / exposed	4 / 55 (7.27%)	0 / 51 (0.00%)
occurrences all number	4	0
Renal and urinary disorders
Glycosuria
subjects affected / exposed	3 / 55 (5.45%)	1 / 51 (1.96%)
occurrences all number	3	1
Metabolism and nutrition disorders
Dyslipidaemia
subjects affected / exposed	2 / 55 (3.64%)	1 / 51 (1.96%)
occurrences all number	2	1
Hyperglycaemia
subjects affected / exposed	4 / 55 (7.27%)	11 / 51 (21.57%)
occurrences all number	5	14
Hyponatraemia
subjects affected / exposed	3 / 55 (5.45%)	2 / 51 (3.92%)
occurrences all number	3	2

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Were there any global substantial amendments to the protocol? Yes

14 Aug 2020

The key changes introduced in protocol version 2.0 (14-Aug-2020) were as follows: The planned total number of subjects was increased from 100 to 150 (N=75 in each group) Concomitant medication was allowed to be given according to local SoC (in version 1.0, this had been qualified with ‘If considered unlikely to interfere with IMP or the outcome of the trial’) The trial was to be conducted at sites globally (version 1.0 was only in the United Kingdom) With the original sample size of 50 subjects per group, there was an approximate 80% power to detect a true CRP reduction of 30 mg/L in C21-treated subjects compared with placebo. With the new sample size of 75 subjects per group, there was an approximate 80% power to detect a true CRP reduction of 25 mg/L in C21-treated subjects compared with placebo

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A randomised, double-blind, placebo-controlled, phase 2 trial investigating the safety and efficacy of C21 in hospitalised subjects with COVID-19 infection not requiring mechanical ventilation

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in C-reactive Protein (CRP) After Treatment With C21 200 mg Daily Dose (100 mg b.i.d.)

Primary: Change From Baseline in C-reactive Protein (CRP) After Treatment With C21 200 mg Daily Dose (100 mg b.i.d.)

Secondary: Change from baseline in body temperature

Secondary: Change from baseline in body temperature

Secondary: Change from baseline in IL-6

Secondary: Change from baseline in IL-6

Secondary: Change from baseline in IL-10

Secondary: Change from baseline in IL-10

Secondary: Change from baseline in TNF

Secondary: Change from baseline in TNF

Secondary: Change from baseline in CA125

Secondary: Change from baseline in CA125

Secondary: Change from baseline in ferritin

Secondary: Change from baseline in ferritin

Secondary: Number of subjects not in need of oxygen supply

Secondary: Number of subjects not in need of oxygen supply

Secondary: Number of subjects not in need of mechanical invasive or non-invasive ventilation

Secondary: Number of subjects not in need of mechanical invasive or non-invasive ventilation

Secondary: Time to need of mechanical invasive or non-invasive ventilation

Secondary: Time to need of mechanical invasive or non-invasive ventilation

Secondary: Time on oxygen supply (for those not needing mechanical invasive or non-invasive ventilation)

Secondary: Time on oxygen supply (for those not needing mechanical invasive or non-invasive ventilation)

Secondary: Adverse Events

Secondary: Adverse Events

Post-hoc: Oxygen Supplementation at Day 14

Post-hoc: Oxygen Supplementation at Day 14

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A randomised, double-blind, placebo-controlled, phase 2 trial investigating the safety and efficacy of C21 in hospitalised subjects with COVID-19 infection not requiring mechanical ventilation