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Clinical Trial Results:
A randomised, blinded, placebo-controlled Phase 2a study to evaluate the safety and efficacy of Artesunate treatment in severely injured trauma patients with traumatic haemorrhage.

Summary
EudraCT number	2015-000301-40
Trial protocol	GB
Global end of trial date	10 Aug 2019

Results information
Results version number	v1(current)
This version publication date	16 Dec 2020
First version publication date	16 Dec 2020
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

009531

ISRCTN number

ISRCTN15731357

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Queen Mary, University of London

Sponsor organisation address

QM Innovation building, 5 Walden Street, London, United Kingdom, E1 2EF

Public contact

Clinical Trials Coordinator, Trauma Sciences, Blizard Institute, Queen Mary University London, 44 02035940728, lourdes.anton@nhs.net

Scientific contact

Clinical Trials Coordinator, Trauma Sciences, Blizard Institute, Queen Mary University London, 44 02035940728, lourdes.anton@nhs.net

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

17 Jul 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

14 May 2019

Global end of trial reached?

Yes

Global end of trial date

10 Aug 2019

Was the trial ended prematurely?

Yes

Main objective of the trial

To determine whether Artesunate is safe and effective in treating severely-injured patients with traumatic haemorrhage in addition to the current standard management.

Protection of trial subjects

Informed Consent Detailed consideration to the informed consent process was undertaken, to ensure that subjects rights to informed consent were protected, whilst minimising distress to the subject and his/her relatives/next of kin. The Mental Capacity Act (England; 2005) and Declaration of Helsinki (World Medical Association; 2013) were used for guidance in the case of incapacitated subjects. Safety The study underwent periodic review by an independent Data Monitoring Comittee (DMC) and a planned formal analysis of safety data was performed at the interim review (after 56 patients were recruited). Based on ongoing review of safety data, an ad hoc further formal safety analysis was conducted after 90 patients were recruited. A trial halt was recommended based on this analysis, due to a potential imbalance of venous thromboembolic events in the treatment arm, and in absence of clear evidence of treatment efficacy.

Background therapy

Patients received full medical and surgical treatment for their injuries, including in the pre-hospital setting, resuscitation room, operating theatre, intensive care unit, and on the wards.

Evidence for comparator

1) Pre-clinical data showing a reduction in organ failure following severe haemorrhage (published, Sordi et al. Annals of Surgery 2016), summarised below: Pre-clinical studies showed that intravenous injection of small doses of Artesunate (1-10 mg/kg) upon resuscitation after severe haemorrhage (rat model) reduced multiple organ failure by enhancing the resistance of organs against injury. This was achieved by a) activating well-known cell-survival pathways, and b) reducing excessive inflammation. 2) Extensive data from human studies of Artesunate in severe malaria demonstrated a favourable safety profile in a critically ill cohort of patients.

Actual start date of recruitment

23 Mar 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

3 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 90

Worldwide total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Recruitment occurred during the following periods: 21/03/2017 - 31/04/2017 30/09/2017 - 30/06/2018 14/11/2018 -15/05/2019

Screening details

Screened = 211. Excluded as ineligible = 106 (Age<16 = 2, Injury>2h = 34, Breastfeeding/Pregnant = 3, Code red downgraded = 6, IMP>4h from injury = 3, MHP activation >1h=5, mortality <48h = 9, non-haemorrhagic = 34, severe TBI = 10). Eligible but not randomised = 15 (out of hours = 8, missed = 5, researcher busy = 2). Total randomised = 90

Period 1 title

Per Protocol (PP) Population

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Assessor

Blinding implementation details

The trial participant, clinical team providing treatment (including pharmacy), research investigators and outcome assessors were blind to group allocation. However, the research investigator who administered the IMP was unblinded due to the slight difference in opalescence of the IMP solution and placebo, and the requirement to visualise the IMP to confirm adequate re-constitution.

Are arms mutually exclusive

PP Placebo

Arm description

The placebo comprises buffered diluent drawn up to the volume that would be necessary to reconstitute active IMP according to the subjects’ weight.

Arm type

Placebo

Investigational medicinal product name

Phosphate buffer diluent

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

The required volume of placebo (phosphate buffer solution only) was calculated to the same volume as if the patient received a dose of active IMP (2.4mg/kg or 4.8mg/kg depending on the stage of the study). This was administered as a single intravenous bolus dose over a period of 1-2 minutes.

PP Artesunate (Total)

Arm description

Artesunate provided as a white crystalline powder in a glass vial containing 110mg, supplied with a second glass vial of reconstitution diluent which is a sterile phosphate buffer. Subjects received either 2.4mg/kg or 4.8mg/kg depending on whether they were randomised during the Low Dose or High Dose phase of the study.

Arm type

Active comparator

Investigational medicinal product name

Artesunate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

The dose of Artesunate was 2.4mg/kg or 4.8mg/kg depending on the stage of the study and was administered as a single dose. It was necessary to reconstitute the IMP (by mixing of the phosphate buffer solution and the dry-filled Artesunate) immediately prior to administration. This was due to the inherent instability of Artesunate in aqueous solutions. After reconstitution, the IMP was administered as a single intravenous bolus dose, over 1-2 minutes.

PP Artesunate (Low Dose)

Arm description

Arm type

Active comparator

Investigational medicinal product name

Artesunate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

The dose of Artesunate was 2.4mg/kg for this arm of the study and was administered as a single dose. It was necessary to reconstitute the IMP (by mixing of the phosphate buffer solution and the dry-filled Artesunate) immediately prior to administration. This was due to the inherent instability of Artesunate in aqueous solutions. After reconstitution, the IMP was administered as a single intravenous bolus dose, over 1-2 minutes.

PP Artesunate (High Dose)

Arm description

Arm type

Active comparator

Investigational medicinal product name

Artesunate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

The dose of Artesunate was 4.8 mg/kg for this arm of the study and was administered as a single dose. It was necessary to reconstitute the IMP (by mixing of the phosphate buffer solution and the dry-filled Artesunate) immediately prior to administration. This was due to the inherent instability of Artesunate in aqueous solutions. After reconstitution, the IMP was administered as a single intravenous bolus dose, over 1-2 minutes.

Number of subjects in period 1	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)
Started	27	48	31	17
Completed	27	48	31	17

Period 2 title

Total Randomised

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Assessor

Blinding implementation details

Are arms mutually exclusive

Yes

Total Randomised Placebo

Arm description

The placebo comprises buffered diluent drawn up to the volume that would be necessary to reconstitute active IMP according to the subjects’ weight.

Arm type

Placebo

Investigational medicinal product name

Phosphate buffer diluent

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Total Randomised Artesunate (Total)

Arm description

Arm type

Active comparator

Investigational medicinal product name

Artesunate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Total Randomised Artesunate (Low Dose)

Arm description

Arm type

Active comparator

Investigational medicinal product name

Artesunate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Total Randomised Artesunate (High Dose)

Arm description

Arm type

Active comparator

Investigational medicinal product name

Artesunate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Number of subjects in period 2	Total Randomised Placebo	Total Randomised Artesunate (Total)	Total Randomised Artesunate (Low Dose)	Total Randomised Artesunate (High Dose)
Started	31	59	37	22
Completed	27	48	31	17
Not completed	4	11	6	5
Consent withdrawn by subject	-	5	4	1
Protocol deviation	4	6	2	4

Baseline characteristics

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Reporting group title

PP Placebo

Reporting group description

The placebo comprises buffered diluent drawn up to the volume that would be necessary to reconstitute active IMP according to the subjects’ weight.

Reporting group title

PP Artesunate (Total)

Reporting group description

Reporting group title

PP Artesunate (Low Dose)

Reporting group description

Reporting group title

PP Artesunate (High Dose)

Reporting group description

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
Justification: The main population for analysis in this study is the per protocol population (as stipulated in the Statistical Analysis Plan, version 2.0, dated 6/8/2018). This population excludes those who were randomised and subsequently withdrawn due to protocol violations, and those who withdrew consent.

Reporting group values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	Total
Number of subjects	27	48	31	17
Age categorical
Units: Subjects
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	30 (18 to 54)	29 (20 to 41)	29 (19 to 39)	32 (23 to 49)	-
Gender categorical
Gender
Units: Subjects
Female	0	9	6	3	9
Male	27	39	25	14	66
Mechanism of Injury
Units: Subjects
Blunt	12	25	17	8	37
Penetrating	15	23	14	9	38
Injury Severity Score
Units: Scale
median (inter-quartile range (Q1-Q3))	20 (9 to 34)	22 (13 to 31)	25 (13 to 34)	22 (14 to 27)	-
Time to admission (mins)
Units: minute
median (inter-quartile range (Q1-Q3))	88 (55 to 102)	71 (47 to 93)	74 (48 to 94)	69 (46 to 90)	-
GCS at admission
Glasgow Coma Score
Units: Scale
median (inter-quartile range (Q1-Q3))	15 (14 to 15)	14 (11 to 15)	14 (9 to 15)	14 (12 to 15)	-
HR at admission (bpm)
Heart Rate
Units: beats per minute
median (inter-quartile range (Q1-Q3))	110 (88 to 123)	114 (97 to 126)	118 (105 to 128)	109 (79 to 123)	-
Systolic BP at admission (mmHg)
Units: mmHg
median (inter-quartile range (Q1-Q3))	89 (71 to 115)	100 (71 to 112)	103 (76 to 114)	90 (65 to 112)	-
BE at admission (mmol/L)
Base Excess
Units: mmol/L
median (inter-quartile range (Q1-Q3))	-4.7 (-9.4 to -3.3)	-9.0 (-12.8 to -4.9)	-9.5 (-13.1 to -4.9)	-8.7 (-11.2 to -5.0)	-
RBCs in 24 hours
Red blood cells
Units: units
median (inter-quartile range (Q1-Q3))	6 (4 to 8)	5 (4 to 9)	6 (4 to 9)	4 (1 to 10)	-
Total blood products in 24h
Units: units
median (inter-quartile range (Q1-Q3))	16 (10 to 19)	13 (9 to 26)	15 (10 to 23)	12 (7 to 29)	-

Subject analysis set title

ITT Placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

The ITT Placebo population includes everyone who was randomised to the Placebo arm, including those who actually received a different treatment than allocated, and those who did not survive or otherwise had no SOFA score at 48h.

Subject analysis set title

ITT Artesunate (Total)

Subject analysis set type

Intention-to-treat

Subject analysis set description

The ITT Artesunate (Total) population includes everyone who was randomised to the Artesunate arms (Low Dose/High Dose), including those who actually received a different treatment than allocated, and those who did not survive or otherwise had no SOFA score at 48h.

Subject analysis set title

ITT Artesunate (Low Dose)

Subject analysis set type

Intention-to-treat

Subject analysis set description

The ITT Artesunate (Low Dose) population includes everyone who was randomised to the Artesunate (Low Dose) arm, including those who actually received a different treatment than allocated, and those who did not survive or otherwise had no SOFA score at 48h.

Subject analysis set title

ITT Artesunate (High Dose)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Safety Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

The safety population is defined as all the patients who were randomised and received any partial dose of IMP. Those patients that did not receive any dose of IMP are not included in this population. Patients were analysed based on actual treatment received.

Subject analysis set title

Safety Artesunate (Total)

Subject analysis set type

Safety analysis

Subject analysis set description

The safety population is defined as all the patients who were randomised and received any partial dose of IMP. Those patients that did not receive any dose of IMP will not be included in this population. Patients will be analysed based on actual treatment received.

Subject analysis set title

Safety Artesunate (Low Dose)

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Safety Artesunate (High Dose)

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis sets values	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)	Safety Placebo	Safety Artesunate (Total)	Safety Artesunate (Low Dose)	Safety Artesunate (High Dose)
Number of subjects	31	54	33	21	29	54	34	20
Age categorical
Units: Subjects
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	26 (18 to 53)	29 (20 to 40)	29 (19 to 39)	29 (23 to 40)	26 (18 to 53)	28 (20 to 39)	28 (19 to 37)	28 (21 to 45)
Gender categorical
Gender
Units: Subjects
Female	1	10	7	3	0	9	6	3
Male	30	44	26	18	29	45	28	17
Mechanism of Injury
Units: Subjects
Blunt	12	27	18	9	12	26	18	8
Penetrating	19	27	15	12	17	28	16	12
Injury Severity Score
Units: Scale
median (inter-quartile range (Q1-Q3))	16 (9 to 29)	19 (13 to 29)	22 (13 to 34)	19 (9 to 27)	17 (9 to 29)	22 (13 to 29)	24 (13 to 34)	19 (10 to 27)
Time to admission (mins)
Units: minute
median (inter-quartile range (Q1-Q3))	86 (55 to 100)	69 (53 to 91)	74 (53 to 93)	64 (53 to 90)	86 (55 to 100)	69 (48 to 91)	74 (57 to 93)	63 (45 to 89)
GCS at admission
Glasgow Coma Score
Units: Scale
median (inter-quartile range (Q1-Q3))	15 (14 to 15)	14 (11 to 15)	14 (9 to 15)	14 (12 to 15)	15 (13 to 15)	14 (12 to 15)	14 (10 to 15)	14 (12 to 15)
HR at admission (bpm)
Heart Rate
Units: beats per minute
median (inter-quartile range (Q1-Q3))	110 (88 to 118)	113 (97 to 127)	118 (105 to 129)	109 (82 to 123)	110 (88 to 118)	113 (97 to 127)	118 (102 to 129)	110 (77 to 125)
Systolic BP at admission (mmHg)
Units: mmHg
median (inter-quartile range (Q1-Q3))	85 (71 to 110)	100 (71 to 110)	103 (80 to 110)	90 (70 to 110)	85 (70 to 115)	96 (71 to 110)	101 (72 to 110)	90 (70 to 110)
BE at admission (mmol/L)
Base Excess
Units: mmol/L
median (inter-quartile range (Q1-Q3))	-4.7 (-7.5 to -3.5)	-9.1 (-13.1 to -4.9)	-9.5 (-13.1 to -4.9)	-8.9 (-13.0 to -5.0)	-4.8 (-8.4 to -3.4)	-8.9 (-12.5 to -4.9)	-8.8 (-12.5 to -4.9)	-8.9 (-15.3 to -5.0)
RBCs in 24 hours
Red blood cells
Units: units
median (inter-quartile range (Q1-Q3))	6 (4 to 8)	5 (3 to 10)	6 (4 to 9)	4 (1 to 11)	6 (4 to 8)	5 (4 to 9)	6 (4 to 9)	4 (1 to 11)
Total blood products in 24h
Units: units
median (inter-quartile range (Q1-Q3))	15 (10 to 19)	13 (9 to 26)	14 (10 to 21)	12 (6 to 29)	16 (10 to 19)	13 (9 to 27)	14 (10 to 23)	13 (7 to 30)

End points

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Reporting group title

PP Placebo

Reporting group description

The placebo comprises buffered diluent drawn up to the volume that would be necessary to reconstitute active IMP according to the subjects’ weight.

Reporting group title

PP Artesunate (Total)

Reporting group description

Reporting group title

PP Artesunate (Low Dose)

Reporting group description

Reporting group title

PP Artesunate (High Dose)

Reporting group description

Reporting group title

Total Randomised Placebo

Reporting group description

The placebo comprises buffered diluent drawn up to the volume that would be necessary to reconstitute active IMP according to the subjects’ weight.

Reporting group title

Total Randomised Artesunate (Total)

Reporting group description

Reporting group title

Total Randomised Artesunate (Low Dose)

Reporting group description

Reporting group title

Total Randomised Artesunate (High Dose)

Reporting group description

Subject analysis set title

ITT Placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

ITT Artesunate (Total)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

ITT Artesunate (Low Dose)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

ITT Artesunate (High Dose)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Safety Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Safety Artesunate (Total)

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Safety Artesunate (Low Dose)

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Safety Artesunate (High Dose)

Subject analysis set type

Safety analysis

Subject analysis set description

Primary: 48-hour SOFA Score

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End point title

48-hour SOFA Score

End point description

48-hour SOFA score

End point type

Primary

End point timeframe

48 hours from admission

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	29	50	33	17
Units: SOFA Score
median (inter-quartile range (Q1-Q3))	4 (2 to 8)	5.5 (2.5 to 10.5)	6 (2 to 11)	5 (3 to 10)	4 (2 to 8)	5 (3 to 10)	5 (3 to 10)	5 (3 to 10)

PP Placebo versus Artesunate (Total)

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.303

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.1

upper limit

0.9

PP Placebo versus Artesunate (Low Dose)

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.411

Method

Wilcoxon (Mann-Whitney)

Confidence interval

PP Placebo versus Artesunate (High Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.326

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.211

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.1

upper limit

0.7

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.297

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.262

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Primary: 48-hour SOFA Score (mean values)

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End point title

48-hour SOFA Score (mean values) ^[1]

End point description

48-hour SOFA Score (mean values)

End point type

Primary

End point timeframe

48 hours

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is a duplicate primary end-point data field in order to report the mean value (in addition to the median values that are already reported). In the SAP, we stated that we would report both the median and the mean central tendencies for the primary outcome measure. The statistical analysis for the primary endpoint is reported under the median value (non-parametric comparison).

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	29	50	33	17
Units: SOFA Score
arithmetic mean (inter-quartile range (Q1-Q3))	5.3 (2.0 to 8.0)	6.4 (2.5 to 10.5)	6.3 (2.0 to 11.0)	6.7 (3.0 to 10.0)	5.1 (2.0 to 8.0)	6.3 (3.0 to 10.0)	6.2 (3.0 to 10.0)	6.7 (3.0 to 10.0)

No statistical analyses for this end point

Secondary: Max SOFA

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End point title

Max SOFA

End point description

Maximum SOFA score during studied period

End point type

Secondary

End point timeframe

Admission to Day 7, Day 28

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	31	52	33	19
Units: SOFA Score
median (inter-quartile range (Q1-Q3))	9 (4 to 10)	10 (5 to 12.5)	10 (5 to 12)	10 (4 to 13)	8 (4 to 10)	10 (5 to 12)	10 (5 to 12)	9 (4 to 13)

PP Placebo versus Artesunate (Total)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.252

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.1

upper limit

0.7

PP Placebo versus Artesunate (Low Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.313

Method

Wilcoxon (Mann-Whitney)

Confidence interval

PP Placebo versus Artesunate (High Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.345

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.112

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

-1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-3.4

upper limit

0.3

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.103

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.34

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Mean SOFA Score

Top of page

End point title

Mean SOFA Score

End point description

Mean SOFA score calculated using scores recorded on days 2-5. Imputations were not performed for missing SOFA scores within this timeframe (e.g. due to death/early discharge) as per the Statistical Analysis Plan (version 2.0, dated 6/8/2018). Patients with missing SOFA scores during this timeframe were therefore excluded from the analysis .

End point type

Secondary

End point timeframe

Day 2 to Day 5

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	29	50	33	17
Units: SOFA Score
median (inter-quartile range (Q1-Q3))	3.3 (2.0 to 8.3)	5.9 (2.3 to 9.0)	5.0 (2.5 to 9.0)	6.3 (1.8 to 8.8)	3.0 (2.0 to 7.5)	5.9 (2.5 to 9.0)	5.0 (2.5 to 9.0)	6.3 (1.8 to 8.8)

PP Placebo versus Artesunate (Total)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.536

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.9

upper limit

1.1

PP Placebo versus Artesunate (Low Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.569

Method

Wilcoxon (Mann-Whitney)

Confidence interval

PP Placebo versus Artesunate (High Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.638

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.344

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.1

upper limit

0.8

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.355

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (Low High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.531

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: CTCOFR Score

Top of page

End point title

CTCOFR Score

End point description

Composite time to organ failure resolution score.

End point type

Secondary

End point timeframe

Admission to Day 14

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	31	54	33	21
Units: CTCOFR Score
median (inter-quartile range (Q1-Q3))	4 (0 to 15)	5 (0 to 15)	6 (0 to 15)	4 (1 to 13)	4 (0 to 15)	5 (0 to 15)	6 (0 to 15)	4 (0 to 15)

PP Placebo versus Artesunate (Total)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.64

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-2.6

upper limit

3.6

PP Placebo versus Artesunate (Low Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.701

Method

Wilcoxon (Mann-Whitney)

Confidence interval

PP Placebo versus Artesunate (High Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.667

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.996

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

2.8

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.989

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.992

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Ventilator Free Days

Top of page

End point title

Ventilator Free Days

End point description

Number of days free from mechanical ventilation out of 28 days

End point type

Secondary

End point timeframe

Admission to Day 28

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	31	54	33	21
Units: day
median (inter-quartile range (Q1-Q3))	26 (12 to 28)	25 (16 to 28)	25 (14 to 28)	26 (19 to 28)	26 (12 to 28)	25 (16 to 28)	25 (15 to 28)	26 (18 to 28)

PP Placebo versus Artesunate (Total)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.591

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-6.2

upper limit

3.2

PP Placebo versus Artesunate (Low Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.768

Method

Wilcoxon (Mann-Whitney)

Confidence interval

PP Placebo versus Artesunate (High Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.474

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.825

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-5.4

upper limit

3.7

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.917

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.758

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Hospital LOS

Top of page

End point title

Hospital LOS

End point description

Hospital Length of Stay

End point type

Secondary

End point timeframe

Admission to Day 28

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	31	54	33	21
Units: day
median (inter-quartile range (Q1-Q3))	28 (10 to 52)	25 (9 to 42)	25 (9 to 43)	26 (9 to 41)	23 (9 to 49)	23 (8 to 40)	25 (10 to 40)	17 (7 to 37)

PP Placebo versus Artesunate (Total)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.77

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-12.2

upper limit

14.6

PP Placebo versus Artesunate (Low Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.779

Method

Wilcoxon (Mann-Whitney)

Confidence interval

PP Placebo versus Artesunate (High Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.838

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.891

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-12.3

upper limit

12.6

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.677

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.391

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: ACCU LOS

Top of page

End point title

ACCU LOS

End point description

Length of stay on the adult critical care unit

End point type

Secondary

End point timeframe

Admission to Day 28

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	31	54	33	21
Units: day
median (inter-quartile range (Q1-Q3))	11 (3 to 24)	8 (5 to 18.5)	8 (5 to 19)	9 (3 to 18)	5 (3 to 22)	7.5 (4 to 18)	8 (5 to 19)	6 (0 to 18)

PP Placebo versus Artesunate (Total)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.736

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

6.3

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

16.2

PP Placebo versus Artesunate (Low Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.87

Method

Wilcoxon (Mann-Whitney)

Confidence interval

PP Placebo versus Artesunate (High Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.629

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

4.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2.9

upper limit

13.7

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.488

Method

Wilcoxon (Mann-Whitney)

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.355

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: Infection

Top of page

End point title

Infection

End point description

Incidence of Infection

End point type

Secondary

End point timeframe

Admission to Day 28

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	31	54	33	21
Units: Infection
Infection	11	19	11	8	11	21	13	8
No Infection	16	29	20	9	20	33	20	13

Placebo versus Artesunate (Total)

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.922

Method

Chi-squared

Confidence interval

Placebo versus Artesunate (Low Dose)

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.681

Method

Chi-squared

Confidence interval

Placebo versus Artesunate (High Dose)

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.68

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.755

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.747

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.848

Method

Chi-squared

Confidence interval

Secondary: Acute Lung Injury

Top of page

End point title

Acute Lung Injury

End point description

Incidence of Acute Lung Injury (Defined as Mild/Moderate/Severe according to Berline Definition)

End point type

Secondary

End point timeframe

Admission to Day 28

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	31	52	33	19
Units: ALI
ALI	20	31	20	11	20	32	21	11
No ALI	7	17	11	8	11	20	12	8

PP Placebo versus Artesunate (Total)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.398

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (Low Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.433

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (High Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.507

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.786

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.942

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.64

Method

Chi-squared

Confidence interval

Secondary: Acue Kidney Injury

Top of page

End point title

Acue Kidney Injury

End point description

Incidence of acute kidney injury (defined as RIFLE Score of 2 or greater)

End point type

Secondary

End point timeframe

Admission to Day 28

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	31	51	33	18
Units: AKI
AKI	20	40	25	15	22	43	27	16
No AKI	17	8	6	2	9	8	6	2

PP Placebo versus Artesunate (Total)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.336

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (Low Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.549

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (High Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.257

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.148

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.306

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.147

Method

Chi-squared

Confidence interval

Secondary: Prolonged Multiple Organ Dysfunction Syndrome

Top of page

End point title

Prolonged Multiple Organ Dysfunction Syndrome

End point description

Incidence of patients with a SOFA>5 on Day 7 after admission

End point type

Secondary

End point timeframe

Day 7

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	26 ^[2]	47 ^[3]	30 ^[4]	17	29	51	32	19
Units: PRMODS
PRMODS	6	10	6	4	6	11	7	4
No PRMODS	20	37	24	13	23	49	25	15

Notes
[2] - 1 patient excluded as died<7 days
[3] - 1 patient excluded as died<7 days
[4] - 1 patient excluded as died<7 days

PP Placebo versus Artesunate (Total)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.859

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (Low Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.78

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (High Dose)

Comparison groups

PP Placebo v PP Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.973

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.941

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.897

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.976

Method

Chi-squared

Confidence interval

Secondary: Mortality (28-day)

Top of page

End point title

Mortality (28-day)

End point description

Mortality at 28 days

End point type

Secondary

End point timeframe

Admission to 28 days

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	31	54	33	21
Units: Mortality
Dead	1	2	2	0	2	4	2	2
Alive	26	46	29	17	29	50	31	19

PP Placebo versus Artesunate (Total)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.922

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (Low Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.637

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (High Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.422

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.868

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 949

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.92

Method

Chi-squared

Confidence interval

Secondary: Mortality (discharge)

Top of page

End point title

Mortality (discharge)

End point description

Mortality at discharge

End point type

Secondary

End point timeframe

Admission to discharge

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	31	54	33	21
Units: mortality
Dead	1	2	2	0	2	4	2	2
Alive	26	46	29	0	29	50	31	19

PP Placebo versus Artesunate (Total)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.922

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (Low Dosel)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.637

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (High Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.422

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.868

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.949

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.92

Method

Chi-squared

Confidence interval

Secondary: Mortality (90 day)

Top of page

End point title

Mortality (90 day)

End point description

Mortality at 90 days after admission

End point type

Secondary

End point timeframe

Admission to 90 days

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	31	54	33	21
Units: mortality
Dead	1	2	1	0	2	4	2	2
Alive	26	46	30	17	29	50	31	19

PP Placebo versus Artesunate (Total)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.922

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (Low Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.637

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (High Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.422

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.868

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.949

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.92

Method

Chi-squared

Confidence interval

Secondary: Alive and Free of MODS

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End point title

Alive and Free of MODS

End point description

Patients who are still alive and free of MODS at the end of 48 hours

End point type

Secondary

End point timeframe

Admission to 48 hours

End point values	PP Placebo	PP Artesunate (Total)	PP Artesunate (Low Dose)	PP Artesunate (High Dose)	ITT Placebo	ITT Artesunate (Total)	ITT Artesunate (Low Dose)	ITT Artesunate (High Dose)
Number of subjects analysed	27	48	31	17	31	54	33	21
Units: MODS
Alive and free of MODS	18	24	15	9	21	28	17	11
Dead or ongoing MODS	9	24	16	8	10	26	16	10

PP Placebo versus Artesunate (Total)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.163

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (Low Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.161

Method

Chi-squared

Confidence interval

PP Placebo versus Artesunate (High Dose)

Statistical analysis description

Per Protocol Analysis

Comparison groups

PP Placebo v PP Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.363

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Total)

Comparison groups

ITT Placebo v ITT Artesunate (Total)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.154

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (Low Dose)

Comparison groups

ITT Placebo v ITT Artesunate (Low Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.187

Method

Chi-squared

Confidence interval

ITT Placebo versus Artesunate (High Dose)

Comparison groups

ITT Placebo v ITT Artesunate (High Dose)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.683

Method

Chi-squared

Confidence interval

Adverse events

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Timeframe for reporting adverse events

Daily from admission to day 28

Adverse event reporting additional description

Clinical research fellows assessed patients for adverse events (AEs) and serious adverse events (SAEs) daily during the monitored study period (admission to day 28). All SAEs were formally recorded on an SAE proforma. The clinical fellow also maintained a daily log of all AEs and followed these up daily to assess for any development into an SAE.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Placebo (Safety Population)

Reporting group description

Placebo comprises buffered diluent drawn up to the volume that would be necessary to reconstitute active IMP according to the subjects’ weight.

Reporting group title

Artesunate (Total) (Safety Population)

Reporting group description

This group comprises all patients who received any partial or complete dose of Artesunate.

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: The study cohort consisted of severely injured trauma patients with major haemorrhage and due to the nature of their injuries, they sustain a high volume of adverse events during the course of their admission. It was therefore agreed with the study sponsor that AEs would be logged by the study team for follow up (to determine if they subsequently develop into SAEs), however formal reporting was not required.

Serious adverse events	Placebo (Safety Population)	Artesunate (Total) (Safety Population)
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 29 (17.24%)	17 / 54 (31.48%)
number of deaths (all causes)	2	3
number of deaths resulting from adverse events	0	0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	1 / 29 (3.45%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Surgical and medical procedures
Iatrogenic vascular injury
Additional description: Iatrogenic vascular injury to L CFA related to REBOA guidewire - thrombus wtihin the left CFA, PFA and R CIA
subjects affected / exposed	0 / 29 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Nervous system disorders
Neurological
Additional description: 1 patient with critical care neuropathy (placebo arm) 1 patient with a cerebral event (tiny cerebral foci of unclear cause)
subjects affected / exposed	1 / 29 (3.45%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Thromboembolic
subjects affected / exposed	1 / 29 (3.45%)	9 / 54 (16.67%)
occurrences causally related to treatment / all	0 / 1	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Organ failure
subjects affected / exposed	1 / 29 (3.45%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Fulminant organ failure
subjects affected / exposed	0 / 29 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory, thoracic and mediastinal disorders
Acute lung injury
subjects affected / exposed	1 / 29 (3.45%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 29 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 29 (3.45%)	2 / 54 (3.70%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 29 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Infection
Additional description: Presence of infection as defined by the criteria by Cole et al., 2014 (Appendix 2 of the Protocol, version 2.1, dated 24/2/2017)
subjects affected / exposed	2 / 29 (6.90%)	2 / 54 (3.70%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Placebo (Safety Population)	Artesunate (Total) (Safety Population)
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 29 (0.00%)	0 / 54 (0.00%)

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

27 May 2016

*Amendment prior to trial start date Change of IMP batch - shelf life stability of diluent. Informed consent - clarity for deceased patients.

25 Apr 2017

*Prior to trial start date Amendement to study co-enrolment policy and inclusion criteria. Change of trial statistician.

29 Mar 2018

IMPD Update: Alteration of inclusion criteria Change of stability protocol Change of batch number Change of label format

28 May 2019

Trial halt- Following a review of trial data during an interim analysis, after enrolment of 75 of the 105 total planned study subjects for the per protocol analysis, the Trial Steering Committee recommended the trial should be terminated early. This was based on the safety analysis performed by the Data Monitoring Committee, which identified the possibility of an increased rate of thrombotic events in the artesunate arm of the trial compared to the placebo arm. The primary outcome analysis at this stage did not identify a treatment benefit to justify continuing the trial to completion.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
01 May 2017	IMP expired - awaiting new batch delivery	29 Sep 2017
01 Jul 2018	Interim Analysis	14 Nov 2018

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

The trial was halted early leading to a reduced sample size.

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Clinical trials

Clinical Trial Results: A randomised, blinded, placebo-controlled Phase 2a study to evaluate the safety and efficacy of Artesunate treatment in severely injured trauma patients with traumatic haemorrhage.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 48-hour SOFA Score

Primary: 48-hour SOFA Score

Primary: 48-hour SOFA Score (mean values)

Primary: 48-hour SOFA Score (mean values)

Secondary: Max SOFA

Secondary: Max SOFA

Secondary: Mean SOFA Score

Secondary: Mean SOFA Score

Secondary: CTCOFR Score

Secondary: CTCOFR Score

Secondary: Ventilator Free Days

Secondary: Ventilator Free Days

Secondary: Hospital LOS

Secondary: Hospital LOS

Secondary: ACCU LOS

Secondary: ACCU LOS

Secondary: Infection

Secondary: Infection

Secondary: Acute Lung Injury

Secondary: Acute Lung Injury

Secondary: Acue Kidney Injury

Secondary: Acue Kidney Injury

Secondary: Prolonged Multiple Organ Dysfunction Syndrome

Secondary: Prolonged Multiple Organ Dysfunction Syndrome

Secondary: Mortality (28-day)

Secondary: Mortality (28-day)

Secondary: Mortality (discharge)

Secondary: Mortality (discharge)

Secondary: Mortality (90 day)

Secondary: Mortality (90 day)

Secondary: Alive and Free of MODS

Secondary: Alive and Free of MODS

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A randomised, blinded, placebo-controlled Phase 2a study to evaluate the safety and efficacy of Artesunate treatment in severely injured trauma patients with traumatic haemorrhage.