Emergency Evaluation of Convalescent Plasma for Ebola Viral Disease (EVD) in Guinea (Ebola-Tx)

• ClinicalTrials.gov Identifier: NCT02342171
• Recruitment Status: Completed
• First Posted: January 19, 2015
• Results First Posted: July 1, 2019
• Last Update Posted: July 22, 2019
• Sponsor: Institute of Tropical Medicine, Belgium
• Collaborators: National Blood Transfusion Centre (NBTC), Conakry, Guinea; Gamal Abdel Nasser University of Conakry; National Center for Training and Research of Maferinyah, Guinea; Institut National de Recherche Biomédicale. Kinshasa, République Démocratique du Congo; University of Oxford; University of Liverpool; London School of Hygiene and Tropical Medicine; Aix Marseille Université; UBIVE, Institut Pasteur, Paris, France; Institut National de la Santé Et de la Recherche Médicale, France; Etablissement Français du Sang; Belgian Red Cross; Institut Pasteur, Dakar, Sénégal; Médecins Sans Frontières, Belgium; World Health Organization; International Severe Acute Respiratory and Emerging Infection Consortium
• Information provided by (Responsible Party): Institute of Tropical Medicine, Belgium

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hemorrhagic Fever, Ebola
• Intervention: Other: Convalescent Plasma
• Enrollment: 606

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Convalescent Plasma	Standard Care
Arm/Group Description	Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg Convalescent Plasma: Patients will be treated with plasma from recovered EVD patients.	The control arm will consist of historical controls having being treated with standard of care
Period Title: Overall Study
Started	99	507
Completed	84	418
Not Completed	15	89
Reason Not Completed
Death	4	87
Received favipiravir	10	0
Missing cycle treshold value	1	0
Unknown outcome	0	1
Missing age data	0	1

Baseline Characteristics

Arm/Group Title		Convalescent Plasma	Standard Care	Total
Arm/Group Description		Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg Convalescent Plasma: Patients will be treated with plasma from recovered EVD patients.	The control arm will consist of historical controls having being treated with standard of care	Total of all reporting groups
Overall Number of Baseline Participants		84	418	502
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	84 participants	418 participants	502 participants
		29; (0 to 75)	28; (0 to 87)	28; (0 to 87)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Age	Number Analyzed	84 participants	418 participants	502 participants
	<5 years	5	23	28
	5-15 years	8	53	61
	16-44 years	56	258	314
	>45 years	15	84	99
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
	Female	48 57.1%	210 50.2%	258 51.4%
	Male	36 42.9%	208 49.8%	244 48.6%
Cycle-threshold on PCR [1]; Median (Full Range); Unit of measure: Number of cycles
	Number Analyzed	84 participants	418 participants	502 participants
		27.3; (19.2 to 35.8)	26.0; (15.2 to 39.4)	26.3; (15.2 to 39.4)
		[1] Measure Description: The value represents the number of cycles the PCR has run before reaching a threshold value of a positive result.
Number of participants per PCR Cycle-threshold interval [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
	<25 cycles	21 25.0%	159 38.0%	180 35.9%
	25.0-29.9 cycles	41 48.8%	183 43.8%	224 44.6%
	>29.9 cycles	22 26.2%	76 18.2%	98 19.5%
		[1] Measure Description: The value represents the number of cycles the PCR has run before reaching a threshold value of a positive result.
Nausea and vomiting; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
		42 50.0%	203 48.6%	245 48.8%
Diarrhea; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
		29 34.5%	155 37.1%	184 36.7%
Weakness or asthenia; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
		77 91.7%	353 84.4%	430 85.7%
Pain; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
		73 86.9%	342 81.8%	415 82.7%
Cough; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
		11 13.1%	40 9.6%	51 10.2%
Difficulty breathing; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
		4 4.8%	11 2.6%	15 3.0%
Difficulty swallowing; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
		15 17.9%	39 9.3%	54 10.8%
Hiccups; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
		7 8.3%	38 9.1%	45 9.0%
Eye redness [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
		34 40.5%	83 19.9%	117 23.3%
		[1] Measure Description: Includes both conjunctivitis and conjunctival bleeding
Unusual bleeding [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
		5 6.0%	21 5.0%	26 5.2%
		[1] Measure Description: Excluding conjunctival bleeding
Disorientation or agitation; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
		0 0.0%	2 0.5%	2 0.4%
Anuria; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
		1 1.2%	1 0.2%	2 0.4%
Seizures; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	418 participants	502 participants
		0 0.0%	1 0.2%	1 0.2%
Duration of symptoms >6 days [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	73 participants	412 participants	485 participants
		14 19.2%	203 49.3%	217 44.7%
		[1] Measure Analysis Population Description: Only including patients with any symptom at baseline
Coexisting chronic medical condition; Measure Type: Count of Participants; Unit of measure: Participants
Infectious	Number Analyzed	84 participants	418 participants	502 participants
		1 1.2%	2 0.5%	3 0.6%
Noninfectious	Number Analyzed	84 participants	418 participants	502 participants
		1 1.2%	3 0.7%	4 0.8%

Outcome Measures

1. Primary Outcome

Title	Survival at Day 14 After Start of Intervention
Description	Effect of convalescent plasma in improving patients survival at day 14; it will be considered clinically significant if there is an absolute decrease in the case fatality rate of 20% or more, compared to SC alone
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Convalescent Plasma	Standard Care
Arm/Group Description:	Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg Convalescent Plasma: Patients will be treated with plasma from recovered EVD patients.	The control arm will consist of historical controls having being treated with standard of care
Overall Number of Participants Analyzed	84	418
Measure Type: Count of Participants; Unit of Measure: Participants
	58 69.0%	260 62.2%

2. Secondary Outcome

Title	Number of Participants With 30 Days Survival
Description	Effect of convalescent plasma in improving patients survival at day 30
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

Outcome was only measured in the intervention group. Data (historical) not available for "Standard care" group.

Arm/Group Title	Convalescent Plasma
Arm/Group Description:	Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg Convalescent Plasma: Patients will be treated with plasma from recovered EVD patients.
Overall Number of Participants Analyzed	84
Measure Type: Count of Participants; Unit of Measure: Participants
	57 67.9%

3. Secondary Outcome

Title	Titer of Ebola Viral RNA
Description	To assess the relationship between EVD antibody levels (EBOV IgG) in donated plasma and the changes in levels of viral RNA in patients who received Convalescent Plasma. The outcome shows the overall association between antibody dose category and change in Cycle threshold (Ct) value pre and post transfusion (Ct is the number of cycles that have to be run before reaching a threshold value of a positive result).
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

Total dose for antibody levels was categorized in three equal-sized groups (tertiles), with the lowest dose category as reference.

71 out of 84 participants were defined as the analysis population. Children (<16 years) were excluded from the analysis as dosing of CP was done according to body weight, which was not recorded for many adult patients.

Arm/Group Title		Convalescent Plasma
Arm/Group Description:		Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg Convalescent Plasma: Patients will be treated with plasma from recovered EVD patients.
Overall Number of Participants Analyzed		71
Mean (95% Confidence Interval); Unit of Measure: Cycles
Lowest dose (antibody range 176.4 - 511.9)	Number Analyzed	24 participants
		1; (1 to 1)
Middle dose (antibody range 513.3 - 740.6)	Number Analyzed	24 participants
		3.24; (0.87 to 5.61)
Highest dose (antibody range 747.9 - 1628.7)	Number Analyzed	23 participants
		2.34; (-0.09 to 4.78)

4. Secondary Outcome

Title	Titer of Ebola Viral RNA
Description	To assess the relationship between EVD antibody levels (neutralizing antibodies) in donated plasma and the changes in levels of viral RNA in patients who received Convalescent Plasma. The outcome shows the overall association between antibody dose category and change in Cycle threshold (Ct) value pre and post transfusion (Ct is the number of cycles that have to be run before reaching a threshold value of a positive result).
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

Total dose for antibody levels was categorized in three equal-sized groups (tertiles), with the lowest dose category as reference.

71 out of 84 participants were defined as the analysis population. Children (<16 years) were excluded from the analysis as dosing of CP was done according to body weight, which was not recorded for many adult patients.

Arm/Group Title		Convalescent Plasma
Arm/Group Description:		Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg Convalescent Plasma: Patients will be treated with plasma from recovered EVD patients.
Overall Number of Participants Analyzed		71
Mean (95% Confidence Interval); Unit of Measure: Cycles
Lowest dose ((antibody range 176.4 - 511.9)	Number Analyzed	24 participants
		1; (1 to 1)
Middle dose (antibody range 513.3 - 740.6)	Number Analyzed	24 participants
		0.30; (-2.30 to 2.90)
Highest dose (antibody range 747.9 - 1628.7)	Number Analyzed	23 participants
		-0.46; (-2.99 to 2.08)

5. Secondary Outcome

Title	Number of Participants Who Died Corresponding to EV Antibody Levels (Anti-EBOV IgG)
Description	To assess the relationship between EVD antibody levels (anti-EBOV IgG) and death in patients who received Convalescent Plasma
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

Overall Number of Participants Analyzed divided in 3 equal groups depending on total dose of antibodies. 71 out of 84 participants were defined as the analysis population. Children (<16 years) were excluded from analysis as dosing of CP was done according to body weight, which was not recorded for many adult patients.

Arm/Group Title		Convalescent Plasma
Arm/Group Description:		Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg Convalescent Plasma: Patients will be treated with plasma from recovered EVD patients.
Overall Number of Participants Analyzed		71
Measure Type: Count of Participants; Unit of Measure: Participants
Low (antibody range 176.4 - 511.9)	Number Analyzed	24 participants
		5 20.8%
Medium (antibody range 513.3 - 740.6)	Number Analyzed	24 participants
		11 45.8%
High (antibody range 747.9 - 1628.7)	Number Analyzed	23 participants
		8 34.8%

6. Secondary Outcome

Title	Number of Participants Who Died Corresponding to EV Antibody Levels (Neutralizing Antibodies)
Description	To assess the relationship between EVD antibody levels (neutralizing antibodies) and death in patients who received CP
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

Overall Number of Participants Analyzed divided in 3 equal groups depending on total dose of antibodies. Children (<16 years) were excluded from analysis as dosing of CP was done according to body weight, which was not recorded for many adult patients.

Arm/Group Title		Convalescent Plasma
Arm/Group Description:		Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg Convalescent Plasma: Patients will be treated with plasma from recovered EVD patients.
Overall Number of Participants Analyzed		71
Measure Type: Count of Participants; Unit of Measure: Participants
Low(antibody range 176.4 - 511.9)	Number Analyzed	24 participants
		6 25.0%
Medium (antibody range 513.3 - 740.6)	Number Analyzed	24 participants
		8 33.3%
High (antibody range 747.9 - 1628.7)	Number Analyzed	23 participants
		10 43.5%

7. Secondary Outcome

Title	Number of Transfusion-related Serious Adverse Reactions (SARs)
Description	To assess the occurrence of serious adverse reactions (SARs) related to CP transfusion in Ebola patients
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Convalescent Plasma
Arm/Group Description:	Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg Convalescent Plasma: Patients will be treated with plasma from recovered EVD patients.
Overall Number of Participants Analyzed	99
Measure Type: Number; Unit of Measure: SARs
	0

8. Secondary Outcome

Title	Number of Professional Safety Incidents
Description	To assess the occurrence of safety risks related to CP transfusion in health workers administering the treatments. This will be observed throughout the study
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

Overall Number of Participants Analyzed refers to health workers administering CP; not to the participants receiving CP.

Arm/Group Title	Convalescent Plasma
Arm/Group Description:	Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg Convalescent Plasma: Patients will be treated with plasma from recovered EVD patients.
Overall Number of Participants Analyzed	12
Measure Type: Number; Unit of Measure: Professional safety incidents
	0

9. Secondary Outcome

Title	Mortality Risk Factor: Ct
Description	To determine Ct as risk factor for mortality despite administration of CP.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

Pre-specified sub-group comparison

Arm/Group Title		Convalescent Plasma	Standard Care
Arm/Group Description:		Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg Convalescent Plasma: Patients will be treated with plasma from recovered EVD patients.	The control arm will consist of historical controls having being treated with standard of care
Overall Number of Participants Analyzed		84	418
Measure Type: Count of Participants; Unit of Measure: Participants
10-24.9 cycles	Number Analyzed	21 participants	159 participants
		11 52.4%	90 56.6%
25-29.9 cycles	Number Analyzed	41 participants	183 participants
		11 26.8%	56 30.6%
30-39.9 cycles	Number Analyzed	22 participants	76 participants
		4 18.2%	12 15.8%

10. Secondary Outcome

Title	Mortality Risk Factor: Age
Description	To determine age as risk factor for mortality despite administration of CP.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

Pre-specified sub-group comparison

Arm/Group Title		Convalescent Plasma	Standard Care
Arm/Group Description:		Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg Convalescent Plasma: Patients will be treated with plasma from recovered EVD patients.	The control arm will consist of historical controls having being treated with standard of care
Overall Number of Participants Analyzed		84	418
Measure Type: Count of Participants; Unit of Measure: Participants
<5 years old	Number Analyzed	5 participants	23 participants
		1 20.0%	15 65.2%
5-15 years old	Number Analyzed	8 participants	53 participants
		1 12.5%	10 18.9%
16-44 years old	Number Analyzed	56 participants	258 participants
		16 28.6%	90 34.9%
>45 years old	Number Analyzed	15 participants	84 participants
		8 53.3%	43 51.2%

Adverse Events

Time Frame	All adverse events related to the intervention up to 4 hours after completion of the transfusion. All deaths possibly related to the intervention up to 14 days after completion of the transfusion.
Adverse Event Reporting Description	Due to the nature of the symptoms of EVD (high mortality rate, hospital admissions, disability and life-threatening conditions), the investigation of safety and tolerability of the intervention will focus on Adverse Reactions. An Adverse Reaction is any untoward and unintended response in a participant to the study treatment, which is related (or has a reasonable possibility of being related) to any dose of the investigational product administered to that participant.
Arm/Group Title	Convalescent Plasma
Arm/Group Description	Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg Convalescent Plasma: Patients will be treated with plasma from recovered EVD patients. No data from "standard care" group available as this is based on historical data.
All-Cause Mortality
	Convalescent Plasma
	Affected / at Risk (%)
Total	26/84 (30.95%)
Serious Adverse Events
	Convalescent Plasma
	Affected / at Risk (%)
Total	0/84 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Convalescent Plasma
	Affected / at Risk (%)
Total	8/84 (9.52%)
General disorders
Increase in temperature *	5/84 (5.95%)
Nausea *	1/84 (1.19%)
Skin and subcutaneous tissue disorders
Itching or skin rash *	4/84 (4.76%)
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

There are clear limitations with respect to the use of a historical control group, and we cannot exclude the possibility that unmeasured confounding factors may have biased the mortality comparison.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Prof. Dr. Johan van Griensven
• Organization: Institute of Tropical Medicine
• Phone: +3232476426
• EMail: jvangriensven@itg.be

Publications of Results:

van Griensven J, Edwards T, de Lamballerie X, Semple MG, Gallian P, Baize S, Horby PW, Raoul H, Magassouba N, Antierens A, Lomas C, Faye O, Sall AA, Fransen K, Buyze J, Ravinetto R, Tiberghien P, Claeys Y, De Crop M, Lynen L, Bah EI, Smith PG, Delamou A, De Weggheleire A, Haba N; Ebola-Tx Consortium. Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea. N Engl J Med. 2016 Jan 7;374(1):33-42. doi: 10.1056/NEJMoa1511812.

van Griensven J, Edwards T, Baize S; Ebola-Tx Consortium. Efficacy of Convalescent Plasma in Relation to Dose of Ebola Virus Antibodies. N Engl J Med. 2016 Dec 8;375(23):2307-2309. doi: 10.1056/NEJMc1609116. Epub 2016 Nov 14.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Edwards T, Semple MG, De Weggheleire A, Claeys Y, De Crop M, Menten J, Ravinetto R, Temmerman S, Lynen L, Bah EI, Smith PG, van Griensven J; Ebola_Tx Consortium. Design and analysis considerations in the Ebola_Tx trial evaluating convalescent plasma in the treatment of Ebola virus disease in Guinea during the 2014-2015 outbreak. Clin Trials. 2016 Feb;13(1):13-21. doi: 10.1177/1740774515621056. Epub 2016 Jan 14.

• Responsible Party: Institute of Tropical Medicine, Belgium
• ClinicalTrials.gov Identifier: NCT02342171
• Other Study ID Numbers: ITM0614
• First Submitted: January 12, 2015
• First Posted: January 19, 2015
• Results First Submitted: December 14, 2017
• Results First Posted: July 1, 2019
• Last Update Posted: July 22, 2019