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

Tracking Information

• First Submitted Date: January 12, 2015
• First Posted Date: January 19, 2015
• Results First Submitted Date: December 14, 2017
• Results First Posted Date: July 1, 2019
• Last Update Posted Date: July 22, 2019
• Study Start Date: February 2015
• Actual Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 8, 2019)

Survival at Day 14 After Start of Intervention [ Time Frame: 14 days ]

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

Original Primary Outcome Measures (submitted: January 14, 2015)

Survival time [ Time Frame: 14 days ]

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

Current Secondary Outcome Measures (submitted: July 2, 2019)

• Number of Participants With 30 Days Survival [ Time Frame: 30 days ]
  Effect of convalescent plasma in improving patients survival at day 30
• Titer of Ebola Viral RNA [ Time Frame: 30 days ]
  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).
• Titer of Ebola Viral RNA [ Time Frame: 30 days ]
  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).
• Number of Participants Who Died Corresponding to EV Antibody Levels (Anti-EBOV IgG) [ Time Frame: 14 days ]
  To assess the relationship between EVD antibody levels (anti-EBOV IgG) and death in patients who received Convalescent Plasma
• Number of Participants Who Died Corresponding to EV Antibody Levels (Neutralizing Antibodies) [ Time Frame: 14 days ]
  To assess the relationship between EVD antibody levels (neutralizing antibodies) and death in patients who received CP
• Number of Transfusion-related Serious Adverse Reactions (SARs) [ Time Frame: 30 days ]
  To assess the occurrence of serious adverse reactions (SARs) related to CP transfusion in Ebola patients
• Number of Professional Safety Incidents [ Time Frame: 9 months ]
  To assess the occurrence of safety risks related to CP transfusion in health workers administering the treatments. This will be observed throughout the study
• Mortality Risk Factor: Ct [ Time Frame: 30 days ]
  To determine Ct as risk factor for mortality despite administration of CP.
• Mortality Risk Factor: Age [ Time Frame: 30 days ]
  To determine age as risk factor for mortality despite administration of CP.

Original Secondary Outcome Measures (submitted: January 14, 2015)

• Survival time [ Time Frame: 30 days ]
  Effect of convalescent plasma in improving patients survival at day 30
• Titer of Ebola viral RNA [ Time Frame: 30 days ]
  To assess the relationship between EVD antibody levels and the changes in levels of viral RNA in patients who received CP
• EV antibody levels [ Time Frame: 14 days ]
  To assess the relationship between EVD antibody levels and survival in patients who received CP
• Number of Transfusion-related Serious Adverse Reactions (SARs) [ Time Frame: 14 days ]
  To assess the occurrence of serious adverse reactions (SARs) related to CP transfusion in Ebola patients
• Number of Professional Safety Incidents [ Time Frame: whole study ]
  To assess the occurrence of safety risks related to CP transfusion in health workers administering the treatments
• Mortality Risk Factors [ Time Frame: whole study ]
  To determine risk factors for mortality despite administration of CP (for identification of patients most likely to benefit)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Emergency Evaluation of Convalescent Plasma for Ebola Viral Disease (EVD) in Guinea
• Official Title: Emergency Evaluation of Convalescent Plasma for Ebola Viral Disease (EVD) in Guinea

Brief Summary

This is an emergency, phase 2/3, open-label, non-randomized, clinical trial that will evaluate Convalescent Plasma (CP) added to standardized supportive care (SC) in patients with confirmed Ebola Virus Disease (EVD). No patient will be refused CP when compatible products are available and all efforts will be made to maximize CP availability during the study. EVD patients recruited during the period before CP becomes available or for whom no compatible CP is available will be given SC and will be followed for study outcomes. Data from these SC patients will be the used as comparator in the analysis of the study. The primary objective of the study is to assess if CP + SC improves the 14 day survival of patients, compared to SC alone.

The Investigators aim to enroll a total number of 130 - 200 patients who will be treated treated with CP assuming equal numbers of patients treated with SC alone. If there would be insufficient patients treated with SC, patients treated at the research site prior to study start may be included in the comparison group.

Patients will be recruited in the Ebola Treatment centre managed by Medecins Sans Frontieres (MSF) in Conakry, Guinea. All patients and/or relatives presenting at the centre will be informed about the study, and will be invited to provide consent at the time of admission inside the treatment centre. Only patients for whom ebola infection is confirmed with polymerase chain reaction (PCR) will be enrolled in the study. After inclusion, eligibility to the intervention will be reassessed on regular intervals. If the eligibility criteria are not met by 48 hours after inclusion, only SC will be continued.

In line with the guidance of the World Health Organization (WHO), two units of CP will be given. EVD patients will be transfused with ABO-compatible CP using standard procedures. Details on the modalities of transfusion can be found in the WHO guidance document and the MSF guidelines on blood transfusion. All patients will be under close observation for transfusion-related adverse reactions during and up to 4 hours after transfusion. 24 hours after the start of transfusion, a blood sample will be collected for viral load assessment. All other aspects of patient management will be according to MSF clinical guidelines. The decision to discharge a patient should be taken on clinical grounds, but can be supported by the laboratory results. After discharge, the patient will be followed up by the study team until day 30.

Detailed Description

West-Africa is being ravaged by the worst outbreak of Ebola Viral Disease (EVD) ever witnessed. Nine months after its onset, the outbreak has spiraled and currently appears to be out of control. One of the key factors contributing to the high mortality is the lack of any proven effective EVD specific treatment. The identification of effective therapies is a medical and public health priority. Convalescent whole blood (CWB) and convalescent plasma (CP) have been prioritized by the World Health Organization (WHO) to be evaluated within a short time span, so that widespread use for therapy could be implemented rapidly if proven effective. Both CWB and CP contain EBV antibodies and either could potentially be of value as EVD therapy, however their efficacy in Ebola must still be demonstrated. .

This is an emergency, phase 2/3, open-label, non-randomized, clinical trial that will evaluate CP added to standardized supportive care (SC) in patients with confirmed EVD. No patient will be refused CP when compatible products are available and all efforts will be made to maximize CP availability during the study. EVD patients recruited during the period before CP becomes available or for whom no compatible CP is available will be given SC and will be followed for study outcomes. Data from these SC patients will be the used as comparator in the analysis of the study.

The primary objective of the study is to assess if CP + SC improves the 14 day survival of patients, compared to SC alone. Secondary objectives are;

• to assess 30 day survival on CP + SC
• to assess the relationship between EV antibody levels in donated CP and survival in patients receiving CP
• to assess the relationship between EV antibody levels in donated CP and changes in levels of viral RNA in the blood of patients receiving CP
• to assess the occurrence of serious adverse reactions (SARs) related to CP transfusion in Ebola patients
• to assess the occurrence of safety risks related to CP transfusion in health workers administering the treatments
• to determine risk factors for mortality despite administration of CP (for identification of patients most likely to benefit)

The Investigators aim to enroll a total number of 130 - 200 patients treated with CP assuming equal numbers of patients treated with SC alone. The number of patients treated with SC will be determined by the time interval for CP to become available for treatment and the availability of CP throughout the study. If there would be insufficient patients treated with SC, patients treated at the research site prior to study start may be included in the comparison group.

Patients will be recruited in the Ebola Treatment centre managed by Medecins Sans Frontieres (MSF) in Conakry. All patients and/or relatives presenting at the centre will be informed about the study, and will be invited to provide consent at the time of admission inside the treatment centre. Only patients for whom ebola infection is confirmed via polymerase chain reaction (PCR) will be enrolled in the study. After inclusion, eligibility to the intervention will be assessed at the time of enrollment (when the patient is moved to the area for patients with confirmed Ebola) and will be reassessed on regular intervals as long as the patient did not receive plasma transfusion. The re-assessment of eligibility to receive CP happens at 8h and at 12h, and is repeated until 48 hours after inclusion. If the eligibility criteria are not met by 48 hours after inclusion, only SC will be continued.

A patient is not eligible to receive CP if they meet one of the following criteria:

• History of allergic reaction to blood or plasma products (as judged by the investigator or treating physician); (this first criterion is definite and will not be re-assessed)
• Medical conditions in which receipt of additional fluid related to the transfusion (250-500 ml or in the case of children 10 ml/kg) may be detrimental to the patient (e.g. decompensated congestive heart failure or renal failure).
• Patients in shock unresponsive to fluid challenge
• Patients in shock with signs of multi-organ failure, defined as oliguria/anuria AND impaired consciousness AND/OR jaundice
• Condition of patient where the procedure of plasma administration carries a risk for the staff

In line with the WHO guidance, two units of CP will be given. EVD patients will be transfused with ABO-compatible CP using standard procedures. Details on the modalities of transfusion can be found in the WHO guidance document and the MSF guidelines on blood transfusion. All patients will be under close observation for transfusion-related adverse reactions during and up to 4 hours after transfusion. 24 hours after the start of transfusion, a blood sample will be collected for viral load assessment. All other aspects of patient management will be according to MSF clinical guidelines.

The decision to discharge a patient should be taken on clinical grounds, but can be supported by the laboratory results. After discharge, the patient will be followed up by the study team until day 30.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• 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

Patients will be treated with plasma from recovered EVD patients.

Study Arms

• Experimental: Convalescent Plasma
  Convalescent Plasma: 400-500 mL from two donors (2 x 200-250 ml) and 10mL/kg for small adults and children <45kg
  Intervention: Other: Convalescent Plasma
• No Intervention: standard care
  The control arm will consist of historical controls having being treated with standard of care

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 8, 2019): 606
• Original Estimated Enrollment (submitted: January 14, 2015): 200
• Actual Study Completion Date: July 2015
• Actual Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• PCR-confirmed, symptomatic infection with Ebola virus
• Patient's, guardian's or representatives' willingness to provide written informed consent

Exclusion Criteria:

A patient is not eligible to receive CP if they meet one of the following criteria:

• History of allergic reaction to blood or plasma products (as judged by the investigator or treating physician);
• Medical conditions in which receipt of additional fluid related to the transfusion (250-500 ml or in the case of children 10 ml/kg) may be detrimental to the patient (e.g. decompensated congestive heart failure or renal failure).
• Patients in shock unresponsive to fluid challenge
• Patients in shock with signs of multi-organ failure, defined as oliguria/anuria AND impaired consciousness AND/OR jaundice
• Condition of patient where the procedure of plasma administration carries a risk for the staff

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Guinea

Administrative Information

• NCT Number: NCT02342171
• Other Study ID Numbers: ITM0614
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Institute of Tropical Medicine, Belgium
• Study 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

Investigators

• Study Chair: Johan van Griensven, MD; ITM
• Principal Investigator: Niankoye Haba, MD; National Blood Transfusion Centre (NBTC), Conakry, Guinea

• PRS Account: Institute of Tropical Medicine, Belgium
• Verification Date: July 2019