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Investigational Therapeutics for the Treatment of People With Ebola Virus Disease

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ClinicalTrials.gov Identifier: NCT03719586
Recruitment Status : Completed
First Posted : October 25, 2018
Results First Posted : September 8, 2021
Last Update Posted : September 8, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Ebola Virus
Interventions Drug: ZMapp
Drug: Remdesivir
Drug: MAb114
Drug: REGN-EB3
Enrollment 681
Recruitment Details Of 681 patients enrolled, one pt was excluded due to a false + PCR result, 50 patients were enrolled prior to addition of the REGN-EB3 arm, and 7 patients underwent randomization during a 2-week period when ZMapp was unavailable. This led to 631 evaluable patients whose timing of enrollment permitted contemporaneous randomization to one of the three study arms versus the control (ZMapp) arm, as stipulated in version 3.0 of the protocol and at outlined in the Statistical Analysis Plan.
Pre-assignment Details Statistical comparisons for efficacy between the three treatment arms and ZMapp as the control arm were limited to those time periods when contemporaneous enrollments could occur. So, for example, comparison between REGN-EB3 recipients and ZMapp recipients were limited to the time period beginning in January 2019 because that is when the REGN-EB3 arm was added as a fourth arm to the study.
Arm/Group Title Arm A: Remdesivir Plus Optimized Standard of Care (oSOC) Arm B: MAb114 Plus Optimized Standard of Care (oSOC) Arm C: REGN-EB3 Plus Optimized Standard of Care (oSOC) Control Arm (D): ZMapp Plus Optimized Standard of Care (oSOC)
Hide Arm/Group Description Remdesivir: Administered intravenously with a loading dose on Day 1 (200 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg one loading dose of remdesivir 5 mg/kg) followed by 9 to 13 days of once-daily maintenance dosing starting on Day 2 and extending through Day 10 to 14 (100 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg remdesivir 2.5 mg/kg) MAb114: 50 mg/kg of body weight administered intravenously on Day 1 as a single infusion REGN-EB3: 150 mg/kg of body weight administered intravenously on Day 1 as a single infusion ZMapp: Three doses of 50 mg/kg of body weight administered intravenously every third day beginning on Day 1
Period Title: Overall Study
Started 177 176 158 [1] 169
Completed 169 [2] 169 [2] 154 [2] 169 [2]
Not Completed 8 7 4 0
Reason Not Completed
"not completed" simply refers to pts who could not be contemporaneously compared to the ZMapp arm             8             7             4             0
[1]
The REGN-EB3 arm was added in 1/2019 after the trial had initially begun in November 2018.
[2]
in 8/2019 the DSMB recommended further randomization only occur to the MAb114 and REGN-EB3 arms.
Arm/Group Title Arm A: Remdesivir Plus Optimized Standard of Care (oSOC) Arm B: MAb114 Plus Optimized Standard of Care (oSOC) Arm C: REGN-EB3 Plus Optimized Standard of Care (oSOC) Control Arm (D): ZMapp Plus Optimized Standard of Care (oSOC) Total
Hide Arm/Group Description Remdesivir: Administered intravenously with a loading dose on Day 1 (200 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg one loading dose of remdesivir 5 mg/kg) followed by 9 to 13 days of once-daily maintenance dosing starting on Day 2 and extending through Day 10 to 14 (100 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg remdesivir 2.5 mg/kg) MAb114: 50 mg/kg of body weight administered intravenously on Day 1 as a single infusion REGN-EB3: 150 mg/kg of body weight administered intravenously on Day 1 as a single infusion ZMapp: Three doses of 50 mg/kg of body weight administered intravenously every third day beginning on Day 1 Total of all reporting groups
Overall Number of Baseline Participants 175 174 155 169 673
Hide Baseline Analysis Population Description
as per the Statistical Analysis Plan, efficacy comparisons between each of the three investigational treatments and the ZMapp control arm were restricted to patients for whom contemporaneous randomization to the study arms was possible.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 175 participants 174 participants 155 participants 169 participants 673 participants
29.6  (17.2) 27.4  (18.5) 28.2  (18.2) 29.7  (16.8) 28.8  (17.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 175 participants 174 participants 155 participants 169 participants 673 participants
Female
98
  56.0%
98
  56.3%
91
  58.7%
87
  51.5%
374
  55.6%
Male
77
  44.0%
76
  43.7%
64
  41.3%
82
  48.5%
299
  44.4%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 175 participants 174 participants 155 participants 169 participants 673 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
175
 100.0%
174
 100.0%
155
 100.0%
169
 100.0%
673
 100.0%
White
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Congo, The Democratic Republic of the Number Analyzed 175 participants 174 participants 155 participants 169 participants 673 participants
175 174 155 169 673
1.Primary Outcome
Title Mortality
Hide Description Number of Participants with Mortality by Day 28
Time Frame 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
patients randomized to receive one of the 4 investigational treatments
Arm/Group Title Arm A: Remdesivir Plus Optimized Standard of Care (oSOC) Arm B: MAb114 Plus Optimized Standard of Care (oSOC) Arm C: REGN-EB3 Plus Optimized Standard of Care (oSOC) Control Arm (D): ZMapp Plus Optimized Standard of Care (oSOC)
Hide Arm/Group Description:
Remdesivir: Administered intravenously with a loading dose on Day 1 (200 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg one loading dose of remdesivir 5 mg/kg) followed by 9 to 13 days of once-daily maintenance dosing starting on Day 2 and extending through Day 10 to 14 (100 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg remdesivir 2.5 mg/kg)
MAb114: 50 mg/kg of body weight administered intravenously on Day 1 as a single infusion
REGN-EB3: 150 mg/kg of body weight administered intravenously on Day 1 as a single infusion
ZMapp: Three doses of 50 mg/kg of body weight administered intravenously every third day beginning on Day 1
Overall Number of Participants Analyzed 175 174 155 169
Measure Type: Number
Unit of Measure: deaths
93 61 52 84
2.Secondary Outcome
Title Time in Days to First Negative Ebola Virus RT-PCR in Blood.
Hide Description This was a measure of the median number of days that it took for the serum PCR to first turn negative after having been positive throughout the patient's earlier course.
Time Frame up to Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
patients in all treatment arms who were randomized contemporaneously with those randomized to the control arm (Arm D).
Arm/Group Title Arm A: Remdesivir Plus Optimized Standard of Care (oSOC) Arm B: MAb114 Plus Optimized Standard of Care (oSOC) Arm C: REGN-EB3 Plus Optimized Standard of Care (oSOC) Control Arm (D): ZMapp Plus Optimized Standard of Care (oSOC)
Hide Arm/Group Description:
Remdesivir: Administered intravenously with a loading dose on Day 1 (200 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg one loading dose of remdesivir 5 mg/kg) followed by 9 to 13 days of once-daily maintenance dosing starting on Day 2 and extending through Day 10 to 14 (100 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg remdesivir 2.5 mg/kg)
MAb114: 50 mg/kg of body weight administered intravenously on Day 1 as a single infusion
REGN-EB3: 150 mg/kg of body weight administered intravenously on Day 1 as a single infusion
ZMapp: Three doses of 50 mg/kg of body weight administered intravenously every third day beginning on Day 1
Overall Number of Participants Analyzed 175 174 155 169
Median (Full Range)
Unit of Measure: Days
NA [1] 
(0 to 28)
16
(0 to 28)
15
(0 to 28)
27
(0 to 28)
[1]
Among patients in the remdesivir group, the estimated median time was actually more than 28 days because mortality exceeded 50% and expired patients were assigned a time of ">28 days".
3.Secondary Outcome
Title Viremia as Determined by CTnp Values on PCR
Hide Description

These are the median CTnp pCR values measured serially on the 4 treatment arms as per protocol.

caveats: Undetectable ctNP values are imputed as ctNP=45.0 (the limit of detection). Missing values (due to gaps in sample collection, discharge, or death) are handled by carrying forward the last observation.

The Day 28 visit includes a ±7-day visit window. The priority for defining the ctNP value for this timepoint, according to days post-randomization, is: 28, 27, 29, 26, 30, 25, 31, 24, 32, 23, 33, 22, 34, 21. For example, the ctNP result from the sample collected 26 days post-randomization will only be used for this timepoint if there are no sample results for 28, 27, or 29 days post-randomization.

Time Frame Days 1, 2, 3, 4, 6, 8, 10, 14, and 28.
Hide Outcome Measure Data
Hide Analysis Population Description
these are the median CTnp PCR measurements performed serially on patients at defined timepoints on the 4 treatment arms
Arm/Group Title Arm A: Remdesivir Plus Optimized Standard of Care (oSOC) Arm B: MAb114 Plus Optimized Standard of Care (oSOC) Arm C: REGN-EB3 Plus Optimized Standard of Care (oSOC) Control Arm (D): ZMapp Plus Optimized Standard of Care (oSOC)
Hide Arm/Group Description:
Remdesivir: Administered intravenously with a loading dose on Day 1 (200 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg one loading dose of remdesivir 5 mg/kg) followed by 9 to 13 days of once-daily maintenance dosing starting on Day 2 and extending through Day 10 to 14 (100 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg remdesivir 2.5 mg/kg)
MAb114: 50 mg/kg of body weight administered intravenously on Day 1 as a single infusion
REGN-EB3: 150 mg/kg of body weight administered intravenously on Day 1 as a single infusion
ZMapp: Three doses of 50 mg/kg of body weight administered intravenously every third day beginning on Day 1
Overall Number of Participants Analyzed 175 174 155 169
Median (Full Range)
Unit of Measure: median CTnp PCR values
ar randomization
23.1
(10 to 45)
23.4
(10 to 45)
22.8
(10 to 45)
23.1
(10 to 45)
Day 1
22.2
(10 to 45)
23.7
(10 to 45)
23.3
(10 to 45)
22.8
(10 to 45)
Day 2
23.0
(10 to 45)
25.1
(10 to 45)
25.2
(10 to 45)
23.7
(10 to 45)
Day 3
23.7
(10 to 45)
28.6
(10 to 45)
28.1
(10 to 45)
24.2
(10 to 45)
Day 4
25.4
(10 to 45)
30.9
(10 to 45)
30.5
(10 to 45)
25.7
(10 to 45)
Day 6
28.6
(10 to 45)
32.7
(10 to 45)
32.7
(10 to 45)
29.4
(10 to 45)
Day 8
30.1
(10 to 45)
34.4
(10 to 45)
34.5
(10 to 45)
32.2
(10 to 45)
Day 10
31.6
(10 to 45)
36.3
(10 to 45)
36.3
(10 to 45)
33.2
(10 to 45)
Day 14
33.2
(10 to 45)
39.1
(10 to 45)
39.8
(10 to 45)
35.2
(10 to 45)
Day 28
37.6
(10 to 45)
45.0
(10 to 45)
45.0
(10 to 45)
38.4
(10 to 45)
4.Secondary Outcome
Title Incidence of Serious Adverse Events/AEs
Hide Description The number of Serious Adverse Events that were tentatively ascribed to one of the four treatment arms by the site investigator and, upon extensive further review and adjudication by an independent Pharmacovigilance committee, were still felt potentially attributable to study drug as opposed to the underlying Ebola infection.
Time Frame up to Day 58
Hide Outcome Measure Data
Hide Analysis Population Description
This table shows the number of SAEs adjudicated to be potentially related to study drug infusion for each of the four study arms. There were 4 SAEs reported in a total of 3 patients.
Arm/Group Title Arm A: Remdesivir Plus Optimized Standard of Care (oSOC) Arm B: MAb114 Plus Optimized Standard of Care (oSOC) Arm C: REGN-EB3 Plus Optimized Standard of Care (oSOC) Control Arm (D): ZMapp Plus Optimized Standard of Care (oSOC)
Hide Arm/Group Description:
Remdesivir: Administered intravenously with a loading dose on Day 1 (200 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg one loading dose of remdesivir 5 mg/kg) followed by 9 to 13 days of once-daily maintenance dosing starting on Day 2 and extending through Day 10 to 14 (100 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg remdesivir 2.5 mg/kg)
MAb114: 50 mg/kg of body weight administered intravenously on Day 1 as a single infusion
REGN-EB3: 150 mg/kg of body weight administered intravenously on Day 1 as a single infusion
ZMapp: Three doses of 50 mg/kg of body weight administered intravenously every third day beginning on Day 1
Overall Number of Participants Analyzed 175 174 155 169
Overall Number of Units Analyzed
Type of Units Analyzed: Doses
1409 171 150 361
Measure Type: Number
Unit of Measure: number of SAEs
1 0 0 3
Time Frame Patients were evaluated from time of randomization (Day 1) through Day 58 of study.
Adverse Event Reporting Description Only SAEs that were felt by site investigators to be possibly study treatment-related and not due to underlying Ebola virus disease were reported, then subjected to rigorous review, additional data collection as necessary, and adjudication by an independent Pharmacovigilance team in order to separate those SAEs still most likely due to underlying Ebola infection from those potentially attributable to infusion(s) of one of the four assigned study drugs.
 
Arm/Group Title Arm A: Remdesivir Plus Optimized Standard of Care (oSOC) Arm B: MAb114 Plus Optimized Standard of Care (oSOC) Arm C: REGN-EB3 Plus Optimized Standard of Care (oSOC) Control Arm (D): ZMapp Plus Optimized Standard of Care (oSOC)
Hide Arm/Group Description Remdesivir: Administered intravenously with a loading dose on Day 1 (200 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg one loading dose of remdesivir 5 mg/kg) followed by 9 to 13 days of once-daily maintenance dosing starting on Day 2 and extending through Day 10 to 14 (100 mg for adults and pediatric patients with body weight >= 40 kg and for pediatric patients weighing < 40 kg remdesivir 2.5 mg/kg) MAb114: 50 mg/kg of body weight administered intravenously on Day 1 as a single infusion REGN-EB3: 150 mg/kg of body weight administered intravenously on Day 1 as a single infusion ZMapp: Three doses of 50 mg/kg of body weight administered intravenously every third day beginning on Day 1
All-Cause Mortality
Arm A: Remdesivir Plus Optimized Standard of Care (oSOC) Arm B: MAb114 Plus Optimized Standard of Care (oSOC) Arm C: REGN-EB3 Plus Optimized Standard of Care (oSOC) Control Arm (D): ZMapp Plus Optimized Standard of Care (oSOC)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   93/175 (53.14%)      61/174 (35.06%)      52/155 (33.55%)      84/169 (49.70%)    
Hide Serious Adverse Events
Arm A: Remdesivir Plus Optimized Standard of Care (oSOC) Arm B: MAb114 Plus Optimized Standard of Care (oSOC) Arm C: REGN-EB3 Plus Optimized Standard of Care (oSOC) Control Arm (D): ZMapp Plus Optimized Standard of Care (oSOC)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/175 (0.57%)      0/174 (0.00%)      0/155 (0.00%)      2/169 (1.18%)    
Gastrointestinal disorders         
death  [1]  1/175 (0.57%)  1 0/174 (0.00%)  0 0/155 (0.00%)  0 2/169 (1.18%)  3
Indicates events were collected by systematic assessment
[1]
4 events leading to death: in 1 patient it was worsening of GI symptoms reported as 2 separate events; in a second pt it was peri-infusional hypotension and hypoxia; in a third patient it was hypotension followed by cardiac arrest.
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Arm A: Remdesivir Plus Optimized Standard of Care (oSOC) Arm B: MAb114 Plus Optimized Standard of Care (oSOC) Arm C: REGN-EB3 Plus Optimized Standard of Care (oSOC) Control Arm (D): ZMapp Plus Optimized Standard of Care (oSOC)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/175 (3.43%)      1/174 (0.57%)      2/155 (1.29%)      6/169 (3.55%)    
Surgical and medical procedures         
incomplete study drug infusion(s)  [1]  6/175 (3.43%)  6 1/174 (0.57%)  1 2/155 (1.29%)  2 6/169 (3.55%)  6
Indicates events were collected by systematic assessment
[1]
These are the number of investigational study drug infusions that were attempted but could not be completed due to various reasons.
By design, efficacy comparisons between the 3 investigational treatment arms and the ZMapp control arm were always restricted to those time periods when both ZMapp and the study drug were available, and there were brief periods when ZMapp became unavailable, accounting for why the total numbers compared between the arms are sometimes lower than the total number of enrolled patients. Also, the REGN-EB3 arm started enrolling later than the other three arms due to a protocol modification.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Richard T. Davey, Jr., M.D., U.S. study PI
Organization: NIAID/NIH
Phone: 301-496-8029
EMail: rdavey@niaid.nih.gov
Layout table for additonal information
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier: NCT03719586    
Other Study ID Numbers: 190003
19-I-0003
First Submitted: October 24, 2018
First Posted: October 25, 2018
Results First Submitted: December 30, 2020
Results First Posted: September 8, 2021
Last Update Posted: September 8, 2021