Key Points
Question
Is the dengue monoclonal antibody (Dengue-mAb) safe and able to neutralize the dengue virus in patients when given as a single-dose intravenous infusion?
Findings
In a randomized clinical trial of 250 adults, treatment with Dengue-mAb demonstrated a rapid clearance of dengue viremia and fever within 24 hours when compared with the placebo group, providing the first clinical evidence of any therapeutic effect against wild-type dengue virus. No safety concerns were observed with administration of Dengue-mAb.
Meaning
These results suggest that the antiviral effect of Dengue-mAb may address the large unmet need of a therapeutic for dengue; these phase 2 study findings warrant further clinical evaluation in a phase 3 study.
This randomized clinical trial examines dengue monoclonal antibody (Dengue-mAb) as a potential therapeutic option for adults infected with dengue virus in India.
Abstract
Importance
Dengue outbreaks are increasing in frequency and intensity. In the absence of any specific treatment, a pan-serotype recombinant monoclonal antibody (Dengue-mAb) was tested in adult patients with dengue as a therapeutic option.
Objective
To assess the safety and effect of a single dose of Dengue-mAb on dengue viremia at different dose levels among patients with dengue.
Design, Setting, and Participants
A phase 2, single-blind, randomized, placebo-controlled clinical trial was conducted from September 19, 2021, to May 13, 2023, at 12 hospitals in India. Study participants were aged 18 to 60 years with dengue and a history of fever onset within 48 hours. Key exclusion criteria were severe dengue, hemoglobin less than 10 g/dL, absolute neutrophil count less than 500/mm3, total leukocyte count less than 1500/mm3, platelet count less than 50 000/mm3, and any other clinically significant disorders. Data were analyzed from January 11, 2024, to March 26, 2024.
Interventions
Participants were randomly allocated 1:1:1:1:1 using an interactive web response system to receive 1 of 4 dose levels of Dengue-mAb (3, 5, 7, or 9 mg/kg) or placebo by slow intravenous infusion.
Main Outcomes and Measures
Primary outcomes were reduction in viremia at 24 hours and causally related serious adverse events (SAEs). Secondary outcomes were RNAemia, fever, and hematologic and pharmacokinetic parameters.
Findings
A total of 250 participants were randomized, with 50 participants in each group. The overall median age was 30 years (IQR, 24-37 years), and 180 participants (72.3%) were male. There were no causally related SAEs. The adjusted mean (SE) viral log reduction at 24 hours was significantly higher with Dengue-mAb—from 1.93 (0.23) with 3 mg/kg (P = .04) to 2.35 (0.27) with 9 mg/kg (P = .003)—compared with placebo (1.29 [0.22]), using a mixed model for repeated measures. Participants with detectable viremia (n = 32) at baseline were negative for dengue virus by 8 hours when treated with a 5- to 9-mg/kg dose of Dengue-mAb compared with 72 hours with placebo. Median time to fever clearance was 3.5 (95% CI, 1.0-24.0) hours (hazard ratio [HR], 2.6 [95% CI, 1.0-6.4]) with Dengue-mAb 5 mg/kg (n = 14) and 2.0 (95% CI, 0.5-6.0) hours (HR, 2.8 [95% CI, 1.2-6.8]) with Dengue-mAb 7 mg/kg (n = 14), compared with 26.8 (95% CI, 1.0-50.5) hours with placebo (n = 12). At 24 hours, between 13 of 14 participants (92.9%; 95% CI, 66.1%-99.8%) with Dengue-mAb (3 mg/kg), 14 of 14 participants (100.0%; 95% CI, 76.8%-100.0%) with Dengue-mAb (5 mg/kg and 7 mg/kg), and 16 of 17 participants (94.1%; 95% CI 71.3%-99.9%) with Dengue-mAb (9 mg/kg); and 7 of 12 participants (58.3%; 95% CI, 27.7%-84.8%) with placebo had fever clearance.
Conclusions and Relevance
In this randomized clinical trial, Dengue-mAb was safe and well tolerated. Dengue-mAb rapidly reduced dengue viremia and fever at doses of 5 mg/kg and 7 mg/kg, making this the first therapeutic against wild-type dengue virus to show preliminary efficacy in humans.
Trial Registration
Clinical Trial Registry-India Identifier: CTRI/2021/07/035290
Introduction
Dengue is a growing global health problem with no specific antidengue virus treatment. Three vaccines (Dengvaxia [Sanofi-Pasteur], Qdenga [Takeda], and Butantan-DV [Butantan Institute]) have been licensed. The vaccine efficacy, however, varied by age and serostatus of the vaccine recipient at baseline and by the dengue virus (DENV) serotype causing the infection.1,2,3 Improvements in case management to reduce the risk of severe dengue are still needed.
Current supportive therapy includes fluid replacement and clinical monitoring.4 No licensed antiviral drug for dengue is available. The association of higher RNAemia levels with severe dengue and rapidly declining RNAemia with reduced risk of clinical outcomes (eg, plasma leakage and severe dengue) support the potential of antiviral drugs in dengue.5
Dengue-mAb (previously, VIS513), an engineered humanized antibody, targets a conserved region of envelope protein domain III.6 In preclinical studies, it demonstrated potent neutralization of all 4 serotypes of DENV and therapeutically protected animals (AG129 mice and cynomolgus macaques) challenged with a lethal dose of DENV.7,8,9 A dose-escalation phase 1 study demonstrated safety in healthy adults.10 This phase 2 study in adult patients with dengue was conducted to determine a safe and efficacious dose.
Methods
Study Design
This randomized, single-blind, placebo-controlled, dose-ranging clinical trial was conducted from September 19, 2021, to May 13, 2023, at 12 tertiary care hospitals in India. The study protocol (Supplement 1) was approved by the Indian regulatory authority and the respective site ethics committees (eTable 1 in Supplement 2). All participants gave written informed consent before their enrollment. The study followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines.11
Participants
Study participants were adults aged 18 to 60 years, with a history of fever, presenting to a hospital within 48 hours from onset, and who had a positive result by rapid dengue nonstructural protein 1 (NS1) antigen test (SD Bioline Dengue Duo, Abbott). Participants were excluded if they had severe dengue, hemoglobin less than 10 g/dL (to convert to g/L, multiply by 10), absolute neutrophil count less than 500/mm3 (to convert to ×109/L, multiply by 0.001), total leukocyte count less than 1500/mm3 (to convert to ×109/L, multiply by 0.001), platelet count less than 50 000/mm3 (to convert to ×109/L, multiply by 1), clinically significant disorders, pregnancy or lactation, history of allergy, or bleeding disorders (Supplement 1).
Randomization and Blinding
Participants were randomly allocated 1:1:1:1:1 using an interactive web-based response system, to receive 1 of 4 dose levels of Dengue-mAb (3 mg/kg, 5 mg/kg, 7 mg/kg, and 9 mg/kg) or placebo. In this single-blind study, participants were masked to treatment allocation, while site staff were aware of treatment allocation. The laboratories analyzing the samples were also masked to treatment allocation.
Study Treatments
Dengue-mAb (manufactured by Serum Institute of India [SIIPL]) in a 30-mL vial containing 25 mg/mL antibody was used. The excipients included histidine, arginine, sodium chloride, sucrose, polysorbate 80, and water for injection. To ensure masking to the participant, the calculated dose of Dengue-mAb was diluted with a formulation buffer to a total volume of 40 mL.
The formulation buffer (manufactured by SIIPL) used as placebo contained all excipients as Dengue-mAb except the antibody in a 30 mL vial. A volume of 40 mL was administered.
Both treatments were administered as a single-dose intravenous infusion over 2 hours using a syringe pump. To minimize the risk of infusion reactions, participants received 1 g of paracetamol before dosing, provided they had not received an antipyretic within the previous 6 hours.
Procedures
Eligible participants were hospitalized for 4 days (96 hours after infusion). They received the treatment on day 1, with follow-up outpatient visits on days 8, 15, 29, 57, 85, 113, and 181. Adverse event (AE) assessments, physical examination, and laboratory testing (hematology and chemistry) were conducted periodically. A subset of 15 participants from each group provided blood samples for pharmacokinetic (PK) assessments. Participants continued to receive the standard of care for dengue as per clinicians’ opinion. The schedule of assessments is described in the protocol (Supplement 1).
Outcomes
The primary outcome measures were the proportion of participants with causally related serious adverse events (SAEs) and viral log reduction (VLR) using NS1 enzyme-linked immunosorbent assay (ELISA)-based 50% tissue culture infectious dose (TCID50) test (NSET) at 24 hours of administration. The primary outcome of VLR was assessed only in a subset of patients with measurable viremia titers at baseline.
The secondary outcome measures included efficacy, safety, and PK end points. The efficacy end points included (1) the viremia-related proportion of participants with negative dengue virus isolation and VLR at 8, 24, 48, 72, 96, and 168 hours; area under the curve up to 96 and 168 hours; and time to negative virus isolation; (2) RNAemia-related VLR at 8, 24, 48, 72, 96, and 168 hours; area under the curve up to 96 and 168 hours; and time to negative RNAemia; (3) time to clearance of fever and proportion of participants with clearance of fever at 24 and 48 hours; (4) proportion of participants progressing to severe dengue; (5) proportion of participants developing either marked thrombocytopenia, leukopenia, or hemoconcentration; and (6) time to clearance of NS1 antigenemia. The safety end points included the proportion of participants with AEs leading to discontinuation of treatment, AEs occurring within 4 hours of infusion start, infusion reactions, lymphopenia, AEs and SAEs throughout the study (up to day 181), clinically significant abnormal hematology and chemistry parameters, and presence of anti–Dengue-mAb antibodies (ADAs) before dosing and at days 29, 85, 113 and 181. The PK assessments were performed before dosing and after infusion completion at 30 minutes, 1 hour, 2 hours, 8 hours, 24 hours, 48 hours, 72 hours, 168 hours, and days 15, 29, 85, 113, and 181.
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (version 2.1; July 2017) was used for severity grading of AEs.12 The safety laboratory tests (hematology and clinical chemistry) were performed at Syngene International, Bengaluru. India.
Study eligibility was based on the rapid NS1 antigen test conducted at the study site, whereas NSET, multiplex quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR), and NS1 ELISA assays were performed at a central laboratory. The viremia and RNAemia in sera samples were estimated by NSET13 and qRT-PCR,14 respectively. Baseline dengue serostatus was assessed in sera samples using dengue immunoglobin (IgG) ELISA15 (Panbio Dengue IgG Capture ELISA, Abbott). Participants with negative results were considered primary dengue cases, whereas those with positive results were secondary dengue cases. Baseline and day 113 neutralizing antibody levels were tested by plaque reduction neutralization test.16 NS1 ELISA was performed using NS1 Ag Microlisa kits (J. Mitra). These assays were performed at the Interactive Research School for Health Affairs, Pune, India (eMethods in Supplement 2).
Time to clearance of fever was defined as the time from the end of treatment (infusion) until the oral temperature dropped to less than 38 °C and remained below this temperature for at least 2 days. On day 1, temperatures were recorded using calibrated thermometers before dosing, at every 30 minutes during infusion, and from end of infusion at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 12 hours. From days 2 to 5, temperatures were monitored at least 4 times daily during hospitalization. Severe dengue was defined according to the World Health Organization 2009 criteria.15
PK parameters and ADAs were estimated using ELISA at Syngene International, Bengaluru, India. ADA response was defined as conversion from negative at baseline to positive or a 2-fold increase in titers in participants who tested positive for ADA at baseline.
Statistical Analysis
Data were analyzed from January 11 to March 26, 2024. A sample size of 25 participants per group gave 80% power for detecting a mean VLR of at least 0.7 for Dengue-mAb compared with the placebo, assuming an SD of 1 and an α of .05.17 We assumed that all participants would have detectable RNAemia by qRT-PCR. However, in the absence of any data on viremia using NSET, we assumed at least 50% would have viremia. Therefore, we recruited 50 participants in each group.
The full analysis population included all randomized participants who received the treatment. This population was used for describing the demographics and other baseline characteristics and safety analyses and served as a supportive population for efficacy analyses. The per-protocol population included all participants who received the assigned study treatment as per randomization with no major protocol deviations. The per-protocol population served as the primary population for efficacy analyses. The PK population included participants who received infusion of Dengue-mAb and had sufficient concentration data to support the accurate estimation of a least 1 PK parameter. Missing data were treated as missing, and no imputation was performed.
The percentage of participants experiencing at least 1 AE was tabulated by treatment group. The VLR for viremia and RNAemia was analyzed using a mixed model for repeated measures with treatment, visit, and treatment-by-visit interaction as fixed effects and the baseline log10-transformed viral load as a covariate. Adjusted mean VLRs were calculated as least squares means (LSMs) and SEs with corresponding 95% CIs. The difference in VLR between each treatment group and placebo was calculated with SEs, 95% CIs, and P values. Participants who had dengue viremia or RNAemia at baseline only were considered for analysis. Time to clearance of fever was summarized using the Kaplan-Meier (KM) method and compared using the log-rank test. Noncompartmental analysis was used to calculate PK parameters. Two-tailed P < .05 was considered statistically significant. Statistical analyses were conducted using SAS, version 9.4 (SAS Institute Inc) for power, efficacy, and safety analyses, and Phoenix WinNonlin, version 8.0 (Certara) for PK analyses.
Results
Baseline Demographic Characteristics
Overall, 288 participants were screened, 38 were excluded at screening, and 250 were randomized. A total of 226 participants (90.8%) completed the study and 23 (9.2%) discontinued. The reasons for discontinuation were consent withdrawal (15 [6.0%]), loss to follow-up (6 [2.4%]), and withdrawal by the investigator (2 [0.8%]) (Figure). One randomized participant (5 mg/kg group) withdrew consent before dosing and was excluded from the full analysis population (n = 249). The per-protocol population included 248 participants.
Figure. Flow Diagram of the Study Participants.
The demographic and baseline characteristics were similar across the groups (Table 1). Overall, the median age of participants was 30 years (IQR, 24-37 years), and mean (SD) weight was 64.5 (12.0) kg. There were 180 male (72.3%) and 69 female (27.7%) participants.
Table 1. Demographics and Baseline Characteristics in the Full Analysis Population.
| Characteristic | Participants, No. (%)a | |||||
|---|---|---|---|---|---|---|
| Placebo (n = 50) | Dengue-mAb group | Overall (N = 249) | ||||
| 3 mg/kg (n = 50) | 5 mg/kg (n = 49) | 7 mg/kg (n = 50) | 9 mg/kg (n = 50) | |||
| Age, median (IQR), y | 33.5 (23-38) | 31 (24-40) | 29 (23-39) | 30 (25-39) | 29 (25-33) | 30 (24-37) |
| Sex | ||||||
| Male | 35 (70.0) | 39 (78.0) | 38 (77.6) | 32 (64.0) | 36 (72.0) | 180 (72.3) |
| Female | 15 (30.0) | 11 (22.0) | 11 (22.4) | 18 (36.0) | 14 (28.0) | 69 (27.7) |
| Weight, mean (SD), kg | 65.16 (12.65) | 64.24 (11.63) | 65.38 (14.16) | 62.99 (10.21) | 64.94 (11.3) | 64.54 (12.0) |
| BMI, mean (SD) | 25.00 (4.52) | 24.37 (3.94) | 24.63 (4.77) | 24.20 (3.9) | 24.99 (4.14) | 24.64 (4.24) |
| Detectable DENV on qRT-PCR | 27 (54.0) | 25 (50.0) | 27 (55.1) | 25 (50.0) | 22 (44.0) | 126 (50.6) |
| Baseline serotypesb | ||||||
| DENV-1 | 8 (16.0) | 10 (20.0) | 12 (24.5) | 14 (28.0) | 5 (10.0) | 49 (19.7) |
| DENV-2 | 19 (38.0) | 13 (26.0) | 17 (34.7) | 11 (22.0) | 16 (32.0) | 76 (30.5) |
| DENV-3 | 7 (14.0) | 9 (18.0) | 8 (16.3) | 7 (14.0) | 6 (12.0) | 37 (14.9) |
| DENV-4 | 0 | 0 | 0 | 0 | 0 | 0 |
| Undetermined | 20 (40.0) | 22 (44.0) | 16 (32.7) | 21 (42.0) | 26 (52.0) | 105 (42.2) |
| Baseline serostatus (IgG ELISA)c | ||||||
| Primary dengue | 29 (58.0) | 30 (60.0) | 33 (67.3) | 29 (58.0) | 30 (60.0) | 151 (60.6) |
| Secondary dengue | 21 (42.0) | 20 (40.0) | 16 (32.7) | 21 (42.0) | 20 (40.0) | 98 (39.4) |
| Baseline NS1 antigen ELISA | ||||||
| Positive | 34 (68.0) | 33 (66.0) | 38 (77.6) | 37 (74.0) | 37 (74.0) | 179 (71.9) |
| Negative | 16 (32.0) | 17 (34.0) | 11 (22.4) | 13 (26.0) | 13 (26.0) | 70 (28.1) |
| Proportion of participants with detectable viremia at baseline | 8 (16.0) | 7 (14.0) | 4 (8.2) | 8 (16.0) | 5 (10.0) | 32 (12.9) |
| Proportion of participants with detectable RNAemia at baseline | 27 (54.0) | 25 (50.0) | 27 (55.1) | 25 (50.0) | 22 (44.0) | 126 (50.6) |
| Proportion of participants with fever (≥38 °C) at baseline | 12 (24.0) | 14 (28.0) | 14 (28.6) | 14 (28.0) | 17 (34.0) | 71 (28.5) |
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); DENV, dengue virus; ELISA, enzyme-linked immunosorbent assay; IgG, immunoglobin; NS1, nonstructural protein 1; qRT-PCR, quantitative reverse transcriptase–polymerase chain reaction.
Unless otherwise specified.
Some participants had more than 1 serotype.
Negative results were considered primary dengue, and positive results were considered secondary dengue.
Among 249 participants, 151 (60.6%) had primary dengue. On qRT-PCR, 126 participants (50.6%) had detectable RNAemia at baseline. DENV-2 was the predominant serotype, followed by DENV-1 and DENV-3 (Table 1). DENV-4 was not isolated in any samples. On NSET, viremia at baseline was detected in 32 participants (12.9%), which were all primary dengue cases.
Primary Outcomes
No participants reported causally related SAEs. For VLR at 24 hours, the differences in adjusted LSMs compared with placebo (n = 8) were 0.77 (95% CI, 0.14-1.39; P = .02), 1.12 (95% CI, 0.39-1.86; P = .003), 1.16 (95% CI, 0.56-1.76; P < .001), and 1.21 (95% CI, 0.52-1.89; P = .001) in the Dengue-mAb 3 mg/kg (n = 7), 5 mg/kg (n = 4), 7 mg/kg (n = 8), and 9 mg/kg (n = 5) groups, respectively (Table 2).
Table 2. Dengue Viremia by NSET in the Per-Protocol Population.
| Variable | Placebo (n = 49) | Dengue-mAb group | |||
|---|---|---|---|---|---|
| 3 mg/kg (n = 50) | 5 mg/kg (n = 49) | 7 mg/kg (n = 50) | 9 mg/kg (n = 50) | ||
| Total No. | 8 | 7 | 4 | 8 | 5 |
| Baseline viremia, geometric mean (95% CI) | 16 822.0 (653.6 to 432 952.9) | 15 835.6 (290.4 to 863 589.2) | 4064.2 (21.1 to 781 605.2) | 7365.2 (667.9 to 81 215.1) | 15 848.9 (225.2 to 1 115 551.5) |
| Adjusted mean viral log reductiona | |||||
| 8 h, No. evaluable | 8 | 7 | 4 | 8 | 5 |
| LSM (SE) [95% CI]b | 1.14 (0.22) [0.72 to 1.57] | 1.91 (0.23) [1.45 to 2.36] | 2.27 (0.31) [1.66 to 2.87] | 2.30 (0.22) [1.88 to 2.73] | 2.35 (0.27) [1.81 to 2.89] |
| Difference (SE) [95% CI]c | NA | 0.77 (0.31) [0.14 to 1.39] | 1.12 (0.37) [0.39 to 1.86] | 1.16 (0.30) [0.56 to 1.76] | 1.21 (0.35) [0.52 to 1.89] |
| P value | NA | .02 | .003 | <.001 | .001 |
| 24 h, No. evaluable | 8 | 7 | 4 | 7 | 5 |
| LSM (SE) [95% CI]b | 1.29 (0.22) [0.86 to 1.71] | 1.93 (0.23) [1.47 to 2.38] | 2.27 (0.31) [1.66 to 2.87] | 2.30 (0.22) [1.87 to 2.74] | 2.35 (0.27) [1.81 to 2.89] |
| Difference (SE) [95% CI]c | NA | 0.64 (0.31) [0.02 to 1.26] | 0.98 (0.37) [0.24 to 1.72] | 1.02 (0.31) [0.41 to 1.63] | 1.06 (0.35) [0.38 to 1.75] |
| P value | NA | .04 | .01 | .001 | .003 |
| 48 h, No. evaluable | 8 | 7 | 4 | 7 | 5 |
| LSM (SE) [95% CI]b | 2.00 (0.22) [1.58 to 2.43] | 1.81 (0.23) [1.35 to 2.26] | 2.27 (0.31) [1.66 to 2.87] | 2.31 (0.23) [1.86 to 2.75] | 2.35 (0.27) [1.81 to 2.89] |
| Difference (SE) [95% CI]c | NA | −0.19 (0.31) [−0.81 to 0.43] | 0.26 (0.37) [−0.47 to 1.00] | 0.31 (0.31) [−0.31 to 0.92] | 0.35 (0.35) [−0.33 to 1.03] |
| P value | NA | .54 | .48 | .33 | .31 |
| 72 h, No. evaluable | 6 | 7 | 4 | 7 | 5 |
| LSM (SE) [95% CI]b | 2.06 (0.23) [1.61 to 2.52] | 2.35 (0.23) [1.90 to 2.81] | 2.27 (0.31) [1.66 to 2.87] | 2.31 (0.23) [1.86 to 2.76] | 2.35 (0.27) [1.81 to 2.89] |
| Difference (SE) [95% CI]c | NA | 0.29 (0.32) [−0.35 to 0.93] | 0.20 (0.38) [−0.55 to 0.96] | 0.24 (0.32) [−0.40 to 0.88] | 0.29 (0.36) [−0.42 to 0.99] |
| P value | NA | .38 | .6 | .45 | .42 |
| 96 h, No. evaluable | 6 | 6 | 4 | 7 | 5 |
| LSM (SE) [95% CI]b | 2.11 (0.24) [1.64 to 2.58] | 2.35 (0.24) [1.88 to 2.82] | 2.27 (0.31) [1.66 to 2.87] | 2.31 (0.23) [1.86 to 2.76] | 2.35 (0.27) [1.81 to 2.89] |
| Difference (SE) [95% CI]c | NA | 0.24 (0.34) [−0.43 to 0.90] | 0.15 (0.39) [−0.61 to 0.92] | 0.19 (0.33) [−0.46 to 0.85] | 0.24 (0.36) [−0.48 to 0.95] |
| P value | NA | .48 | .69 | .56 | .51 |
| 168 h, No. evaluable | 5 | 5 | 2 | 7 | 4 |
| LSM (SE) [95% CI]b | 2.15 (0.25) [1.65 to 2.64] | 2.36 (0.25) [1.87 to 2.84] | 2.28 (0.36) [1.57 to 3.00] | 2.31 (0.23) [1.86 to 2.76] | 2.35 (0.28) [1.80 to 2.91] |
| Difference (SE) [95% CI]c | NA | 0.21 (0.35) [−0.48 to 0.91] | 0.14 (0.44) [−0.74 to 1.01] | 0.16 (0.34) [−0.51 to 0.84] | 0.21 (0.38) [−0.54 to 0.96] |
| P value | NA | .55 | .76 | .63 | .58 |
| Time to negative viremia | |||||
| Median KM estimates (95% CI), h | 16.12 (8.00 to NE) | 8.07 (6.00 to 24.08) | 8.00 (8.00 to NE) | 8.04 (7.03 to 8.17) | 8.13 (8.00 to NE) |
| P valued | NA | .40 | .02 | .05 | .20 |
| Hazard ratio (95% CI) | NA | 1.60 (0.51 to 5.04) | 4.45 (0.94 to 21.14) | 3.11 (0.92 to 10.53) | 2.30 (0.61 to 8.69) |
| Proportion of participants with negative viremia, No. (%) [95% CI]e | |||||
| 8 h | 4 (50.0) [15.7 to 84.3] | 5 (71.4) [29.0 to 96.3] | 4 (100.0) [39.8 to 100.0] | 7 (100.0) [59.0 to 100.0] | 5 (100.0) [47.8 to 100.0] |
| 24 h | 4 (50.0) [15.7 to 84.3] | 6 (85.7) [42.1 to 99.6] | 4 (100.0) [39.8 to 100.0] | 7 (100.0) [59.0 to 100.0] | 5 (100.0) [47.8 to 100.0] |
| 48 h | 6 (75.0) [34.9 to 96.8] | 6 (85.7) [42.1 to 99.6] | 4 (100.0) [39.8 to 100.0] | 7 (100.0) [59.0 to 100.0] | 5 (100.0) [47.8 to 100.0] |
| 72 h | 6 (100.0) [54.1 to 100.0] | 7 (100.0) [59.0 to 100.0] | 4 (100.0) [39.8 to 100.0] | 7 (100.0) [59.0 to 100.0] | 5 (100.0) [47.8 to 100.0] |
| 96 h | 6 (100.0) [54.1 to 100.0] | 6 (100.0) [54.1 to 100.0] | 4 (100.0) [39.8 to 100.0] | 7 (100.0) [59.0 to 100.0] | 5 (100.0) [47.8 to 100.0] |
| 168 h | 5 (100.0) [47.8 to 100.0] | 5 (100.0) [47.8 to 100.0] | 2 (100.0) [15.8 to 100.0] | 7 (100.0) [59.0 to 100.0] | 4 (100.0) [39.8 to 100.0] |
Abbreviations: LSM, least squares mean; KM, Kaplan-Meier; mAb, monoclonal antibody; NA, not applicable; NE, not evaluable; NSET, non-structural protein 1 enzyme-linked immunosorbent assay–based 50% tissue culture infectious dose test; TCID50, 50% tissue culture infectious dose.
Values are expressed in log10 TCID50/mL.
Based on mixed model for repeated measures with treatment, visit, and treatment-by-visit interaction as fixed effects. Baseline log10-transformed viral load value added to the model as covariate.
Estimate of difference in adjusted mean viral log reduction between each treatment group and placebo.
Log-rank test comparing the treatment group vs placebo.
Percentages are calculated based on the evaluable participants at the specific time point. For each treatment group, 95% CIs were estimated using exact binomial method (ie, Clopper-Pearson method).
Secondary Outcomes
Safety
Overall, 58 participants (23.3%) experienced 84 AEs: 10 (20.0%) in placebo, and 10 (20.0%), 12 (24.5%), 10 (20.0%), and 16 (32.0%) in the Dengue-mAb 3, 5, 7, and 9 mg/kg groups, respectively (eTable 2 in Supplement 2). The study drug was temporarily stopped and resumed due to AEs in 10 participants (4.0%; 1, 2, 1, and 6 participants, respectively, in the Dengue-mAb 3, 5, 7, and 9 mg/kg groups). Among these 10 participants, 9 experienced chills, and 1 experienced pain (generalized body ache). The study drug was permanently discontinued in 1 participant in the 7 mg/kg group due to an unrelated AE of fever.
The majority of the AEs were grade 1 or 2 in severity. There were 13 treatment-related AEs, all in the Dengue-mAb groups, that occurred within 4 hours of administration, and all participants recovered without sequelae. Chills were reported in 1 (2.0%), 2 (4.1%), 1 (2.0%), and 5 participants (10.0%) in the Dengue-mAb 3, 5, 7, and 9 mg/kg groups, respectively. Erythema and pruritus were reported in 1 participant (2.0%) in the 5 mg/kg group. Pruritus was reported in 2 participants (4.0%) in the Dengue-mAb 9 mg/kg group.
Three SAEs were reported: 2 extended hospitalizations for continued management of dengue beyond protocol-defined 4-day period (1 each in the 5 mg/kg and 7 mg/kg groups) and 1 acid peptic disease (7 mg/kg group). All SAEs recovered without sequelae, and none were related to Dengue-mAb.
Eight participants (16.0%) in the placebo group and 37 (18.6%) in the Dengue-mAb groups showed an ADA response, most of which were transient. Persistent ADA response was observed in 1 participant (12.5%) in the placebo group and 16 participants (8.0%) in the Dengue-mAb groups (eTable 3 in Supplement 2). Dengue neutralizing antibody titers were not affected by treatment with Dengue mAb (eTable 9 in Supplement 2).
Preliminary Efficacy
Viremia
At 8 hours, the adjusted LSMs for VLR were significantly higher in all Dengue-mAb groups (3 mg/kg [n = 7]: 1.91 [95% CI, 1.45-2.36]; P = .02; 5 mg/kg [n = 4]: 2.27 [95% CI, 1.66-2.87]; P = .003; 7 mg/kg [n = 8]: 2.30 [95% CI, 1.88-2.73]; P < .001; and 9 mg/kg [n = 5]: 2.35 [95% CI, 1.81-2.89]; P = .001) than in the placebo group (n = 8; 1.14 [95% CI, 0.72-1.57]), whereas no significant differences were observed after 48 hours (Table 2). At 8 hours, compared with 4 participants (50%) in the placebo group, 5 (71.4%) in Dengue-mAb 3 mg/kg group and all participants (100%) in the Dengue-mAb 5 mg/kg (n = 4), 7 mg/kg (n = 8), and 9 mg/kg (n = 5) groups were negative for viremia. All participants were negative for viremia at 72 hours in the placebo (n = 8) and Dengue-mAb 3 mg/kg (n = 7) groups (Table 2). The median KM estimate for time to negative viremia was significantly lower with Dengue-mAb compared with placebo (5 mg/kg group: hazard ratio [HR], 4.45; 95% CI, 0.94-21.14; P = .02); 7 mg/kg group: HR, 3.11; 95% CI, 0.92-10.53; P = .05) (Table 2 and eFigure 3 in Supplement 2). The decline in viremia titers was faster in Dengue mAb groups compared with placebo (eFigure 1 in Supplement 2).
RNAemia
Among the patients with RNAemia at baseline, at 24 hours, the LSMs of VLR in RNAemia were significantly higher in the Dengue-mAb 5 mg/kg (n = 25; 2.03 [95% CI, 1.55-2.52]; P = .05), 7 mg/kg (n = 24; 2.10 [95% CI, 1.60-2.61]; P = .03), and 9 mg/kg (n = 22; 2.06 [95% CI, 1.53-2.59]; P = .05) groups compared with placebo (n = 27; 1.33 [95% CI, 0.85-1.81]) (Table 3). No significant differences in the VLR in RNAemia were observed between the placebo and Dengue mAb groups at 8, 48, 72, 96, and 168 hours (Table 3). The median KM estimate for time to negative RNAemia was lower but not statistically significant with Dengue-mAb compared with placebo (Table 3 and eFigure 4 in Supplement 2). The decline in RNAemia titers was faster in Dengue mAb groups compared with placebo upto 48 hours (eFigure 2 in Supplement 2).
Table 3. Dengue RNAemia by qRT-PCR in the Per-Protocol Population.
| Variable | Placebo (n = 49) | Dengue-mAb group | |||
|---|---|---|---|---|---|
| 3 mg/kg (n = 50) | 5 mg/kg (n = 49) | 7 mg/kg (n = 50) | 9 mg/kg (n = 50) | ||
| Total No. | 27 | 25 | 27 | 25 | 22 |
| Baseline RNAemia, geometric mean (95% CI) | 2053.2 (460.9 to 9147.0) | 3304.9 (941.9 to 11596.5) | 896.0 (259.1 to 3098.4) | 713.0 (152.8 to 3327.8) | 984.6 (227.3 to 4264.7) |
| Adjusted mean viral log reductiona | |||||
| 8 h, No. evaluable | 27 | 24 | 26 | 24 | 22 |
| LSM (SE) [95% CI]b | 1.64 (0.24) [1.16 to 2.12] | 1.77 (0.26) [1.27 to 2.28] | 2.27 (0.25) [1.78 to 2.75] | 1.74 (0.26) [1.23 to 2.24] | 2.01 (0.27) [1.48 to 2.54] |
| Difference (SE) [95% CI]c | NA | 0.13 (0.35) [−0.56 to 0.83] | 0.63 (0.35) [−0.06 to 1.31] | 0.10 (0.35) [−0.60 to 0.79] | 0.37 (0.36) [−0.35 to 1.08] |
| P value | NA | .71 | .07 | .79 | .31 |
| 24 h, No. evaluable | 27 | 24 | 25 | 24 | 22 |
| LSM (SE) [95% CI]b | 1.33 (0.24) [0.85 to 1.81] | 1.93 (0.26) [1.42 to 2.43] | 2.03 (0.25) [1.55 to 2.52] | 2.10 (0.26) [1.60 to 2.61] | 2.06 (0.27) [1.53 to 2.59] |
| Difference (SE) [95% CI]c | NA | 0.59 (0.35) [−0.10 to 1.29] | 0.70 (0.35) [0.02 to 1.38] | 0.77 (0.35) [0.07 to 1.46] | 0.73 (0.36) [0.02 to 1.45] |
| P value | NA | .09 | .05 | .03 | .05 |
| 48 h, No. evaluable | 27 | 24 | 27 | 24 | 22 |
| LSM (SE) [95% CI]b | 2.33 (0.24) [1.85 to 2.81] | 2.42 (0.26) [1.91 to 2.92] | 2.80 (0.24) [2.32 to 3.28] | 2.87 (0.26) [2.37 to 3.38] | 2.67 (0.27) [2.14 to 3.20] |
| Difference (SE) [95% CI]c | NA | 0.09 (0.35) [−0.61 to 0.78] | 0.47 (0.35) [−0.21 to 1.15] | 0.54 (0.36) [−0.15 to 1.24] | 0.34 (0.36) [−0.38 to 1.05] |
| P value | NA | .81 | .17 | .13 | .35 |
| 72 h (evaluable), No. | 25 | 25 | 26 | 24 | 21 |
| LSM (SE) [95% CI]b | 2.45 (0.25) [1.96 to 2.94] | 2.58 (0.25) [2.08 to 3.08] | 2.82 (0.25) [2.34 to 3.31] | 3.22 (0.26) [2.71 to 3.73] | 3.10 (0.27) [2.57 to 3.64] |
| Difference (SE) [95% CI]c | NA | 0.13 (0.36) [−0.57 to 0.82] | 0.37 (0.35) [−0.32 to 1.06] | 0.76 (0.36) [0.06 to 1.47] | 0.65 (0.37) [−0.08 to 1.38] |
| P value | NA | .72 | .29 | .03 | .08 |
| 96 h, No. evaluable | 24 | 24 | 26 | 24 | 21 |
| LSM (SE) [95% CI]b | 2.96 (0.25) [2.46 to 3.46] | 2.92 (0.26) [2.41 to 3.42] | 3.12 (0.25) [2.64 to 3.61] | 3.19 (0.26) [2.69 to 3.70] | 3.21 (0.27) [2.67 to 3.75] |
| Difference (SE) [95% CI]c | NA | −0.04 (0.36) [−0.75 to 0.67] | 0.16 (0.36) [−0.53 to 0.86] | 0.24 (0.36) [−0.48 to 0.95] | 0.25 (0.37) [−0.48 to 0.99] |
| P value | NA | .91 | .64 | .51 | .50 |
| 168 h, No. evaluable | 21 | 22 | 21 | 23 | 19 |
| LSM (SE) [95% CI]b | 3.47 (0.27) [2.94 to 3.99] | 3.43 (0.26) [2.91 to 3.94] | 3.07 (0.26) [2.56 to 3.58] | 3.40 (0.26) [2.89 to 3.92] | 3.32 (0.28) [2.77 to 3.87] |
| Difference (SE) [95% CI]c | NA | −0.04 (0.37) [−0.77 to 0.69] | −0.40 (0.37) [−1.13 to 0.34] | −0.06 (0.37) [−0.79 to 0.67] | −0.14 (0.39) [−0.90 to 0.61] |
| P value | NA | .92 | .29 | .87 | .71 |
| Time to negative RNAemia | |||||
| Median KM, estimates (95% CI), h | 168.00 (48.58 to 336.22) | 96.17 (24.15 to 169.00) | 48.08 (8.10 to 168.13) | 48.17 (24.28 to 72.08) | 60.17 (8.15 to 349.50) |
| P valued | NA | .19 | .24 | .04 | .76 |
| Hazard ratio (95% CI) | NA | 1.51 (0.80 to 2.83) | 1.45 (0.77 to 2.71) | 1.91 (1.03 to 3.54) | 1.11 (0.57 to 2.14) |
| Proportion of participants with negative RNAemia, No. (%) [95% CI]e | |||||
| 8 h | 5 (18.5) [6.3 to 38.1] | 6 (25.0) [9.8 to 46.7] | 9 (34.6) [17.2 to 55.7] | 7 (29.2) [12.6 to 51.1] | 7 (31.8) [13.9 to 54.9] |
| 24 h | 2 (7.4) [0.9 to 24.3] | 7 (29.2) [12.6 to 51.1] | 7 (28.0) [12.1 to 49.4] | 6 (25.0) [9.8 to 46.7] | 5 (22.7) [7.8 to 45.4] |
| 48 h | 7 (25.9) [11.1 to 46.3] | 9 (37.5) [18.8 to 59.4] | 14 (51.9) [32.0 to 71.3] | 13 (54.2) [32.8 to 74.4] | 9 (40.9) [20.7 to 63.6] |
| 72 h | 7 (28.0) [12.1 to 49.4] | 8 (32.0) [15.0 to 53.5] | 14 (53.8) [33.4 to 73.4] | 17 (70.8) [48.9 to 87.4] | 10 (47.6) [25.7 to 70.2] |
| 96 h | 9 (37.5) [18.8 to 59.4] | 9 (37.5) [18.8 to 59.4] | 16 (61.5) [40.6 to 79.8] | 14 (58.3) [36.6 to 77.9] | 13 (61.9) [38.4 to 81.9] |
| 168 h | 11 (52.4) [29.8 to 74.3] | 16 (72.7) [49.8 to 89.3] | 14 (66.7) [43.0 to 85.4] | 18 (78.3) [56.3 to 92.5] | 13 (68.4) [43.4 to 87.4] |
Abbreviations: LSM, least squares mean; KM, Kaplan-Meier; mAb, monoclonal antibody; NA, not applicable; PFU, plaque forming unit; qRT-PCR, quantitative reverse transcriptase–polymerase chain reaction.
Values are expressed in PFU/mL.
Based on mixed model for repeated measures with treatment, visit, and treatment-by-visit interaction as fixed effects. Baseline log10-transformed viral load value added to the model as covariate.
Estimate of difference in adjusted mean viral log reduction between each treatment group and placebo.
Log-rank test comparing the treatment group vs placebo.
Percentages are calculated based on the evaluable participants at the specific time point. For each treatment group, 95% CIs were estimated using exact binomial method (ie, Clopper-Pearson method).
Fever
Paracetamol was recorded as prior medication (within the previous 6 hours) in 2 participants in the Dengue-mAb 7 mg/kg group and 1 participant in the Dengue-mAb 9 mg/kg group. All other participants received paracetamol as a premedication about 30 minutes before the infusion. Fever at baseline was reported in 12 participants (24.5%) in the placebo group and ranged from 14 (28.0%) to 17 (34.0%) in the Dengue-mAb groups (Table 4).
Table 4. Fever Clearance in the Per-Protocol Population.
| Variable | Placebo (n = 49) | Dengue-mAb group | |||
|---|---|---|---|---|---|
| 3 mg/kg (n = 50) | 5 mg/kg (n = 49) | 7 mg/kg (n = 50) | 9 mg/kg (n = 50) | ||
| Participants with fever at baseline, No. | 12 | 14 | 14 | 14 | 17 |
| Time to clearance of fever | |||||
| Median KM estimate (95% CI), h | 26.79 (1.02-50.50) | 16.06 (1.03-35.97) | 3.51 (1.00-24.05) | 2.00 (0.50-6.00) | 8.03 (1.00-30.00) |
| P valuea | NA | .29 | .03 | .02 | .12 |
| Hazard ratio (95% CI) | NA | 1.56 (0.68-3.57) | 2.56 (1.03-6.37) | 2.83 (1.17-6.84) | 1.90 (0.83-4.35) |
| Proportion of participants with fever clearance at 24 and 48 h | |||||
| 24 h, No. (%) [95% CI] | 7 (58.3) [27.7-84.8] | 13 (92.9) [66.1-99.8] | 14 (100.0) [76.8-100.0] | 14 (100.0) [76.8-100.0] | 16 (94.1) [71.3-99.8] |
| 48 h, No. (%) [95% CI] | 10 (83.3) [51.6-97.9] | 13 (92.9) [66.1-99.8] | 14 (100.0) [76.8-100.0] | 14 (100.0) [76.8-100.0] | 17 (100.0) [80.5-100.0] |
Abbreviations: KM, Kaplan-Meier; mAb, monoclonal antibody; NA, not applicable.
Log-rank test comparing the treatment group vs placebo.
Time to clearance of fever was significantly lower in the Dengue-mAb 5 mg/kg group (HR, 2.56; 95% CI, 1.03-6.37; P = .03) and the 7 mg/kg group (HR, 2.83; 95% CI, 1.17-6.84; P = .02) compared with the placebo group. At 24 hours, clearance of fever occurred in 7 participants (58.3%) in placebo group and ranged from 13 (92.9%) to 17 (100%) in the Dengue-mAb groups (Table 4). Similar effect on fever clearance was seen in participants with positive NS1 ELISA or qRT-PCR at baseline (eTables 5 and 6 in Supplement 2).
Other Efficacy End Points
No participant progressed to severe dengue. The proportion of participants developing either marked thrombocytopenia, leukopenia, or hemoconcentration was 20 participants (40.8%) in the placebo group and ranged from 13 (26.0%) to 14 (28.0%) in the Dengue-mAb groups (eTable 8 in Supplement 2). The median KM estimated time to clearance of NS1 antigenemia based on rapid NS1 antigen test was 72 hours across the groups (eTable 7 in Supplement 2). There was a more rapid recovery of platelet counts and less increase in hematocrit in Dengue mAb groups compared with placebo, although these differences were not statistically significant (eFigures 5 and 6 in Supplement 2).
Pharmacokinetics
Maximum concentrations of Dengue-mAb occurred at a median time of approximately 1 to 8 hours across the dose range, with no dose-dependent trend observed. Thereafter, concentrations declined and remained quantifiable until the last sampling time (4320 hours). The geometric mean half-life was similar across the groups (438 to 557 hours), except for 9 mg/kg group (204 hours). Clearance was dose independent across the 3-mg/kg to 7-mg/kg groups (eTable 4 in Supplement 2).
Discussion
This first-in-patient phase 2 randomized clinical trial demonstrated the safety of Dengue-mAb and its action on the clearance of dengue virus and fever. This is, to our knowledge, the first evidence of a preliminary therapeutic effect in patients with dengue.
Previously, several drugs,18 including celgosivir,17 ivermectin,19 chloroquine,20 prednisolone,21 lovastatin,22 and balapiravir,23 have been empirically tested in patients with dengue and have not shown any antiviral activity. Dengue-mAb showed reduction in viremia as early as 8 hours and in RNAemia at 24 hours compared with placebo. Its antiviral activity was earlier demonstrated in a non-human primate challenge model. Our findings suggest this antiviral activity extends to patients with dengue.8
The earlier dengue therapeutic studies used RT-PCR for evaluation of RNAemia; however, this study may be the first to use viremia as well as RNAemia for assessment. NSET detects the replicating dengue virus by measuring the NS1 protein (produced only by the live virus) by ELISA in the supernatant of cell culture. It is validated against the plaque assay. The plaque assay is known to be less sensitive for heterogeneous wild-type dengue viruses, as the plaque-forming ability may be different for each strain.8 NSET may be more sensitive than plaque assay.24
The frequent assessments for viremia, RNAemia, fever, and hematological parameters allowed us to assess their trend in treatment groups. This effect was studied both in primary and secondary dengue cases. Viremia and RNAemia clears faster in secondary dengue cases.25,26 In addition, the reduction in viremia and RNAemia with Dengue-mAb was accompanied by faster fever clearance, demonstrating the known correlation of fever and viremia.27 Although the number of patients is small, the observed significant reductions in viremia, RNAemia, and fever clearance may lead to reduction in severity of illness and decline in transmission of dengue.28,29
Limitations
This study has a few limitations. Baseline viremia (12.9%) and RNAemia (50.6%) were very low against the assumption of 50% viremia and 100% RNAemia at baseline. Thus, the study was underpowered to make robust conclusions. The baseline viremia and RNAemia suggest that many participants arrived for treatment later than 48 hours after fever onset; therefore, the peak of viremia or RNAemia might have been missed in many participants. The history of fever onset was based on participants’ memory recall, and a defined start time could not be established. This lack of recall is a limitation for dengue therapeutic studies, especially in developing countries, because most people with fever usually self-medicate initially and seek intervention only when the symptoms are not resolving.
There was discordance in the results between the rapid NS1 antigen test, NS1 ELISA, and qRT-PCR. All patients had a clinical picture suggestive of dengue during the active season and were clinically diagnosed by a physician as having dengue. Despite known high specificity of the SD Bioline Dengue Duo kits for NS1 antigen (98.4%),30 the specificity of rapid NS1 antigen tests, in general, has been reported to range from 73% to 90%.31 The detection rate by NS1 ELISA (71.9%) and qRT-PCR (50.6%) indicates the possibility of few false-positive cases. qRT-PCR was performed using the Centers for Disease Control and Prevention (CDC) assay following a previously published methodology.14 The low detection rate and sensitivity observed in the present study might have been due to mismatch in sequence between the primers and probes (designed with DENV sequences available up to 2012) and the currently circulating DENV strains. Lower clinical sensitivity of the CDC qRT-PCR assay, particularly for detection of emerging and contemporary DENV strains, has been reported previously.32,33 For NSET, the live dengue virus may grow better in C6/36 cell culture than in Vero cell culture, and the use of C6/36 cells might increase sensitivity.34 For the ongoing phase 3 study, C6/36 cells will be used for NSET, and updated primers and probes (designed by including contemporary DENV sequences) will be used for qRT-PCR.
An additional limitation was the single-blind design, in which the study personnel were aware of the treatment assignments. However, efficacy outcomes were objective in nature, and the analyzing laboratories were masked to treatment allocation. Moreover, after dilution with formulation buffer, the Dengue-mAb was largely indistinguishable from placebo.
The efficacy data were analyzed only in patients with baseline viremia and RNAemia. Therefore, the interpretation of efficacy results was not impacted by suspected false-positive dengue cases. In addition, very few self-limiting, transient, treatment-related AEs were reported, suggesting that the suspected false-positive cases did not affect the interpretation of safety outcomes. The incidence of adverse reactions was substantially lower in the present study (1.2%) compared with the phase 1 study (20.0%). ADA development is possible and is reported with other humanized mAbs.35 Considering that both the placebo and Dengue-mAb groups showed ADA, there may be some cross-reactive antibodies detected by the assay. The effect of ADA on redosing in cases of subsequent episode of dengue is not known and may need further evaluation.
The dose-dependent PK results seen in the phase 1 study in healthy participants were not seen in this study.10 The lower half-life in this study was probably due to use of Dengue-mAb in virus neutralization and the variable baseline viral loads across the groups.
Conclusions
In this randomized clinical trial, treatment with Dengue-mAb was safe in adults with dengue and demonstrated a reduction in viremia and RNAemia as well as rapid fever clearance. These preliminary findings will be confirmed in an ongoing phase 3 study.
Trial Protocol
eTable 1. Ethics Committee Approvals
eMethods. Description of Assays
eTable 2. Adverse Events (Full Analysis Population)
eTable 3. Anti-Drug Antibody (ADA) Response (Full Analysis Population)
eTable 4. Geometric mean (Geometric CV%) Serum Pharmacokinetic Parameters of Dengue-mAb (Pharmacokinetic Population)
eTable 5. Effect on Fever in Baseline NS1 ELISA Positive Participants (Per Protocol Population)
eTable 6. Effect on Fever in Baseline qRT-PCR Positive Participants (Per Protocol Population)
eTable 7. Time to Clearance of NS1 Antigenemia (Rapid NS1 Test) Through 14 Days (Per Protocol Population)
eTable 8. Proportion of Participants with Either Marked Thrombocytopenia, Leukopenia or Hemoconcentration (Per Protocol Population)
eTable 9. PRNT50 Titres against Dengue Serotypes (Full Analysis Population)
eFigure 1. Viremia Titres Assessed by NSET (Per Protocol Population)
eFigure 2. RNAemia Titres Assessed by qRT-PCR (Per Protocol Population)
eFigure 3. Kaplan-Meier Plot of Time to Negative Dengue Virus Isolation Assessed by NSET (Per Protocol Population)
eFigure 4. Kaplan-Meier Plot of Time to Negative Dengue RNAemia Assessed by qRT-PCR (Per Protocol Population)
eFigure 5. Line Plot of Mean of Platelets (Full Analysis Population)
eFigure 6. Line Plot of Mean of Hematocrit (Ratio) (Full Analysis Population)
Nonauthor Collaborators
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eTable 1. Ethics Committee Approvals
eMethods. Description of Assays
eTable 2. Adverse Events (Full Analysis Population)
eTable 3. Anti-Drug Antibody (ADA) Response (Full Analysis Population)
eTable 4. Geometric mean (Geometric CV%) Serum Pharmacokinetic Parameters of Dengue-mAb (Pharmacokinetic Population)
eTable 5. Effect on Fever in Baseline NS1 ELISA Positive Participants (Per Protocol Population)
eTable 6. Effect on Fever in Baseline qRT-PCR Positive Participants (Per Protocol Population)
eTable 7. Time to Clearance of NS1 Antigenemia (Rapid NS1 Test) Through 14 Days (Per Protocol Population)
eTable 8. Proportion of Participants with Either Marked Thrombocytopenia, Leukopenia or Hemoconcentration (Per Protocol Population)
eTable 9. PRNT50 Titres against Dengue Serotypes (Full Analysis Population)
eFigure 1. Viremia Titres Assessed by NSET (Per Protocol Population)
eFigure 2. RNAemia Titres Assessed by qRT-PCR (Per Protocol Population)
eFigure 3. Kaplan-Meier Plot of Time to Negative Dengue Virus Isolation Assessed by NSET (Per Protocol Population)
eFigure 4. Kaplan-Meier Plot of Time to Negative Dengue RNAemia Assessed by qRT-PCR (Per Protocol Population)
eFigure 5. Line Plot of Mean of Platelets (Full Analysis Population)
eFigure 6. Line Plot of Mean of Hematocrit (Ratio) (Full Analysis Population)
Nonauthor Collaborators
Data Sharing Statement
