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A total of 100 subjects were screened and 60 were randomized to Groups A–C. One participant refused blood sample collection on day 42 and was therefore designated as lost to follow-up. Except for one participant in Group A who did not complete the follow-up, there were no other protocol violations/deviations (Figure 1).
There was no significant difference in the demographic characteristics among the three groups (Table 1). The average age of the subjects was 37.73 ± 9.04 years, and there was no significant difference among the groups. Subjects were mainly women (33, 55.0%), and the mean weight was 68.10 ± 12.26 kg. No missing baseline data were reported.
Characteristics Group Group A
(n = 20)Group B
(n = 20)Group C
(n = 20)Total
(n = 60)Statistic/P Age, y (mean ± SD) 35.05 ± 9.23 38.17 ± 9.18 39.96 ± 8.44 37.73 ± 9.04 F = 1.5356,
P = 0.2241Sex*, n (%) Women 8 (40.00) 13 (65.00) 12 (60.00) 33 (55.00) P = 0.3495 Men 12 (60.00) 7 (35.00) 8 (40.00) 27 (45.00) Weight, kg (mean ± SD) 70.40 ± 12.27 66.75 ± 12.63 67.15 ± 12.18 68.10 ± 12.26 F = 0.5247,
P = 0.5946Note. Analysis of variance was used for the comparison between groups of age and weight, and *Fisher's exact probability was used for the comparison between groups of gender. Table 1. Demographics characteristics of study participants (FAS)
At baseline, there was no significant difference in the detection rate and GMC of RVNA among the three groups (Tables 2a and 3a). All subjects (100%) developed detectable RVNA (> 0.05 IU/mL) on days 3, 7, 14, 28, and 42 (Table 2a). Significant RVNA was induced after NM57/HRIG administration in the three groups, with a peak on day 3 (Figure 2A). The RVNA level increased most evidently in Group B. At each time point, the GMC in Group B was significantly higher than that in Groups A and C, but no significant difference was found between Groups A and C (Table 3a). The results of the mITT were similar to those of the FAS (Tables 2b and 3b, Figure 2B).
Figure 2. Geometric mean concentration of RVNA at different visits (FAS and mITT). All subjects (100%) developed detectable RVNA (> 0.05 IU/mL) on days 3, 7, 14, 28, and 42. On day 3, peak RVNA levels were achieved in the three groups. At each follow-up point, the GMC in Group B (40 IU/mL NM57) was significantly higher than that in Group A (20 IU/mL NM57) and Group C (20 IU/mL HRIG), but no significant difference was found in the latter two groups. The FAS and the mITT showed similar trends.
Time Detection rate of RVNA (%) Group A
(n = 20)Group B
(n = 20)Group C
(n = 20)Statistic/P Baseline Mean
(95% CI)45.00
(23.06−68.47)40.00
(19.12−63.95)55.00
(31.53−76.94)χ2 = 0.9219,
P = 0.6307Day 3 Mean
(95% CI)100.00
(83.16−100.00)100.00
(83.16−100.00)100.00
(83.16−100.00)NA Day 7 Mean
(95% CI)100.00
(83.16−100.00)100.00
(83.16−100.00)100.00
(83.16−100.00)NA Day 14 Mean
(95% CI)100.00
(83.16−100.00)100.00
(83.16−100.00)100.00
(83.16−100.00)NA Day 28 Mean
(95% CI)100.00
(83.16−100.00)100.00
(83.16−100.00)100.00
(83.16−100.00)NA Day 42 Mean
(95% CI)100.00
(83.16−100.00)100.00
(83.16−100.00)100.00
(83.16−100.00)NA Note. To compare the detection rate of RVNA among three groups, χ2 test was used. If the difference was statistically significant, Fisher’s exact test was performed to make pairwise comparisons. FAS, full analysis set. Table 2a. Detection rate (95% CI) of RVNA (FAS)
Time Detection rate of RVNA (%) Group A
(n = 11)Group B
(n = 12)Group C
(n = 9)Statistic/P Baseline Mean
(95% CI)0.00
(0.00−28.49)0.00
(0.00−26.46)0.00
(0.00−33.63)NA Day 3 Mean
(95% CI)100.00
(71.51−100.00)100.00
(73.54−100.00)100.00
(66.37−100.00)NA Day 7 Mean
(95% CI)100.00
(71.51−100.00)100.00
(73.54−100.00)100.00
(66.37−100.00)NA Day 14 Mean
(95% CI)100.00
(71.51−100.00)100.00
(73.54−100.00)100.00
(66.37−100.00)NA Day 28 Mean
(95% CI)100.00
(71.51−100.00)100.00
(73.54−100.00)100.00
(66.37−100.00)NA Day 42 Mean
(95% CI)100.00
(71.51−100.00)100.00
(73.54−100.00)100.00
(66.37−100.00)NA Note. To compare the detection rate of RVNA among three groups, χ2 test was used. If the difference was statistically significant, Fisher’s exact test was performed to make pairwise comparisons. mITT, modified intention-to-treat analysis. Table 2b. Detection rate (95% CI) of RVNA (mITT)
Time Geometric mean
concentrations (IU/mL)Group A
(n = 20)Group B
(n = 20)Group C
(n = 20)Statistic/P Baseline Mean ± SD
Min, Max0.0579 ± 2.3249
0.01, 0.280.0546 ± 2.3213
0.01, 0.460.0666 ± 2.8540
0.01, 0.57NA Day 3 Mean ± SD
Min, Max0.2139 ± 1.4608
0.11, 0.420.3660 ± 1.2499
0.19, 0.530.1994 ± 1.5007
0.14, 0.53F = 24.4898, P < 0.0001 Group A−Group C
Group B−Group C
Group A−Group BF = 0.8984, P = 0.3473
F = 41.8703, P < 0.0001
F = 30.7518, P < 0.0001Day 7 Mean ± SD
Min, Max0.1764 ± 1.3100
0.13, 0.310.3324 ± 1.4084
0.15, 0.530.1677 ± 1.6196
0.06, 0.52F = 25.1773, P < 0.0001 Group A−Group C
Group B−Group C
Group A−Group BF = 0.4261, P = 0.5166
F = 41.4284, P < 0.0001
F = 33.7164, P < 0.0001Day 14 Mean ± SD
Min, Max0.1890 ± 1.4142
0.14, 0.410.2895 ± 1.5185
0.08, 0.580.1612 ± 1.3714
0.12, 0.41F = 18.4065, P < 0.0001 Group A−Group C
Group B−Group C
Group A−Group BF = 3.0383, P = 0.0868
F = 34.8119, P < 0.0001
F = 17.4403, P < 0.0001Day 28 Mean ± SD
Min, Max0.1535 ± 1.3770
0.10, 0.400.2082 ± 1.4844
0.12, 0.530.1468 ± 1.5690
0.06, 0.46
F = 9.7662, P = 0.0002Group A−Group C
Group B−Group C
Group A−Group BF = 0.7359, P = 0.3946
F = 17.4650, P = 0.0001
F = 11.1251, P = 0.0015Day 42 Mean ± SD
Min, Max0.1209 ± 1.4190
0.08, 0.390.1557 ± 1.3644
0.08, 0.400.1308 ± 1.2538
0.08, 0.19F = 7.4864, P = 0.0013 Group A−Group C
Group B−Group C
Group A−Group BF = 0.4611, P = 0.4999
F = 8.7129, P = 0.0046
F = 13.2711, P = 0.0006Note. Analysis of covariance (ANCOVA) was used to test the log10 transformed GMC difference among three groups, and the covariate was the baseline data. Pairwise comparisons would also be performed if the difference between groups was statistically significant. FAS, full analysis set. Table 3a. Geometric mean concentrations (GMC) of RVNA (FAS)
Time Geometric mean
concentrations (IU/mL)Group A
(n = 11)Group B
(n = 12)Group C
(n = 9)Statistic/P Baseline Mean ± SD
Min, Max0.0337 ± 1.8405
0.01, 0.050.0340 ± 1.8083
0.01, 0.050.0279 ± 1.8725
0.01, 0.05NA Day 3 Mean ± SD
Min, Max0.2006 ± 1.4122
0.15, 0.420.3392 ± 1.2724
0.19, 0.440.1578 ± 1.1288
0.14, 0.19F = 23.7957, P < 0.0001 Group A−Group C
Group B−Group C
Group A−Group BF = 4.2586, P = 0.0484
F = 43.4173, P < 0.0001
F = 22.9064, P < 0.0001Day 7 Mean ± SD
Min, Max0.1779 ± 1.3107
0.14, 0.310.3075 ± 1.4502
0.15, 0.410.1271 ± 1.3808
0.06, 0.18F = 20.1924, P < 0.0001 Group A−Group C
Group B−Group C
Group A−Group BF = 5.7304, P = 0.0236
F = 38.4918, P < 0.0001
F = 16.1363, P = 0.0004Day 14 Mean ± SD
Min, Max0.1884 ± 1.3847
0.14, 0.410.2499 ± 1.5706
0.08, 0.390.1342 ± 1.0677
0.12, 0.15F = 8.8018, P = 0.0011 Group A−Group C
Group B−Group C
Group A−Group BF = 5.2464, P = 0.0297
F = 17.5908, P = 0.0002
F = 3.9431, P = 0.0569Day 28 Mean ± SD
Min, Max0.1321 ± 1.1110
0.100, 0.1400.1730 ± 1.2773
0.120, 0.3300.1130 ± 1.3296
0.060, 0.150F = 9.4840, P = 0.0007 Group A−Group C
Group B−Group C
Group A−Group BF = 2.2434, P = 0.1454
F = 17.7762, P = 0.0002
F = 8.2361, P = 0.0077Day 42 Mean ± SD
Min, Max0.1018 ± 1.2181
0.08, 0.130.1362 ± 1.2126
0.08, 0.180.1117 ± 1.2049
0.08, 0.14F = 6.6392, P = 0.0044 Group A−Group C
Group B−Group C
Group A−Group BF = 1.2904, P = 0.2656
F = 4.8545, P = 0.0360
F = 12.8374, P = 0.0013Note. Analysis of covariance (ANCOVA) was used to test the log10 transformed GMC difference among three groups, and the covariate was the baseline data. Pairwise comparisons would also be performed if the difference between groups was statistically significant. mITT, modified intention-to-treat analysis. Table 3b. Geometric mean concentrations (GMC) of RVNA (mITT)
The mean AUC over 0–14 days in Group B (4.43 IU/mL per day) was significantly larger than that in Group A (2.63 IU/mL per day) and Group C (2.57 IU/mL per day) (P < 0.001), but showed no significant difference between Groups A and C (P > 0.05). The mean AUC over 0–42 days in Group B (10.92 IU/mL per day) was also larger than that in Group A (7.24 IU/mL per day) and Group C (7.00 IU/mL per day), and similar in the latter two groups (Table 4a). The results of the mITT were similar to those of the FAS (Table 4b). Anti-antibodies only originated from NM57. We reported anti-antibody profiles in Groups A and B, and only one participant was positive for anti-antibody in Group B.
Time AUC of RVNA
(IU/mL per day)Group A
(n = 20)Group B
(n = 20)Group C
(n = 20)Statistic/P Days
0–14Mean ± SD
(95% CI)2.63 ± 0.71
(2.3–3.0)4.43 ± 1.04
(3.9–4.9)2.57 ± 1.39
(1.9–3.2)χ2 = 26.7982,
P < 0.0001Days
0–42Mean ± SD
(95% CI)7.24 ± 2.37
(6.1–8.3)10.92 ± 3.18
(9.4–12.4)7.00 ± 3.11
(5.5–8.5)χ2 = 23.7446,
P < 0.0001Note. Comparisons for AUCs were performed by Kruskal-Wallis test. If the difference was statistically significant, Wilcoxon rank-sum test was performed to make pairwise comparisons. FAS, full analysis set. Table 4a. Area under curve (AUC) of RVNA (FAS)
Time AUC of RVNA
(IU/mL per day)Group A
(n = 11)Group B
(n = 12)Group C
(n = 9)Statistic/P Days
0–14Mean ± SD
(95% CI)2.52 ± 0.59
(2.1−2.9)4.01 ± 0.86
(3.5−4.6)1.80 ± 0.22
(1.6−2.0)χ2 = 22.4400,
P < 0.0001Days
0–42Mean ± SD
(95% CI)6.49 ± 1.07
(5.8−7.2)9.36 ± 1.44
(8.4−10.3)5.17 ± 0.43
(4.8−5.5)χ2 = 24.3174,
P < 0.0001Note. Comparisons for AUCs were performed by Kruskal-Wallis test. If the difference was statistically significant, Wilcoxon rank-sum test was performed to make pairwise comparisons. mITT, modified intention-to-treat analysis. Table 4b. Area under curve (AUC) of RVNA (mITT)
A total of 15 (25.0%) AEs were reported, of which 12 (20.0%) were considered to be ARs related to the study drugs (Tables 5 and 6). Injection site erythema, asthenia, fatigue, and pyrexia were the most common ARs. Except for one case of grade 2 myalgia in Group C, the other ARs were all grade 1. No SAEs were reported.
System Organ Class
Preferred TermNo (%) Group A
(n = 20)Group B
(n = 20)Group C
(n = 20)Total
(n = 60)Number of subjects with ≥ 1 AE 6 (30.0) 4 (20.0) 5 (25.0) 15 (25.0) Investigations 0 0 1 (5.0) 1 (1.7) White blood cells urine positive 0 0 1 (5.0) 1 (1.7) Red blood cells urine positive 0 0 1 (5.0) 1 (1.7) Nervous system disorders 0 1 (5.0) 0 1 (1.7) Headache 0 1 (5.0) 0 1 (1.7) Ear and labyrinth disorders 0 0 1 (5.0) 1 (1.7) Tinnitus 0 0 1 (5.0) 1 (1.7) Musculoskeletal and connective tissue disorders 1 (5.0) 0 1 (5.0) 2 (3.3) Myalgia 1 (5.0) 0 1 (5.0) 2 (3.3) Skin and subcutaneous tissue disorders 0 0 1 (5.0) 1 (1.7) Dermatitis 0 0 1 (5.0) 1 (1.7) General disorders and administration site conditions 4 (20.0) 4 (20.0) 1 (5.0) 9(15.0) Pyrexia 1 (5.0) 0 1 (5.0) 2(3.3) Asthenia 2 (10.0) 2 (10.0) 0 4(6.7) Fatigue 2 (10.0) 2 (10.0) 0 4(6.7) Injection site erythema 1 (5.0) 2 (10.0) 1 (5.0) 4(6.7) Injection site pain 1 (5.0) 0 0 1 (1.7) Injection site pruritus 1 (5.0) 0 0 1 (1.7) Gastrointestinal disorders 1 (5.0) 0 0 1 (1.7) Diarrhoea 1 (5.0) 0 0 1 (1.7) Note. The number of adverse events or reactions represents the number of participants who had at least one adverse event or reaction of this type. For example, a participant with several events would be only calculated once in “adverse events”, and would also be calculated once in “Number of subjects with ≥ 1 AE” or “Number of subjects with ≥ 1 ADR”. AE, adverse events. ADR, adverse drug reaction. Table 5. Details of adverse events
System organ class preferred term No. (%) Group A
(n = 20)Group B
(n = 20)Group C
(n = 20)Total
(n = 60)Number of subjects with ≥ 1 ADR 4 (20.0) 4 (20.0) 4 (20.0) 12 (20.0) Investigations 0 0 1 (5.0) 1 (1.7) White blood cells urine positive 0 0 1 (5.0) 1 (1.7) Red blood cells urine positive 0 0 1 (5.0) 1 (1.7) Nervous system disorders 0 1 (5.0) 0 1 (1.7) Headache 0 1 (5.0) 0 1 (1.7) Musculoskeletal and connective tissue disorders 0 0 1 (5.0) 1 (1.7) Myalgia 0 0 1 (5.0) 1 (1.7) Skin and subcutaneous tissue disorders 0 0 1 (5.0) 1 (1.7) Dermatitis 0 0 1 (5.0) 1 (1.7) General disorders and administration site conditions 4 (20.0) 4 (20.0) 1 (5.0) 9 (15) Pyrexia 1 (5.0) 0 1 (5.0) 2 (3.3) Asthenia 2 (10.0) 2 (10.0) 0 4 (6.7) Fatigue 2 (10.0) 2 (10.0) 0 4 (6.7) Injection site erythema 1 (5.0) 2 (10.0) 1 (5.0) 4 (6.7) Injection site pain 1 (5.0) 0 0 1 (1.7) Injection site pruritus 1 (5.0) 0 0 1 (1.7) Note. The number of adverse events or reactions represents the number of participants who had at least one adverse event or reaction of this type. For example, a participant with several events would be only calculated once in “adverse events”, and would also be calculated once in “Number of subjects with ≥ 1 AE” or “Number of subjects with ≥ 1 ADR”. AE, adverse events. ADR, adverse drug reaction. Table 6. Details of adverse reactions
Rabies Virus Neutralizing Activity, Safety, and Immunogenicity of Recombinant Human Rabies Antibody Compared with Human Rabies Immunoglobulin in Healthy Adults
doi: 10.3967/bes2022.103
- Received Date: 2021-07-16
- Accepted Date: 2022-06-07
-
Key words:
- Recombinant human rabies antibody /
- NM57 /
- Human rabies immunoglobulin /
- Rabies virus neutralizing activity /
- Safety /
- Immunogenicity
Abstract:
Citation: | ZHANG Jun Nan, MENG Ya Juan, BAI Yun Hua, LI Yu Feng, YANG Li Qing, SHI Nian Min, HAN Hui Xia, GAO Jian, ZHU Li Juan, LI Shu Ping, ZHANG Jing, ZHAO Qin Hua, WANG Xiu Qin, WEI Jing Shuang, REN Le Min, CAO Chen Hua, CHEN Chen, ZHAO Wei, LI Li. Rabies Virus Neutralizing Activity, Safety, and Immunogenicity of Recombinant Human Rabies Antibody Compared with Human Rabies Immunoglobulin in Healthy Adults[J]. Biomedical and Environmental Sciences, 2022, 35(9): 782-791. doi: 10.3967/bes2022.103 |