Real-world effectiveness of an intranasal spray A8G6 antibody … – Nature.com

Study design

In this study, an open-label, non-randomized, two-arm, blank-controlled, investigator-initiated trial was designed to assess the efficacy and safety of the intranasal spray cocktail A8G6 in preventing SARS-CoV-2 infection among close contacts with COVID-19 patients. The clinical trial was conducted at 6 designated quarantine hotels in Yuzhong District, Chongqing, China from November 27, 2022 and was completed on December 12, 2022.

Recruited participants in the treatment group self-administrated a three doses of 0.7mg (140l) A8G6 nasal spray per day for 7 treatment days. The drug was supplied by Chongqing Mingdao Haoyue Biotechnology Co., LTD (Chongqing, China), stored at 28C. In the blank control group, participants did not receive any treatment. After enrollment, SARS-CoV-2 infection was confirmed by a reverse transcription polymerase chain reaction (RT-PCR) test of oropharyngeal swab. During this trial, with the adaption of the anti-COVID-19 policy, not only RT-PCR, but also rapid antigen tests were used to confirm the SARS-CoV-2 infection status.

The trial was carried out in accordance with all applicable national and local regulatory requirements. Data and Safety Monitoring Board of The Second Affiliated Hospital of Chongqing Medical University oversaw trial conduct and documentation. The protocol has been approved by the Chinese clinical test registration center (the world health organization international clinical trials registered organization registered platform (ICTRP), the registration number: ChiCTR2200066416) and the Ethics Committees of The Second Affiliated Hospital of Chongqing Medical University (the approval number: 2022127-1).

During November COVID-19 wave in Chongqing, China, when patients had been diagnosed as COVID-19 with the positive RT-PCR test for SARS-CoV-2 (index cases), their close contacts were immediately transferred to the designated quarantine sites. At 6 quarantine sites in Chongqing, healthy adults aged between 18 to 65 years who had a close contact with index cases within 72hours were enrolled into this study. The maximum time interval between exposure to treatment was 72h. All vaccination status is eligible for inclusion. Exclusion criteria included positive RT-PCR at baseline, nasal discomfort, the use of other COVID-19 antibody drugs and drug-drug interference with participants regular medication (additional details about eligibility criteria were described in the appendix).

All study participants were capable of self-administrating the intranasal spray, recording and recalling clinical signs. All participants were provided and voluntarily signed written informed consent before the study.

At six quarantine sites in the Yuzhong District, Chongqing, site investigation was carried out to screen eligible participants. Eligible participants were given the choice to join the A8G6 treatment group or blank control group. For eligible participants that showed no preference in either group, they were randomly assigned to A8G6 treatment group or blank control group. Oropharyngeal swabs were taken for quantitative and qualitative RT-PCR assessments at baseline prior to treatment and though the treatment period and a follow-up period. Subjects with positive RT-PCR results before treatment were excluded. The SARS-CoV-2 viral load was present by viral genome copies per mL log10 values with the conversion of the open reading frame of 1ab (ORF1ab) and nucleocapsid (N-gene) cycle threshold (Ct) values (RT-PCR was conducted by Yuzhong District Center for Disease Control and Prevention, in Chongqing, China. Conversion of Ct values to viral genome copies was calculated according to the manufacturers instructions of 2019-nCoV viral RNA kit produced by BioPerfectus Technologies, catalog number: JC10223-1N).

Subjects demographic data, health and COVID-19 vaccination status were recorded at the baseline visit (Day 0). The use of nasal spray, rapid antigen tests or RT-PCR test for COVID-19 were recorded every day during the study participation. When participants in both groups were diagnosed with SARS-CoV-2 infection, the related symptoms and symptomatic treatment for COVID-19 were reported until the trial completed. In the treatment group, all participants were requested to self-report and record the adverse events. Due to the relaxation of COVID-19 control and policy starting from December 4, 2022, some participants returned to home for further isolation. The follow-up visits were adjusted to retrospective telephonic visit according to a questionnaire form from that day.

The primary endpoint analysis included all participants in both the treatment and control groups. The primary endpoint was to assess the efficacy of the intranasal spray A8G6 for post-exposure prophylaxis of COVID-19. In this study, we compared the COVID-19 incidence of the close contacts between the A8G6 treatment individuals and the blank-controlled individuals. We also compared the time from enrollment to SARS-CoV-2 infection between the two groups. The secondary efficacy analysis included the quantitative data of SARS-CoV-2 RNA (log10 copies per mL) at baseline of the positive COVID-19 and the time to conversion of SARS-CoV-2 RNA from positive to negative (viral clearance).

Safety endpoints was adverse event types and the incidence rate of adverse events among all participants of the A8G6 treatment group during the study. An adverse effect was defined as any abnormal signs or symptoms and harmful results caused by the study drug.

The sample size in this clinical trial was determined on the basis of statistical power calculations. We proposed greater than 90% power to detect a 20% relative difference between the A8G6 treated and control group at a two-sided alpha level of 0.05 (ie., a 20% prevention efficacy of A8G6). The formula is as follows:

$$n={frac{2pq({Z}_{1-frac{alpha }{2}}+{Z}_{1-beta })}{{delta }^{2}}}^{2}$$

which p is the proportion of participants develop COVID-19 in A8G6 treated group, q is in the control group, is the difference between two group, is two-sided alpha level, and 1- is statistical power. In this clinical trial, we assume that q is 0.1, 20% relative reduction of A8G6 treated group is 0.08. Assuming a dropout rate of 20%, at total of 5160 participants will be recruited.

The primary efficacy endpoints including COVID-19 incidence and time to confirmed SARS-CoV-2 infection. The COVID-19 incidence was analyzed using the KaplanMeier method and log-rank test, and the time to confirmed SARS-CoV-2 infection was analyzed using Wilcoxon rank-sum test. The secondary efficacy endpoints including viral load when confirmed SARS-CoV-2 infection and the time to negative conversion of SARS-CoV-2 determined by RT-PCR. The viral load when confirmed SARS-CoV-2 infection was analyzed using Wilcoxon rank-sum test, negative conversion of SARS-CoV-2 and remission time were conducted using KaplanMeier method and log-rank-test. Safety was assessed in participants in the full analysis set who received A8G6 nasal spray treatment during the 8-day quarantine period.

Database from the Service Platform for COVID-19 Prevention and Control created by Yuzhong District Center for Disease Control and Prevention were authorized for us to use and analyze. Data including demographic and clinical characteristics of the cohorts, endpoints in this clinical trial were collected from an applet of WeChat (a social media platform in China), called Yuzhong Information Exchange. All data were summarized with descriptive statistics (number of subjects (%), median (IQR), meansd). The credible interval for nasal spray was calculated with the use of a beta-binomial model with prior beta (1, 1) adjusted for the treatment duration time. Continuous variables were compared with the MannWhitney U-test, and Categorical variables were conducted using 2 test or Fishers exact test. A P value of <0.05 was considered statistically significant. Statistical analyses were performed using R software, version 3.6.0.

The rest is here:

Real-world effectiveness of an intranasal spray A8G6 antibody ... - Nature.com