Recombinant monoclonal antibody siltartoxatug versus plasma-derived human tetanus immunoglobulin for tetanus: a randomized, double-blind, active-controlled, phase 3 trial

Categories: Disease & Virus

July 9, 2025

Trial design and treatment

This was a randomized, double-blind, parallel-group, active-controlled, phase 3 study to compare the efficacy and safety of siltartoxatug and HTIG as prophylaxis against tetanus in patients with tetanus-prone wounds. Eligible participants were randomized at a 2:1 ratio to receive a single intramuscular gluteal injection of siltartoxatug 10 mg or HTIG 250 IU. Randomization was stratified based on whether or not the adsorbed tetanus vaccine was concomitantly administered, as determined at randomization. In the current clinical practice in China, the proportion of patients concomitantly receiving tetanus vaccines is low. Furthermore, antibodies induced by the tetanus vaccine could interfere with the comparison of antibody levels produced by the two passive immunizing agents, siltartoxatug and HTIG. To mitigate this, the study limited concomitant vaccination to approximately 10% of participants, administered exclusively at four designated study sites certified for vaccine administration. The randomization code was generated by an independent randomization specialist. Investigators registered participants and assigned them according to the randomization code obtained from an Interactive Response Technology system. Participants, investigators and study site personnel (apart from the unblinded pharmacist and/or unblinded study nurses responsible for drug preparation and administration) remained blinded to all randomization assignments throughout the study. Siltartoxatug and HTIG were both administered via intramuscular gluteal injection. Due to the different volumes of the two drugs, measures were taken to block the participants’ line of sight during the injection process to maintain blinding. Both study drugs were administered over 10 (±1) s.

The study lasted for approximately 106 days for each participant and included a screening period, a treatment period (within 24 h after injury) and a follow-up period (105 days). Clinical data were captured electronically using Medidata Rave EDC v.2022.3.0–v.2023.1.4. Serum samples were collected at the following timepoints: preadministration, and 12 h, 3, 7, 28 and 90 days postadministration, to analyze both siltartoxatug and HTIG anti-tetanus neutralizing antibody levels, as well as siltartoxatug concentration. For immunogenicity analysis, samples were collected at preadministration and at 7, 28 and 90 days postadministration. The samples were analyzed at a central laboratory.

The study was conducted at 28 hospitals across China in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The study protocol (Supplementary Information) was approved by the independent ethics committees of two lead study sites, Peking University People’s Hospital and The First Affiliated Hospital of Guangzhou Medical University, as well as by the ethics committee of each participating study site (detailed in ‘List of ethical committees’; Supplementary Information). The trial is registered at ClinicalTrials.gov (NCT05664750).

Participants

Eligible participants must meet all the following inclusion criteria:

(1)

Voluntary signing of the informed consent form;
(2)

Male or female participants aged ≥18 years;
(3)

Participants with unclean or contaminated wounds resulting from various injuries, including incised wounds, burns, traffic-related injuries, animal scratches and bites, who required passive immunization for tetanus prophylaxis;
(4)

The time from the injuries to study drug administration was required to be less than 24 h;
(5)

Sexually active women of childbearing potential who are at risk of pregnancy, as well as men, must agree to use at least one of the highly effective contraceptive methods throughout the study and for 150 days after dosing.

Participants were excluded if they met any of the following criteria:

(1)

All wounds were clean;
(2)

Requirement for HTIG 500 IU due to severe contaminated wounds, as determined by the investigator;
(3)

Suspected or diagnosed tetanus;
(4)

Fever (body temperature ≥38 °C) in the 3 days before dosing;
(5)

History of receiving at least three doses of tetanus toxoid or a tetanus toxoid-containing vaccine;
(6)

History of tetanus infection;
(7)

Previously diagnosed with IgA deficiency with anti-IgA antibodies;
(8)

Receipt of immunoglobulins, blood or blood products within 6 months before dosing, or planned to receive live viral vaccines within 3 months after dosing;
(9)

Participants with hemorrhagic conditions or at high risk of bleeding, clinically relevant active bleeding, abnormal platelet function, prothrombin time >3 s above the upper limit of normal, or platelet count <100 × 10⁹ l⁻¹ (except for bleeding associated with injury);
(10)

Use of anticoagulants in the 3 weeks before dosing;
(11)

Pregnant female participants; female participants of childbearing potential who planned to become pregnant during the study; breastfeeding female participants;
(12)

Current alcohol abuse, drug abuse or drug addiction;
(13)

Known or suspected allergy to the test product or its excipients, or a history of allergy to human immunoglobulin products or other therapeutic monoclonal immunoglobulins;
(14)

Participation in other clinical studies involving investigational drugs or devices within 3 months or five times the drug’s half-life (whichever was longer) before dosing, except for observational or noninterventional studies;
(15)

Investigator site staff, sponsor employees directly involved in the study, site staff under the investigator’s supervision and their family members;
(16)

Any other factors deemed by the investigator to render the participant ineligible for the study.

All participants provided written informed consent before enrollment, including consent for reporting and sharing individual-level data. Participants’ sex was determined based on self-report and official identification records before being documented in the electronic case report form. Study objectives and endpoints were designed regardless of sex.

Endpoints and assessment

The primary efficacy endpoint was the increase of anti-tetanus neutralizing antibody titer from baseline (ΔTiter) at 12 h postadministration. The estimand for the primary efficacy endpoint was the proportion of participants with anti-tetanus neutralizing antibody ΔTiter ≥0.01 IU ml⁻¹ at 12 h postadministration, in all randomized participants who have received study drug.

The secondary efficacy endpoint was the tetanus protection rate (1 − tetanus incidence) within 28 days postadministration. Tertiary efficacy endpoints included the anti-tetanus neutralizing antibody ΔTiter at 3, 7, 28 and 90 days postadministration and the tetanus protection rate within 90 and 105 days postadministration. Since the antibodies induced by tetanus vaccine could interfere with the comparison of anti-tetanus neutralizing antibody levels between siltartoxatug and HTIG, analyses for tertiary efficacy endpoints were conducted in patients who had not received tetanus vaccine by the corresponding timepoints. The investigators assessed potential occurrence of tetanus through patient interviews conducted at each study visit.

The safety assessment included AEs, SAEs, laboratory tests, vital signs, physical examinations and electrocardiograms. The severity of an AE was classified into three grades: mild (asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated), moderate (requiring small, local or noninvasive treatment; restricted in age-appropriate instrumental activities of daily living) and severe (serious or clinically consequential but not immediately life-threatening; requiring hospitalization or prolongation of hospitalization; disabling; restricted in self-care activities of daily living).

An SAE was defined as an untoward medical event that met any of the following criteria after a participant received the study drug at any dose: resulting in death, life-threatening, hospitalization or prolongation of hospitalization, permanent or clinically consequential disability/dysfunction, congenital anomalies/birth defects or important medical event.

The immunogenicity was assessed via the presence of ADAs in participants who received siltartoxatug. The pharmacokinetic endpoint was the serum siltartoxatug concentration.

Two quantitative determination methods were developed for the siltartoxatug and HTIG groups to measure the levels of anti-tetanus neutralizing antibodies. A quantitative ligand-binding electrochemiluminescence assay using a Meso Scale Discovery (QUICKPLEX SQ120MM, model 1300) platform was utilized to quantify anti-tetanus neutralizing monoclonal antibodies in the siltartoxatug group, referred to as the TNM002 PD bioanalytical method. A quantitative ligand-binding chemiluminescence assay, referred to as the HTIG PD bioanalytical method, was developed to detect anti-tetanus neutralizing polyclonal antibodies produced by participants in the HTIG group. The titers determined by the two ligand-binding assays are comparable, as both have been validated for consistency with the in vivo neutralization assay in mice, which is considered the gold standard method to assess the anti-tetanus antibody levels³⁰.

The anti-tetanus neutralizing antibody ∆Titer in each group was calculated as the postadministration value at each timepoint minus the baseline value measured by the respective bioanalytical method. Furthermore, the HTIG PD bioanalytical method was also utilized to evaluate the levels of anti-tetanus antibodies (polyclonal antibodies) in the subgroup of participants who received the concomitant adsorbed tetanus vaccine, as well as to measure the baseline anti-tetanus antibody levels of all participants.

Statistical methods

Sample size calculation was based on the following hypotheses and assumptions: (1) the lower limit of the 95% CI of the difference (siltartoxatug group vs HTIG group) in the primary efficacy outcome would be >0; (2) the proportion of participants with ∆Titer ≥ 0.01 IU ml⁻¹ at 12 h after receiving siltartoxatug and HTIG would be 91.8% and 55.9%, respectively, based on the results of the phase 2 trial; (3) a 2:1 randomization ratio between the siltartoxatug and HTIG groups and a one-sided type I error of 0.025; (4) the dropout rate was expected to be 20% and (5) siltartoxatug required adequate exposure during clinical development to fully understand its safety. The planned sample size was 675 participants, that is, 450 in the siltartoxatug group and 225 in the HTIG group. This would provide a power of >99% to evaluate the above efficacy hypothesis, while ensuring adequate exposure of siltartoxatug to evaluate its safety.

The efficacy analysis was conducted in the full analysis set, which included all randomized participants who received the study drugs. Additionally, a per-protocol set analysis was performed, encompassing all participants from the full analysis set who did not have important protocol deviations that could substantially impact the primary efficacy endpoint. Safety was analyzed in the safety set, including all treated participants with at least one postadministration safety evaluation. Immunogenicity was analyzed in all randomized participants who received siltartoxatug and had available immunogenicity data for at least one postadministration timepoint (immunogenicity set).

For primary and secondary endpoint analyses, the proportion of participants with ΔTiter ≥ 0.01 IU ml⁻¹ and the tetanus protection rate were calculated, and the corresponding 95% CI was estimated using the Clopper–Pearson method. A 95% CI for intergroup difference was calculated using the Miettinen–Nurminen method, stratified by whether concomitantly administered with the tetanus vaccine as determined at randomization. A P value was reported for the primary efficacy endpoint. The following analyses were performed to verify the robustness of primary efficacy analysis, guided by ICH E9 (R1): a sensitivity analysis using stratified Newcombe Wilson method for intergroup difference 95% CI construction, supplementary analysis I using ‘while on treatment strategy’ to handle the intercurrent events compared with ‘treatment policy strategy’ used for the primary efficacy analysis, and supplementary analysis II conducted in the per-protocol set in lieu of the full analysis set.

The tertiary efficacy endpoints summarized the anti-tetanus neutralizing antibody ΔTiter level at different timepoints other than 12 h, conducted in participants who had not received the tetanus vaccine by the corresponding timepoint, since the antibodies produced by the vaccine may interfere with the antibody assessment of the study drugs. The proportion of participants with ΔTiter ≥ 0.01 IU ml⁻¹ was analyzed using the same methods as the primary endpoint. A mixed-effect model for repeated measures was used to compare and analyze ΔTiter between groups at each scheduled timepoint.

In the subgroup consisting of participants who received the tetanus vaccine, the anti-tetanus antibody titers measured by HTIG PD bioanalytical method were summarized using descriptive statistics.

Safety and immunogenicity were summarized using descriptive statistics. All statistical analyses were performed with SAS v.9.4. The statistical analysis plan is available in Supplementary Information.