Fifty adults out of 122 screened were enrolled in the study.
Main inclusion criteria.
Healthy male or female subjects (oral body temperature, 35.0 to 37.5°C; systolic/diastolic blood pressure, 90 to 140/50 to 90 mm Hg; pulse rate, 40 to 90 beats per min), aged between 18 to 55 years (body weight, ≥50 kg; body mass index [BMI], 18 to 29 kg/m2) and with a negative tuberculin skin test reaction (purified protein derivative [PPD], 5 TU; <5-mm induration; 48 to 72 h after administration at the screening visit or within 2 months prior to the screening visit), were included. Subjects who had a positive PPD skin test (as defined by existing guidelines) with a documentation of Mycobacterium bovis BCG vaccination, who were at low environmental risk for tuberculosis infection or reactivation, and who had a negative chest X-ray were also included. Female subjects were required not to be lactating and to have a negative pregnancy test at screening and prior to dosing and were required to use an effective method of contraception (e.g., birth control pills, double-barrier contraception, etc.) during the study (from the date of screening) and for at least 3 months following dosing. Male subjects had to use two acceptable methods of contraception and refrain from fathering a child in the 3 months following study drug administration.
Key exclusion criteria.
Exclusion criteria included vaccination of any kind during the preceding year; meningococcal vaccination at any time in the past; influenza virus vaccination in the 2 years prior to screening; allergy to vaccination, investigational compound/compound class, or egg products; active infection; autoimmune or other significant systemic diseases; liver or respiratory diseases; impaired renal function; use of any prescription drugs/herbal supplements within 4 weeks prior to initial dosing; use of over-the-counter (OTC) medication or dietary supplements (vitamins included) within 2 weeks prior to initial dosing; history of drug or alcohol abuse within 12 months prior to dosing; pregnancy; any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs or which might jeopardize study participation.
All subjects provided written informed consent, and the study was conducted in accordance with the International Conference on Harmonization (ICH) guidelines for good clinical practice (GCP). The study received approval from the local ethical review committee and health authorities.
This was a phase 1, single-center, open-label, randomized, parallel-group, single-dose study to evaluate the effectiveness of influenza vaccination and conjugated group C meningococcal (MenC) vaccination following concomitant (≤2 weeks) exposure to a single dose of secukinumab (150 mg subcutaneously [s.c.]). A scheme of the study design and the groups is given in . In this trial, we defined efficacy as the ability of vaccinations to elicit an antibody response, defined as 4 times the baseline titer, at 4 weeks postvaccination for each vaccine in subjects treated with secukinumab compared to the control group.
Study design scheme and groupsa
The primary endpoint was the proportion of subjects with at least a 4-fold increase in titer at 4 weeks postvaccination for meningococcus and in at least 2 out of 3 serotypes for influenza virus. The secondary endpoint was the proportion of subjects showing an increase from a nonprotective baseline level of <1/40 to ≥1/40 in protective antibodies for influenza virus and an increase from <1/8 to ≥1/8 for meningococcus.
The study included a 14-day screening period, and after measurement of antibody titers at baseline, eligible subjects were randomized to a single secukinumab dose (150 mg s.c.) or no treatment (control group), followed by inactivated trivalent subunit unadjuvanted influenza virus (Agrippal) and conjugated alum-adjuvanted MenC (Menjugate) vaccines given separately intramuscularly in both arms after 2 weeks. The influenza virus vaccine contained 15 μg of hemagglutinin (HA) of the following virus strains: A/California/7/2009 (H1N1)-like strain, A/Perth/16/2009 (H3N2)-like strain, and B/Brisbane/60/2008. Both vaccines were from Novartis Vaccines and Diagnostics, Siena, Italy. They were sourced locally and are licensed in several countries worldwide.
Efficacy and safety assessments.
The primary efficacy variable was the antibody response to vaccination, defined as ≥4 times the baseline titer, at 4 weeks postvaccination for each vaccine in subjects treated with secukinumab compared to the control group. For influenza virus, response was defined as a ≥4-fold increase in titer postvaccination in at least 2 out of 3 serotypes (there was only one serogroup for meningococcus). Secondary efficacy variables were the antibody responses to vaccination, defined as ≥4 times the baseline titer, at 2 and 6 weeks postvaccination for each vaccine in subjects treated with secukinumab compared to the control group.
Vaccine-specific serum antibody responses were assessed on day 15 (prevaccination) and on days 21, 29, 43, and 57 (1, 2, 4, and 6 weeks postvaccination, respectively). The antibody response to the 3 influenza vaccine virus strains was evaluated by the hemagglutination inhibition (HI; LOQ, titer of 10) test according to standard procedures. The determination of titers was carried out at the Novartis Vaccines and Diagnostics facilities in Marburg (Germany). The antibody response to MenC was evaluated by serum bactericidal assay (SBA; LOQ, titer of 4) using the MenC C11 strain and prescreened human serum as a source of complement. Antibody responses are reported as a ≥4-fold increase in titer for influenza virus and MenC vaccines and also as rises in antibodies from a nonprotective baseline level of <1/40 to ≥1/40 for influenza virus and of <1/8 to ≥1/8 for MenC compared to the baseline. Geometric mean antibody titers were also calculated for the 3 influenza virus antigens and for MenC.
The safety assessments of treatment with secukinumab consisted of the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs), hematology and biochemistry parameters, pregnancy tests, vital signs, and physical examinations.
The sample size determination was based on the primary endpoints, i.e., the proportion of subjects with a ≥4-fold increase in antibody titer 4 weeks postvaccination for influenza and meningococcus. With a sample size of 50 subjects (25 subjects per group) for influenza virus vaccination, the study would have 99% power at a one-sided alpha level of 0.05 to establish noninferiority, assuming a control response rate of 88% and a noninferiority margin of 40%. For meningitis vaccination, the study would have 88% power at a one-sided alpha level of 0.05 to establish noninferiority, assuming a control response rate of 72% and a noninferiority margin of 40%. The noninferiority threshold and response rates assumed were similar to those seen in a previous study. The study had an overall power of 87% to demonstrate noninferiority for both vaccinations, assuming there was no real effect of treatment. The difference in proportions of responders in the 2 groups together with 90% confidence intervals (CI) was calculated, and noninferiority was concluded if the lower 90% CI excluded a difference of 40% or more. Efficacy and safety variables were summarized using descriptive statistics.