Phase 1, randomized, rater and participant blinded placebo-controlled study of the safety, reactogenicity, tolerability and immunogenicity of H1N1 influenza vaccine delivered by VX-103 (a MIMIX microneedle patch [MAP] system) in healthy adults.

BACKGROUND: The MIMIX platform is a novel microneedle array patch (MAP) characterized by slowly dissolving microneedle tips that deploy into the dermis following patch application. We describe safety, reactogenicity, tolerability and immunogenicity for MIMIX MAP vaccination against influenza. METHODOLOGY: The trial was a Phase 1, exploratory, first-in-human, parallel randomized, rater, participant, study analyst-blinded, placebo-controlled study in Canada. Forty-five healthy participants (18 to 39 years of age, inclusive) were randomized in a 1:1:1 ratio to receive either 15 µg or 7.5 µg of an H1N1 influenza vaccine, or placebo delivered via MIMIX MAP to the volar forearm. A statistician used a computer program to create a randomization scheme with a block size of 3. Post-treatment follow-up was approximately 180 days. Primary safety outcomes included the incidence of study product related serious adverse events and unsolicited events within 180 days, solicited application site and systemic reactogenicity through 7 days after administration and solicited application site erythema and/or pigmentation 14, 28, 56 and 180 days after administration. Immunogenicity outcomes included antibody titers and percentage of seroconversion (SCR) and seroprotection (SPR) rates determined by the hemagglutination inhibition (HAI) assay. Exploratory outcomes included virus microneutralization (MN) titers, durability and breadth of the immune response. The trial was registered with ClinicalTrials.gov, number NCT06125717. FINDINGS: Between July 7, 2022 and March 13, 2023 45 participants were randomized to a treatment group. One participant was lost to follow up in the 15 µg group and 1 participant withdrew from the 7.5 µg dose group. Safety analyses included n = 15 per group, immunogenicity analyses included n = 14 for the 15 µg and 7.5 µg treatment groups and n = 15 for the placebo group. No SAEs were reported in any of the treatment groups. All treatment groups reported solicited local events within 7 days after vaccination, with mild (Grade 1) erythema being the most frequent symptom reported. Other local symptoms reported included mostly mild (Grade 1) induration/swelling, itching, pigmentation, skin flaking, and tenderness. Within 7 days after vaccination, 2 participants (4.4%) reported moderate (Grade 2) erythema, 1 participant (2.2%) reported moderate (Grade 2) induration/swelling, and 1 participant (2.2%) reported moderate (Grade 2) itching. There was an overall reduction in erythema and pigmentation reported on Days 15, 29, 57, and 180 among all treatment groups. Systemic symptoms reported within 7 days after vaccination, included mild (Grade 1) fatigue reported among all treatment groups, and mild (Grade 1) headache reported by 1 participant in the 7.5 µg treatment group. No study drug related severe symptoms were reported in the study. Group mean fold rises in HAI titers ranged between 8.7 and 12-fold, SCRs were >76% and SPRs were >92% for both VX-103 dose groups thereby fulfilling serological criteria established by the EMA and FDA for seasonal influenza vaccines. Longitudinal assessments demonstrate persistence of the immune response through at least Day 180. CONCLUSIONS: The MIMIX MAP platform is safe, well tolerated and elicits robust antibody responses.

Safety and immunogenicity of an AS03-adjuvanted plant-based SARS-CoV-2 vaccine in Adults with and without Comorbidities.

The rapid spread of SARS-CoV-2 continues to impact humanity on a global scale with rising total morbidity and mortality. Despite the development of several effective vaccines, new products are needed to supply ongoing demand and to fight variants. We report herein a pre-specified interim analysis of the phase 2 portion of a Phase 2/3, randomized, placebo-controlled trial of a coronavirus virus-like particle (CoVLP) vaccine candidate, produced in plants that displays the SARS-CoV-2 spike glycoprotein, adjuvanted with AS03 (NCT04636697). A total of 753 participants were recruited between 25th November 2020 and 24th March 2021 into three groups: Healthy Adults (18-64 years: N = 306), Older Adults (≥65 years: N = 282) and Adults with Comorbidities (≥18 years: N = 165) and randomized 5:1 to receive two intramuscular doses of either vaccine (3.75 µg CoVLP/dose+AS03) or placebo, 21 days apart. This report presents safety, tolerability and immunogenicity data up to 6 months post-vaccination. The immune outcomes presented include neutralizing antibody (NAb) titres as measured by pseudovirion assay at days 21 and 42 as well as neutralizing antibody cross-reactivity to several variants of concern (VOCs): Alpha, Beta, Gamma, Delta, and Omicron (BA.1), up to 201 days post-immunization. Cellular (IFN-γ and IL-4 ELISpot) response data in day 21 and 42 peripheral blood are also presented. In this study, CoVLP+AS03 was well-tolerated and adverse events (AE) after each dose were generally mild to moderate and transient. Solicited AEs in Older Adults and Adults with Comorbidities were generally less frequent than in Healthy Adults and the reactogenicity was higher after the second dose. CoVLP+AS03 induced seroconversion in >35% of participants in each group after the first dose and in ~98% of participants, 21 days after the second dose. In all cohorts, 21-days after the second dose, NAb levels in sera against the vaccine strain were ~10-times those in a panel of convalescent sera. Cross-reactivity to Alpha, Beta and Delta variants was generally retained to day 201 (>80%) while cross-reactivity to the Gamma variant was reduced but still substantial at day 201 (73%). Cross-reactivity to the Omicron variant fell from 72% at day 42 to 20% at day 201. Almost all participants in all groups (>88%) had detectable cellular responses (IFN-γ, IL-4 or both) at 21 days after the second dose. A Th1-biased response was most evident after the first dose and was still present after the second dose. These data demonstrated that CoVLP+AS03 is well-tolerated and highly immunogenic, generating a durable (at least 6 months) immune response against different VOCs, in adults ≥18 years of age, with and without comorbidities.

Single dose peramivir for the treatment of acute seasonal influenza: integrated analysis of efficacy and safety from two placebo-controlled trials.

BACKGROUND: Current influenza treatment options include oral or inhaled antiviral agents. There is an unmet need for parenteral antiviral treatments. METHODS: Peramivir, a parenteral influenza neuraminidase inhibitor (NAI), was administered by single-dose intramuscular (IM) injection in two placebo-controlled studies in adult outpatients with acute, uncomplicated influenza during two consecutive influenza seasons. RESULTS: In a Phase II study, peramivir treatment significantly shortened duration of fever and reduced viral load in nasopharyngeal secretions. A subsequent Phase III study was not fully enrolled; however, in both studies, the magnitude of the treatment effect favouring peramivir was consistent with that reported for other NAIs. A post-hoc analysis was conducted by integrating efficacy and safety results of 427 subjects from both studies. The median time to alleviation of symptoms (TTAS) in subjects receiving peramivir 300 mg (113.2 h) was shorter than for placebo (134.8 h; P=0.161 adjusted for smoking behaviour, influenza season and virus type; unadjusted P=0.047). The median time to resolution of fever was reduced by 24 h after treatment with peramivir 300 mg compared with placebo (P=0.004). The proportion of subjects shedding influenza virus was significantly decreased over 48 h following peramivir treatment (P=0.009). Detection of post-treatment viruses with decreased susceptibility to NAIs was uncommon. Peramivir was generally safe and well-tolerated with types and rates of adverse event similar to placebo. CONCLUSIONS: The results of these studies are consistent with previous reports of peramivir administered by intravenous infusion, and demonstrate a positive risk-benefit profile for peramivir in patients with acute uncomplicated influenza.

Efficacy and tolerability of once-daily oral telithromycin compared with clarithromycin for the treatment of community-acquired pneumonia in adults.

BACKGROUND: Telithromycin is a new antibacterial agent of the ketolide class designed to provide optimal treatment against common bacterial respiratory tract pathogens. Telithromycin was derived by structural modification of the basic macrolide molecule to allow tight binding to the bacterial ribosome that enhances potency and minimizes the risk for the development of resistant strains. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of telithromycin 800 mg once daily with those of high-dose clarithromycin (500 mg twice daily), each for 10 days, in the treatment of adult patients with community-acquired pneumonia (CAP). METHODS: This randomized, double-blind, double-dummy, parallel-group clinical trial was conducted at 54 centers in the United States, Canada, Argentina, and Chile. Patients aged >or=18 years with acute CAP were randomized to receive 10-day treatment with oral telithromycin 800 mg once daily (administered as two 400-mg encapsulated tablets in the morning) and placebo (administered as 2 encapsulated tablets identical to the telithromycin in the evening) or high-dose clarithromycin (500 mg administered as two 250-mg identical encapsulated tablets twice daily). The primary outcome measure was clinical outcome at the posttherapy, test-of-cure visit (days 17-24 after the completion of therapy) in the clinically assessable per-protocol population. Secondary efficacy variables included bacteriologic outcome at the posttherapy, test-of-cure visit, and clinical and bacteriologic outcomes at the late posttherapy visit (day 31-45). Tolerability was assessed using investigator observation, patient self-reporting, clinical laboratory data, a 12-lead electrocardiogram, and physical examination (including vital signs). RESULTS: A total of 493 patients were enrolled and 448 patients received >or=1 dose of study medication (224 patients/group). A diagnosis of CAP was confirmed in 416 patients (205 men, 211 women; median age, 43 years; telithromycin, n = 204; clarithromycin, n = 212). Clinical cure rates were 88.3% (143/162) in the telithromycin group and 88.5% ( 138/56) in the clarithromycin group. Bacterial eradication rates were comparable between treatment groups (telithromycin, (28/32) [87.5%]; clarithromycin, (29/30) [96.7%]. Both treatment were fairly well tolerated; adverse events were experienced in 57.0% of the patients treated with telithromycin and 49.1% of those treated with clarithromycin; most of these were assessed as mild. CONCLUSIONS: In this study of adult patients with CAP, telithromycin 800 mg once daily was an effective and fairly well-tolerated regimen for initial empiric treatment, with clinical and bacteriologic efficacy and tolerability equivalent to therapy with high-dose clarithromycin (500 mg twice daily).

Comparison of hospitalization rates in patients with community-acquired pneumonia treated with telithromycin for 5 or 7 days or clarithromycin for 10 days.

AIMS: To compare the impact on hospitalization rates and the clinical efficacy of oral telithromycin and clarithromycin treatment in patients with community-acquired pneumonia (CAP). METHODS: A total of 581 patients with CAP were enrolled in this randomized, double-blind, parallel group, multinational study, of whom 575 were evaluated for healthcare resource utilization from a payer perspective (intent to treat [ITT] population). Patients received telithromycin 800 mg once daily for 5 (n = 193) or 7 (n = 195)days, or clarithromycin 500 mg once daily for 10 days (n = 187). The primary efficacy endpoint was clinical outcome at test of cure (Days 17-24) in the per-protocol population. Frequency of CAP-related hospitalizations, physician visits/tests/procedures, and additional respiratory tract infection-related antibacterial use were compared by treatment group (ITT) up to late post- for clarithromycin vs dollars 37930 (difference: -26446; therapy (Days 31-36). Study investigators blinded to treatment assessed whether hospital admissions were CAP-related or not. CAP-related hospitalization costs (USdollars) for telithromycin and clarithromycin were compared. RESULTS: Clinical cure rates were similar in patients who received clarithromycin for 10 days and telithromycin for 5 or 7 days: 91.8% (134/146), 89.3% (142/159), and 88.8% (143/161), respectively, and both 5- and 7-day telithromycin were statistically equivalent to clarithromycin (difference: -2.5 and -3.0%, respectively; 95% CI: -9.7, 4.7 and -10.2, 4.3, respectively). There were 7 CAP-related hospital admissions among clarithromycin patients vs 3 (p = 0.283) and 1 (p = 0.021) admissions among 5- and 7-day telithromycin patients, respectively. The number of hospital days/100 patients was 40.1 for clarithromycin vs 17.1 and 7.2 for 5- and 7-day telithromycin, respectively. Projected hospitalization costs/100 patients were dollars 86205 95% CI: -66 654; 13 762) and dollars 16 091 (difference: -37 847; 95% CI: -77953; 2259) for 5- and 7-day telithromycin, respectively. CONCLUSIONS: Data from this study demonstrate that telithromycin 800 mg once daily for 5 or 7 days with fewer hospital days and potentially lower is an effective treatment for CAP,and that telithromycin treatment of CAP may be associated hospitalization costs than clarithromycin treatment.

Efficacy and tolerability of telithromycin for 5 or 10 days vs amoxicillin/clavulanic acid for 10 days in acute maxillary sinusitis.

Telithromycin (HMR 3647) is a new ketolide antimicrobial that was developed for the treatment of community-acquired respiratory tract injections. We conducted a randomized, double-blind, multicenter study to compare the clinical efficacy and safety of oral telithromycin, at 800 mg once daily for 5 or 10 days, with that of amoxicillin/clavulanic acid, at 500/125 mg three times daily for 10 days, in adults with acute maxillary sinusitis (AMS). A total of 754 patients with AMS of less than 28 days' duration were randomized to receive either telithromycin for 5 days followed by placebo for 5 days, telithromycin for 10 days, or amoxicillin/clavulanic acid for 10 days. Clinical outcome was assessed at a test-of-cure (TOC) visit between days 17 and 24 and at a late post-therapy visit between days 31 and 45. Analysis of clinical outcome on a per-protocol basis (n = 434) demonstrated therapeutic equivalence among the three regimens at the TOC visit; in each treatment group, the clinical cure rate was approximately 75%. Only a few patients (3 to 5 in each group) had relapsed by the late post-therapy follow-up visit. Telithromycin was generally safe and well tolerated. The most common adverse events were mild or moderate gastrointestinal effects, which occurred with similar frequency in all three groups. We conclude that 5 or 10 days of telithromycin at 800 mg once daily is as effective clinically and as well tolerated as 10 days of treatment with amoxicillin/clavulanic acid. Telithromycin, therefore, appears to be a valuable option for the treatment of AMS.

Telithromycin for the treatment of acute bacterial maxillary sinusitis: a review of a new antibacterial agent.

OBJECTIVE: Telithromycin, the first approved ketolide antibiotic, was developed to treat community-acquired respiratory tract infections, including acute bacterial maxillary sinusitis (ABMS). A previously published study showed that a 5-day course of 800 mg telithromycin once daily is as effective as a 10-day course in the treatment of ABMS. MATERIALS AND METHODS: Data were pooled from two controlled, multinational, prospective, randomized, double-blinded ABMS trials comparing 5-day telithromycin (800 mg once daily) with 10-day amoxicillin-clavulanate (500/125 mg 3 times daily) and cefuroxime axetil (250 mg twice daily). Clinical cure and bacteriologic eradication rates were compared by means of descriptive statistics. RESULTS: The clinical cure rate for telithromycin was 80.9% versus 77.4% for comparators; bacteriologic eradication rate for telithromycin was 84.9% versus 81.7% for comparators. Most adverse events were mild to moderate in intensity and, most commonly, gastrointestinal in nature. CONCLUSIONS: These results support the conclusion that 5 days of treatment with telithromycin is as safe and effective in patients with ABMS as a 10-day course of treatment with amoxicillin-clavulanate or cefuroxime axetil.

Clinical and bacteriological efficacy and safety of 5 and 7 day regimens of telithromycin once daily compared with a 10 day regimen of clarithromycin twice daily in patients with mild to moderate community-acquired pneumonia.

OBJECTIVES: This study was conducted to investigate the potential equivalence in clinical efficacy and assess safety of a 5 or 7 day regimen of oral telithromycin (800 mg once daily) and a 10 day regimen of oral clarithromycin (500 mg twice daily) in treating community-acquired pneumonia (CAP). Bacteriological efficacy was also compared. METHODS: This was a multicentre, randomized, double-blind, active-controlled study. Patients with mild to moderate CAP received telithromycin 800 mg once a day for 5 (n=193) or 7 (n=195) days or clarithromycin 500 mg twice a day for 10 days (n=187). In these groups, 159, 161 and 146 patients, respectively, completed the study. RESULTS: At the post-therapy/test-of-cure evaluation, clinical cure rates (per-protocol clinical population) were 89.3% (5 days) and 88.8% (7 days) for telithromycin, and 91.8% for clarithromycin 10 days. Satisfactory bacteriological outcome rates (per-protocol bacteriological population) were 87.7% and 80.0% for 5 and 7 days of telithromycin, respectively, and 83.3% for 10 days of clarithromycin. Bacteriological eradication rates in the respective treatment groups were, for Streptococcus pneumoniae, 95.8% (23/24), 96.7% (29/30) and 88.5% (23/26); for Haemophilus influenzae, 88.0% (22/25), 84.0% (21/25) and 88.2% (15/17) and for Moraxella catarrhalis, 1/1, 4/5 and 3/4. Both telithromycin regimens demonstrated clinical efficacy against pneumococcal bacteraemia (19/19), atypical pathogens (9/9) and erythromycin-resistant S. pneumoniae isolates (5/5). Most treatment-emergent adverse events were mild to moderate in intensity with most commonly reported adverse events involving the gastrointestinal system. CONCLUSIONS: Telithromycin 800 mg administered once a day for 5 or 7 days was as effective and safe as clarithromycin 500 mg administered twice a day for 10 days in treating patients with CAP caused by common respiratory pathogens, including macrolide-resistant isolates, and pneumococcal bacteraemia.