Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1.

BACKGROUND: Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides. METHODS: We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate. RESULTS: Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients. CONCLUSIONS: In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.).

One-year immunogenicity kinetics and safety of a purified chick embryo cell rabies vaccine and an inactivated Vero cell-derived Japanese encephalitis vaccine administered concomitantly according to a new, 1-week, accelerated primary series.

BACKGROUND: Conventional rabies pre-exposure prophylaxis (PrEP) and Japanese encephalitis (JE) primary series vaccination regimens each require up to 4 weeks to complete and, thus, may not be feasible for individuals who need these immunizations on short notice. This Phase 3b, randomized, controlled, observer-blind study evaluated the immunogenicity and safety of concomitant administration of a purified chick embryo cell culture rabies vaccine and an inactivated, adsorbed JE vaccine according to an accelerated (1 week) regimen when compared with the conventional regimens (4 weeks). This report describes the kinetics of immune responses up to 1 year after vaccination. METHODS: A total of 661 healthy adults (18 to ≤65 years) were randomized into the following accelerated or conventional vaccine regimens: Rabies + JE-Conventional, Rabies + JE-Accelerated, Rabies-Conventional and JE-Conventional. Immunogenicity was assessed by virus neutralization tests. Safety and tolerability were also evaluated. RESULTS: Irrespective of rabies vaccination regimen, ≥97% of subjects had adequate levels of rabies virus neutralizing antibody (RVNA) concentrations (≥0.5 IU/ml) up to Day 57, with percentages of subjects with RVNA concentrations ≥0.5 IU/ml at Day 366 ranging between 68% in the Rabies + JE-Accelerated group and 80% of subjects in the Rabies-Conventional group. The Rabies + JE-Accelerated group revealed high JE neutralizing antibody titers at all-time points. At Day 366, the percentage of subjects with antibody titers indicative of seroprotection (PRNT50 titers ≥1:10) remained high across JE vaccine groups (86-94%). CONCLUSIONS: The accelerated PrEP rabies and JE vaccination regimens, once licensed, could represent a valid alternative in the short-term to currently recommended conventional regimens. The concomitant administration of these two vaccines does not compromise immune responses to any of the vaccine antigens particularly when aiming for short-term protection. Further evidence will clarify the need for and timing to administration of rabies vaccine booster doses in subjects primed with an accelerated PrEP regimen. (NCT01662440).

A 2013/2014 northern hemisphere season surface antigen inactivated trivalent influenza vaccine--Assessing the immunogenicity and safety in an open label, uncontrolled study.

The present study evaluated the safety and immunogenicity of the 2013/2014 trivalent surface antigen inactivated subunit seasonal influenza virus vaccine Fluvirin® in healthy adults (18 - ≤ 60 years) and elderly (>60 years). The vaccine contained 15 µg haemagglutinin protein from each of influenza A/California/7/2009 (H1N1)pdm09-like strain, A/Victoria/361/2011 (H3N2)-like strain and B/Massachusetts/2/2012-like strain (B/Yamagata) as recommended by the WHO in the 2013/2014 Northern Hemisphere season. Antibody response to each influenza antigen after vaccination was measured prior to vaccination and 21 d after by single radial hemolysis (SRH) assay or hemagglutination inhibition (HI) assay in accordance with Guidance CPMP/BWP/214/96. 125 subjects (61 adults and 64 elderly) were enrolled in the study. Pre-vaccination protective antibody levels (SRH area ≥ 25 mm(2)) against A(H1N1), A(H3N2) and the B strain were detected in 17%, 20% and 57% of adults and in 36%, 20% and 55% of elderly, respectively, Post-vaccination, SRH area ≥ 25 mm(2) was detectable in 95%, 82% and 92% in adult and in 80%, 84% and 92% of the elderly subjects for A(H1N1), A(H3N2) and the B strain, respectively. Geometric mean ratio (GMR) was higher in adult subjects (2.62-7.62) than in elderly subjects (2.33-3.42). All three CHMP licensure criteria were met for all strains contained in the vaccine for both age groups. The most frequently reported solicited local and systemic reactions were pain at the injection side, headache and fatigue. In conclusion, the vaccine demonstrated a good immunogenicity and an acceptable safety profile in both adults and elderly.

Short-Term Immunogenicity and Safety of an Accelerated Pre-Exposure Prophylaxis Regimen With Japanese Encephalitis Vaccine in Combination With a Rabies Vaccine: A Phase III, Multicenter, Observer-Blind Study.

BACKGROUND: The current Japanese encephalitis (JE) vaccination regimen requires two doses and 4 weeks to complete, which may not always be feasible for travelers on short notice. One of the primary endpoints of this phase III study was to demonstrate noninferiority of immune responses to a JE vaccine following an accelerated 1-week JE vaccination regimen administered concomitantly with a rabies vaccine as compared to a standard 4-week JE regimen alone. In addition, the immunogenicity of concomitant administration of JE and rabies vaccines following standard regimens was evaluated, as well as the tolerability and safety profile of each regimen under study. METHODS: Healthy adults aged 18 to ≤65 years were randomized to regimens with an accelerated or standard schedule: JE+rabies-standard (n = 167), JE+rabies-accelerated (n = 217) or JE-standard (n = 56). Immunogenicity against JE antigen was assessed by a 50% plaque reduction neutralization test (PRNT50 ) titer of ≥1 : 10, measured 28 days after last active vaccine (LAV) administration. Solicited reactions were collected 7 days after each vaccination; spontaneously reported adverse events (AEs) and serious AEs were monitored up to day 57. This paper reports results until day 57. RESULTS: Noninferiority of immune responses was established for JE+rabies-accelerated compared to the JE-standard regimen 28 days after LAV administration. Overall, 99% and 100% of subjects in the JE+rabies-accelerated and JE-standard groups, respectively, achieved PRNT50 titers of ≥1 : 10 at 28 days after LAV administration. No impact of concomitant rabies vaccination was observed either on immune responses or on the safety profile of the JE vaccine. CONCLUSIONS: This was the first randomized, controlled trial that demonstrated the strong short-term immunogenicity of a new, accelerated, 1-week JE-regimen, which was noninferior to that of the standard regimen, with a satisfactory tolerability and safety profile and no impact of concomitant rabies vaccination. This accelerated regimen, if licensed, could potentially be a valid alternative for individuals requiring a primary series of JE vaccination and rabies pre-exposure prophylaxis on short notice.

Immunogenicity and safety of concomitant administration of a combined hepatitis A/B vaccine and a quadrivalent meningococcal conjugate vaccine in healthy adults.

BACKGROUND: This phase 3b randomized, open-label study evaluated the immunogenicity and safety of coadministration of a hepatitis A and/or B vaccine with a quadrivalent oligosaccharide meningococcal CRM197 -conjugate vaccine (MenACWY-CRM), in the context of an accelerated hepatitis A and/or B immunization schedule. METHODS: A total of 252 healthy adult subjects were randomized to three groups to receive hepatitis A/B only (HepA/B), hepatitis A/B coadministered with MenACWY-CRM (HepA/B+MenACWY-CRM), or MenACWY-CRM only (MenACWY-CRM). Hepatitis A and/or B vaccination was administered in the form of a single booster dose or a primary three-dose series, depending on the hepatitis A and/or B vaccination history of subjects. Antibody responses to hepatitis A/B vaccination were assessed 1 month following the last hepatitis A and/or B dose. Serum bactericidal activity with human complement (hSBA) against meningococcal serogroups A, C, W-135, and Y was assessed 1 month post-MenACWY-CRM vaccination. Safety was monitored throughout the study. RESULTS: At 1 month following the final hepatitis A and/or B vaccination, concomitant administration of hepatitis A/B and MenACWY-CRM was non-inferior to administration of hepatitis A/B alone in terms of geometric mean concentrations of antibodies against the hepatitis A and B antigens. One month post-MenACWY-CRM vaccination, the percentages of subjects achieving hSBA titers ≥8 for serogroups A, C, W-135, and Y in the HepA/B+MenACWY-CRM group (76, 87, 99, and 94%, respectively) were comparable to those in the MenACWY-CRM group (67, 82, 96, and 88%, respectively). The percentages of subjects reporting adverse events (AEs) were similar across study groups and a majority of the reported AEs were mild to moderate in nature. There were no study vaccine-related serious AEs. CONCLUSIONS: MenACWY-CRM can be administered concomitantly with a hepatitis A and/or B vaccine in the context of an accelerated hepatitis A and/or B immunization schedule without increasing safety concerns or compromising the immune responses to any of the vaccine antigens. [NCT01453348].

Co-administration of a meningococcal glycoconjugate ACWY vaccine with travel vaccines: a randomized, open-label, multi-center study.

BACKGROUND: Potential interactions between vaccines may compromise the immunogenicity and/or safety of individual vaccines so must be assessed before concomitant administration is recommended. In this study, the immunogenicity and safety of travel vaccines against Japanese encephalitis (JEV) and rabies (PCECV) administered together with or without a quadrivalent meningococcal glycoconjugate ACWY-CRM vaccine were evaluated (NCT01466387). METHOD: Healthy adults aged 18 to ≤60 years were randomized to one of four vaccine regimens: JEV + PCECV + MenACWY-CRM, JEV + PCECV, PCECV or MenACWY-CRM. Immunogenicity at baseline and 28 days post-complete vaccination was assessed by serum bactericidal assay using human complement or neutralization tests. Adverse events (AEs) were collected throughout the study period. RESULTS: JEV + PCECV + MenACWY-CRM was non-inferior to JEV + PCECV. Post-vaccination seroprotective neutralizing titers or concentrations were achieved in 98-99% (JE) and 100% (rabies) of subjects across the vaccine groups. Antibody responses to vaccine meningococcal serogroups were in the same range for MenACWY-CRM and JEV + PCECV + MenACWY-CRM. Rates of reporting of AEs were similar for JEV + PCECV and JEV + PCECV + MenACWY-CRM. CONCLUSIONS: MenACWY-CRM was administered with an inactivated adjuvanted JE and a purified chick embryo cell-culture rabies vaccine without compromising immunogenicity or safety of the individual vaccines. These data provide evidence that MenACWY-CRM could be effectively incorporated into travel vaccination programs. TRIAL NUMBER: NCT01466387.

Immunogenicity and safety of an inactivated 2012/2013 trivalent influenza vaccine produced in mammalian cell culture (Optaflu®): an open label, uncontrolled study.

BACKGROUND: The present study aimed to evaluate immunogenicity and safety of the 2012/2013 seasonal influenza vaccine (Optaflu(®)) after the World Health Organization recommended two new strains for the composition. RESULTS: Twenty-one days post-vaccination geometric mean titers (GMTs) against A(H1N1), A(H3N2) and the B strain were 528, 935, and 201 for adults and 272, 681, and 101 for elderly subjects, respectively. The proportion of subjects with a HI titer of ≥ 40 against the three strains A(H1N1), A(H3N2) and B was 98%, 100%, and 98% in adults and 100%, 100%, and 85% in elderly subjects, respectively. Optaflu(®) met the CHMP criteria of the Committee for Medicinal Products for Human Use (CPMP/BWP/214/96). Pre-vaccination titers indicated seroprotection against the A(H1N1), the A(H3N2) and the B strain in 56%, 86%, and 54% of the adults and in 61%, 85%, and 40% of the elderly with highest titers against the A(H3N2) strain. In the safety analysis injection site pain (37%) and myalgia (31%) were the most common local and systemic reactions. No serious adverse events were recorded. CONCLUSION: The 2012/2013 seasonal influenza vaccine Optaflu(®) showed good immunogenicity and an acceptable safety profile in both adults and elderly. METHODS: In this trial, 126 subjects (63 adults ≥18 to ≤60 y, 63 elderly ≥61 y) were vaccinated with a single dose Optaflu(®) containing each of the three virus strains recommended for the 2012/2013 season (A/California/7/2009(H1N1)-like strain, A/Victoria/361/2011(H3N2)-like strain, and B/Wisconsin/1/2010-like strain). Immunogenicity was assessed by hemagglutinin inhibition (HI) and single radial hemolysis (SRH) assays on day 22, the safety profile was investigated throughout the whole study period.

Clinical trial to evaluate the safety and immunogenicity of a trivalent surface antigen seasonal influenza vaccine produced in mammalian cell culture and administered to young and elderly adults with and without A(H1N1) pre-vaccination.

UNLABELLED: Vaccination against influenza is an important means of reducing morbidity and mortality in subjects at risk. The prevalent viral strains responsible for seasonal epidemics usually change annually, but the WHO recommendations for the 2011/2012-season in the Northern hemisphere included the same antigens as for the previous season. We conducted a single-center, single-arm study involving 62 younger (18-60 years) and 64 older (>60 years) adults to test the immunogenicity, safety and tolerability of a trivalent surface antigen, inactivated influenza vaccine produced in mammalian cell-culture. The vaccine contained 15 µg hemagglutinin of each of the virus strains recommended for the 2011-2012 Northern hemisphere winter season (A/California/7/09 (H1N1)-; A/Perth/16/09 (H3N2)-; B/Brisbane/60/08-like strain) in a non-adjuvanted preservative-free formulation. Antibody response was measured by hemagglutination inhibition 21 days after immunization. Adverse events and safety were assessed using subject diary cards and telephone interviews. Seroconversion or a 4-fold antibody increase in antibody titers was detectable against A(H1N1) in 68% of both younger and older adults, against A(H3N2) in 53% and 27%, and against the B influenza strain in 35% and 17%. Antibody titers of 40 or more were observed against A(H1N1) in 87% and 90% of younger and older adults, against A(H3N2) in 98% and 98%, and against the B influenza strain in 93% and 90%. Pre-vaccination antibody titers were protective against A(H1N1), A(H3N2) and B in 38%, 58% and 58%, respectively, of younger and in 43%, 88% and 70% of older adults. Among subjects with previous A(H1N1) vaccination only 48% of younger and 47% of older adults had protective A(H1N1) antibodies at inclusion. Adverse reactions were generally mild. The most frequently reported reactions were pain at the injection site, myalgia and fatigue. The vaccine generated protective antibodies against all three viral strains and had an acceptable safety profile in both younger and older adults. TRIAL REGISTRATION: ClinicalTrials.govNCT01422512.