Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4·5-year results from a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: About half of the world's population lives in dengue-endemic areas. We aimed to evaluate the long-term efficacy and safety of two doses of the tetravalent dengue vaccine TAK-003 in preventing symptomatic dengue disease of any severity and due to any dengue virus (DENV) serotypes in children and adolescents. METHODS: In this ongoing double-blind, randomised, placebo-controlled trial, we enrolled healthy participants aged 4-16 years at 26 medical and research centres across eight dengue-endemic countries (Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). The main exclusion criteria were febrile illness (body temperature ≥38°C) at the time of randomisation, hypersensitivity or allergy to any of the vaccine components, pregnancy or breastfeeding, serious chronic or progressive disease, impaired or altered immune function, and previous receipt of a dengue vaccine. Participants were randomly assigned 2:1 (stratified by age and region) using an interactive web response system and dynamic block assignment to receive two subcutaneous doses of TAK-003 or placebo 3 months apart. Investigators, participants, and their parents or legal guardians were blinded to group assignments. Active febrile illness surveillance and RT-PCR testing of febrile illness episodes were performed for identification of virologically confirmed dengue. Efficacy outcomes were assessed in the safety analysis set (all randomly assigned participants who received ≥1 dose) and the per protocol set (all participants who had no major protocol violations), and included cumulative vaccine efficacy from first vaccination to approximately 4·5 years after the second vaccination. Serious adverse events were monitored throughout. This study is registered with ClinicalTrials.gov, NCT02747927. FINDINGS: Between Sept 7, 2016, and March 31, 2017, 20 099 participants were randomly assigned (TAK-003, n=13 401; placebo, n=6698). 20 071 participants (10 142 [50·5%] males; 9929 [49·5%] females; safety set) received TAK-003 or placebo, with 18 257 (91·0%) completing approximately 4·5 years of follow-up after the second vaccination (TAK-003, 12 177/13 380; placebo, 6080/6687). Overall, 1007 (placebo: 560; TAK-003: 447) of 27 684 febrile illnesses reported were virologically confirmed dengue, with 188 cases (placebo: 142; TAK-003: 46) requiring hospitalisation. Cumulative vaccine efficacy was 61·2% (95% CI 56·0-65·8) against virologically confirmed dengue and 84·1% (77·8-88·6) against hospitalised virologically confirmed dengue; corresponding efficacies were 53·5% (41·6-62·9) and 79·3% (63·5-88·2) in baseline seronegative participants (safety set). In an exploratory analysis, vaccine efficacy was shown against all four serotypes in baseline seropositive participants. In baseline seronegative participants, vaccine efficacy was shown against DENV-1 and DENV-2 but was not observed against DENV-3 and low incidence precluded evaluation against DENV-4. During part 3 of the trial (approximately 22-57 months after the first vaccination), serious adverse events were reported for 664 (5·0%) of 13 380 TAK-003 recipients and 396 (5·9%) of 6687 placebo recipients; 17 deaths (6 in the placebo group and 11 in the TAK-003 group) were reported, none were considered study-vaccine related. INTERPRETATION: TAK-003 demonstrated long-term efficacy and safety against all four DENV serotypes in previously exposed individuals and against DENV-1 and DENV-2 in dengue-naive individuals. FUNDING: Takeda Vaccines. TRANSLATIONS: For the Portuguese, Spanish translations and plain language summary of the abstract see Supplementary Materials section.

Bridging the immunogenicity of a tetravalent dengue vaccine (TAK-003) from children and adolescents to adults.

Immunobridging is an important methodology that can be used to extrapolate vaccine efficacy estimates to populations not evaluated in clinical studies, and that has been successfully used in developing many vaccines. Dengue, caused by a mosquito-transmitted flavivirus endemic to many tropical and subtropical regions, is traditionally thought of as a pediatric disease but is now a global threat to both children and adults. We bridged immunogenicity data from a phase 3 efficacy study of a tetravalent dengue vaccine (TAK-003), performed in children and adolescents living in endemic areas, with an immunogenicity study in adults in non-endemic areas. Neutralizing antibody responses were comparable in both studies following receipt of a two-dose TAK-003 schedule (months 0 and 3). Similar immune responses were observed across exploratory assessments of additional humoral responses. These data support the potential for clinical efficacy of TAK-003 in adults.

Effect of the Tetravalent Dengue Vaccine TAK-003 on Sequential Episodes of Symptomatic Dengue.

In the pivotal phase 3 efficacy trial (NCT02747927) of the TAK-003 dengue vaccine, 5 of 13,380 TAK-003 recipients and 13 of 6,687 placebo recipients experienced two episodes of symptomatic dengue between the first dose and the end of the study, ∼57 months later (patients received the second dose 3 months after the first dose). Two of these participants experienced repeat infection with the same serotype (i.e., homotypic reinfection). In comparison with placebo, the relative risk of a subsequent episode of symptomatic dengue was 0.19 (95% CI, 0.07-0.54) in TAK-003 recipients. Based on the small number of subsequent episodes, these data suggest a potential incremental effect of TAK-003 beyond prevention of the first episode of symptomatic dengue after vaccination.

Three-year Efficacy and Safety of Takeda's Dengue Vaccine Candidate (TAK-003).

BACKGROUND: Takeda's live attenuated tetravalent dengue vaccine candidate (TAK-003) is under evaluation in a long-term clinical trial across 8 dengue-endemic countries. Previously, we have reported its efficacy and safety in both seronegative and seropositive participants and that its performance varies by serotype, with some decline in efficacy from first to second year postvaccination. This exploratory analysis provides an update with cumulative and third-year data. METHODS: Healthy 4-16 year olds (n = 20099) were randomized 2:1 to receive TAK-003 or placebo (0, 3 month schedule). The protocol included baseline serostatus testing of all participants and detection of all symptomatic dengue throughout the trial with a serotype specific reverse transcriptase-polymerase chain reaction. RESULTS: Cumulative efficacy after 3 years was 62.0% (95% confidence interval, 56.6-66.7) against virologically confirmed dengue (VCD) and 83.6% (76.8-88.4) against hospitalized VCD. Efficacy was 54.3% (41.9-64.1) against VCD and 77.1% (58.6-87.3) against hospitalized VCD in baseline seronegatives, and 65.0% (58.9-70.1) against VCD and 86.0% (78.4-91.0) against hospitalized VCD in baseline seropositives. Efficacy against VCD during the third year declined to 44.7% (32.5-54.7), whereas efficacy against hospitalized VCD was sustained at 70.8% (49.6-83.0). Rates of serious adverse events were 2.9% in TAK-003 group and 3.5% in placebo group during the ongoing long-term follow-up (ie, second half of the 3 years following vaccination), but none were related. No important safety risks were identified. CONCLUSIONS: TAK-003 was efficacious against symptomatic dengue over 3 years. Efficacy declined over time but remained robust against hospitalized dengue. A booster dose evaluation is planned.

Efficacy of a Dengue Vaccine Candidate (TAK-003) in Healthy Children and Adolescents 2 Years after Vaccination.

BACKGROUND: Takeda's dengue vaccine is under evaluation in an ongoing phase 3 efficacy study; we present a 2-year update. METHODS: Children (20 099, 4-16 years old) were randomized to receive 2 doses of TAK-003 or placebo 3 months apart and are under surveillance to detect dengue by serotype-specific RT-PCR. RESULTS: Cumulative efficacy against dengue approximately 27 months since first dose was 72.7% (95% confidence interval [CI], 67.1%-77.3%), including 67.0% (95% CI, 53.6%-76.5%) in dengue-naive and 89.2% (95% CI, 82.4%-93.3%) against hospitalized dengue. In the second year, decline in efficacy was observed (56.2%; 95% CI, 42.3%-66.8%) with the largest decline in 4-5 year olds (24.5%; 95% CI, -34.2% to 57.5%); efficacy was 60.6% (95% CI, 43.8%-72.4%) in 6-11 year and 71.2% (95% CI, 41.0%-85.9%) in 12-16 year age groups. As TAK-003 efficacy varies by serotype, changes in serotype dominance partially contributed to efficacy differences in year-by-year analysis. No related serious adverse events occurred during the second year. CONCLUSIONS: TAK-003 demonstrated continued benefit independent of baseline serostatus in reducing dengue with some decline in efficacy during the second year. Three-year data will be important to see if efficacy stabilizes or declines further.Clinical Trials Registration. NCT02747927.Takeda's tetravalent dengue vaccine (TAK-003) continued to demonstrate benefit in reducing dengue independent of baseline serostatus up to 2 years after completing vaccination with some decline in efficacy during the second year in 4-16 year olds in dengue-endemic countries.

Immunogenicity and safety of a tetravalent dengue vaccine in dengue-naïve adolescents in Mexico City.

OBJECTIVE: To describe the immunogenicity and safety of a tetravalent dengue vaccine (TAK-003) in healthy adolescents living in Mexico City, an area considered non-endemic for dengue (NCT03341637). METHODS: Participants aged 12-17 years were randomized 3:1 to receive two doses (Month 0 and Month 3) of TAK-003 or placebo. Immunogenicity was assessed by microneutralization assay of dengue neutralizing antibodies at baseline, Months 4 and 9. Solicited and unsolicited adverse events (AEs) were recorded after each vaccination. Serious (SAEs) and medically-attended AEs (MAAEs) were recorded throughout the study. RESULTS: 400 adolescents were enrolled, 391 (97.8%) completed the study. Thirty-six (9%) were baseline seropositive to ≥1 serotypes (reciprocal titer ≥10). Geometric mean titers (GMTs) in baseline seronegative TAK-003 recipients were 328, 1743, 120, and 143 at Month 4, and 135, 741, 46, and 38 at Month 9 against DENV-1, -2, -3, and -4, respectively. Placebo GMTs remained <10. Tetravalent seropositivity rates in vaccine recipients were 99.6% and 85.8% at Months 4 and 9, respectively. One MAAE in each group was considered treatment-related (TAK-003: injection-site erythema, and placebo: pharyngitis). CONCLUSION: TAK-003 was immunogenic against all four serotypes and was well tolerated in dengue-naïve adolescents living in Mexico City.

Immunogenicity and safety of a tetravalent dengue vaccine in dengue-naïve adolescents in Mexico City

[ABSTRACT]. Objective. To describe the immunogenicity and safety of a tetravalent dengue vaccine (TAK-003) in healthy adolescents living in Mexico City, an area considered non-endemic for dengue (NCT03341637). Methods. Participants aged 12–17 years were randomized 3:1 to receive two doses (Month 0 and Month 3) of TAK-003 or placebo. Immunogenicity was assessed by microneutralization assay of dengue neutralizing antibodies at baseline, Months 4 and 9. Solicited and unsolicited adverse events (AEs) were recorded after each vaccination. Serious (SAEs) and medically-attended AEs (MAAEs) were recorded throughout the study. Results. 400 adolescents were enrolled, 391 (97.8%) completed the study. Thirty-six (9%) were baseline seropositive to ≥1 serotypes (reciprocal titer ≥10). Geometric mean titers (GMTs) in baseline seronegative TAK-003 recipients were 328, 1743, 120, and 143 at Month 4, and 135, 741, 46, and 38 at Month 9 against DENV-1, -2, -3, and -4, respectively. Placebo GMTs remained <10. Tetravalent seropositivity rates in vaccine recipients were 99.6% and 85.8% at Months 4 and 9, respectively. One MAAE in each group was considered treatment-related (TAK-003: injection-site erythema, and placebo: pharyngitis). Conclusion. TAK-003 was immunogenic against all four serotypes and was well tolerated in dengue-naïve adolescents living in Mexico City.

[RESUMEN]. Objetivo. Describir la inmunogenicidad y la seguridad de una vacuna tetravalente contra el dengue (TAK-003) en adolescentes sanos residentes en Ciudad de México, considerada un área no endémica de dengue (NCT03341637). Métodos. Se asignó de manera aleatoria a un grupo de participantes de 12 a 17 años en una proporción 3:1 para que recibieran dos dosis (en el mes 0 y en el mes 3) de la vacuna TAK-003 o de un placebo. Se evaluó la inmunogenicidad mediante un análisis de microneutralización de anticuerpos neutralizantes del virus del dengue al inicio del estudio y en los meses 4 y 9. Se registraron los eventos adversos de notificación solicitada y los referidos por iniciativa propia después de cada vacunación. A lo largo del estudio se registraron los eventos adversos graves y los que requirieron atención médica. Resultados. Participaron 400 adolescentes y 391 (97,8%) finalizaron el estudio. 36 adolescentes (9%) fueron seropositivos a ≥1 serotipos (título recíproco ≥10) al inicio del estudio. La media geométrica de los títulos en las personas seronegativas vacunadas con TAK-003 al inicio del estudio fue de 328, 1743, 120 y 143 en el mes 4 y 135, 741, 46 y 38 en el mes 9 en relación con DENV-1, -2, -3 y -4, respectivamente. La media geométrica de los títulos de las personas que recibieron un placebo se mantuvo en <10. Las tasas de seropositividad tetravalente en los vacunados fueron 99,6% y 85,8% a los meses 4 y 9, respectivamente. Se consideró relacionado con el tratamiento un evento adverso con atención médica que tuvo lugar en cada grupo (TAK-003: eritema en el lugar de la inyección; placebo: faringitis). Conclusiones. TAK-003 fue inmunogénica ante los cuatro serotipos y bien tolerada en los adolescentes sin exposición previa al dengue que vivían en Ciudad de México.

[RESUMO]. Objetivo. Descrever a imunogenicidade e a segurança de uma vacina tetravalente contra dengue (TAK-003) em adolescentes saudáveis residentes da Cidade do México, área considerada não endêmica para dengue (ClinicalTrials.gov: NCT03341637). Métodos. Participantes com idade entre 12 e 17 anos foram randomizados a uma proporção de 3:1 para receber duas doses da vacina TAK-003 ou placebo (no mês 0 e no mês 3). A imunogenicidade foi avaliada pelos títulos de anticorpos neutralizantes contra dengue determinados em ensaio de microneutralização ao início do estudo, no mês 4 e no mês 9. A ocorrência de eventos adversos solicitados ou espontâneos foi registrada após cada rodada de vacinação. Eventos adversos graves e eventos adversos que exigiram atendimento médico foram monitorados ao longo de todo o estudo. Resultados. De 400 adolescentes incluídos na amostra estudada, 391 (97,8%) completaram o estudo. Trinta e seis (9%) apresentaram positividade basal a um ou mais sorotipos virais da dengue (título recíproco ≥10). A média geométrica dos títulos de anticorpos nos vacinados com TAK-003 que eram soronegativos ao início do estudo foi de 328, 1743, 120 e 143 no mês 4 e 135, 741, 46 e 38 no mês 9, contra os sorotipos virais DENV-1, DENV-2, DENV-3 e DENV-4, respectivamente. A média geométrica dos títulos de anticorpos no grupo placebo se manteve abaixo de 10. A taxa de soropositividade tetravalente nos vacinados foi de 99,6% no mês 4 e 85,8% no mês 9. Um único evento adverso que exigiu atendimento médico em cada grupo foi considerado relacionado ao tratamento (eritema no local de aplicação no grupo TAK-003 e faringite no grupo placebo). Conclusão. A vacina TAK-003 demonstrou ser imunogênica contra os quatro sorotipos virais da dengue e foi bem tolerada em adolescentes residentes da Cidade do México sem história pregressa de infecção pela dengue.

Efficacy of a tetravalent dengue vaccine in healthy children aged 4-16 years: a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: A substantial unmet need remains for safe and effective vaccines against dengue virus disease, particularly for individuals who are dengue-naive and those younger than 9 years. We aimed to assess the efficacy, safety, and immunogenicity of a live attenuated tetravalent dengue vaccine (TAK-003) in healthy children aged 4-16 years. METHODS: We present data up to 18 months post-vaccination from an ongoing phase 3, randomised, double-blind trial of TAK-003 in endemic regions of Asia and Latin America (26 medical and research centres across Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). Healthy children aged 4-16 years were randomly assigned 2:1 (stratified by age and region) to receive two doses of TAK-003 or two doses of placebo, 3 months apart. Investigators, participants and their parents or guardians, and sponsor representatives advising on trial conduct were masked to trial group assignments. Participants presenting with febrile illness were tested for virologically confirmed dengue (VCD) by serotype-specific RT-PCR. In timeframes beginning 30 days post-second dose, the primary endpoint (overall vaccine efficacy) was assessed in the first 11 months, and the secondary endpoints (efficacy by baseline serostatus, serotype, hospitalised dengue, and severe dengue) in the first 17 months. This study is registered with ClinicalTrials.gov, NCT02747927. FINDINGS: 20 099 participants were randomly assigned and vaccinated between Sept 7, 2016, and Aug 18, 2017; 19 021 (94·6%) were included in the per protocol analysis, and 20 071 (99·9%) in the safety set. The primary endpoint was achieved with an overall vaccine efficacy of 80·2% (95% CI 73·3 to 85·3; 61 cases of VCD in the TAK-003 group vs 149 cases of VCD in the placebo group). In the secondary endpoint assessment timeframe, an overall vaccine efficacy of 73·3% (95% CI 66·5 to 78·8) was observed. Analysis of secondary endpoints showed efficacies of 76·1% (95% CI 68·5 to 81·9) in individuals who were seropositive at baseline, 66·2% (49·1 to 77·5) in individuals who were seronegative at baseline, 90·4% (82·6 to 94·7) against hospitalised dengue, and 85·9% (31·9 to 97·1) against dengue haemorrhagic fever. Efficacy varied by individual serotypes (DENV 1, 69·8% [95% CI 54·8 to 79·9]; DENV 2, 95·1% [89·9 to 97·6]; DENV 3, 48·9% [27·2 to 64·1]; DENV 4, 51·0% [-69·4 to 85·8]). Cumulative rates of serious adverse events were similar in TAK-003 (4·0%) and placebo (4·8%) recipients, and were consistent with expected medical disorders in the study population. Infection was the most frequent reason leading to serious adverse events. 20 participants (<0·1% of the safety set) were withdrawn from the trial due to 21 adverse events by the end of part two; 14 of these participants received TAK-003 and six received placebo. INTERPRETATION: TAK-003 was well tolerated and efficacious against symptomatic dengue in children regardless of serostatus before immunisation. Vaccine efficacy varied by serotype, warranting continued follow-up to assess longer-term vaccine performance. FUNDING: Takeda Vaccines.

Efficacy of a Tetravalent Dengue Vaccine in Healthy Children and Adolescents.

BACKGROUND: Dengue, a mosquito-borne viral disease, was designated a World Health Organization top 10 threat to global health in 2019. METHODS: We present primary efficacy data from part 1 of an ongoing phase 3 randomized trial of a tetravalent dengue vaccine candidate (TAK-003) in regions of Asia and Latin America in which the disease is endemic. Healthy children and adolescents 4 to 16 years of age were randomly assigned in a 2:1 ratio (stratified according to age category and region) to receive two doses of vaccine or placebo 3 months apart. Participants presenting with febrile illness were tested for virologically confirmed dengue by serotype-specific reverse-transcriptase polymerase chain reaction. The primary end point was overall vaccine efficacy in preventing virologically confirmed dengue caused by any dengue virus serotype. RESULTS: Of the 20,071 participants who were given at least one dose of vaccine or placebo (safety population), 19,021 (94.8%) received both injections and were included in the per-protocol analysis. The overall vaccine efficacy in the safety population was 80.9% (95% confidence interval [CI], 75.2 to 85.3; 78 cases per 13,380 [0.5 per 100 person-years] in the vaccine group vs. 199 cases per 6687 [2.5 per 100 person-years] in the placebo group). In the per-protocol analyses, vaccine efficacy was 80.2% (95% CI, 73.3 to 85.3; 61 cases of virologically confirmed dengue in the vaccine group vs. 149 cases in the placebo group), with 95.4% efficacy against dengue leading to hospitalization (95% CI, 88.4 to 98.2; 5 hospitalizations in the vaccine group vs. 53 hospitalizations in the placebo group). Planned exploratory analyses involving the 27.7% of the per-protocol population that was seronegative at baseline showed vaccine efficacy of 74.9% (95% CI, 57.0 to 85.4; 20 cases of virologically confirmed dengue in the vaccine group vs. 39 cases in the placebo group). Efficacy trends varied according to serotype. The incidence of serious adverse events was similar in the vaccine group and placebo group (3.1% and 3.8%, respectively). CONCLUSIONS: TAK-003 was efficacious against symptomatic dengue in countries in which the disease is endemic. (Funded by Takeda Vaccines; TIDES ClinicalTrials.gov number, NCT02747927.).

Relative bioavailability of diclofenac potassium from softgel capsule versus powder for oral solution and immediate-release tablet formulation.

The oral bioavailability of diclofenac potassium 50 mg administered as a soft gelatin capsule (softgel capsule), powder for oral solution (oral solution), and tablet was evaluated in a randomized, open-label, 3-period, 6-sequence crossover study in healthy adults. Plasma diclofenac concentrations were measured using a validated liquid chromatography-mass spectrometry/mass spectrometry method, and pharmacokinetic analysis was performed by noncompartmental methods. The median time to achieve peak plasma concentrations of diclofenac was 0.5, 0.25, and 0.75 hours with the softgel capsule, oral solution, and tablet formulations, respectively. The geometric mean ratio and associated 90%CI for AUCinf, and Cmax of the softgel capsule formulation relative to the oral solution formulation were 0.97 (0.95-1.00) and 0.85 (0.76-0.95), respectively. The geometric mean ratio and associated 90%CI for AUCinf and Cmax of the softgel capsule formulation relative to the tablet formulation were 1.04 (1.00-1.08) and 1.67 (1.43-1.96), respectively. In conclusion, the exposure (AUC) of diclofenac with the new diclofenac potassium softgel capsule formulation was comparable to that of the existing oral solution and tablet formulations. The peak plasma concentration of diclofenac from the new softgel capsule was 67% higher than the existing tablet formulation, whereas it was 15% lower in comparison with the oral solution formulation.

Pharmacokinetic and pharmacodynamic interaction of siponimod (BAF312) and propranolol in healthy subjects.

OBJECTIVE: To evaluate the cardiac and pulmonary effects of siponimod (BAF312) and propranolol co-administration in healthy subjects. METHODS: Healthy subjects (n=76) were randomized in a doubleblind manner to receive propranolol at siponimod steady state (group A), siponimod at propranolol steady state (group B), placebo (group C) and propranolol (group D). Pharmacodynamic evaluations included maximum change from baseline in time-matched hourly average heart rate (Emax HR) and mean arterial blood pressure (Emax MABP) over 24 hours postdose, change from baseline in PR intervals, cardiac rhythm, and forced expiratory volume in 1 second (FEV1). Pharmacokinetic and safety parameters were also assessed. RESULTS: Siponimod and propranolol when administered alone resulted in similar HR decrease at steady state. Compared to propranolol alone, the combination at steady state had an additional 6.21 bpm (95%CI: 2.32, 10.11) decrease of mean EmaxHR, a decrease of 5.04 bpm (0.52, 9.56) for group A and 7.39 bpm (2.87, 11.90) for group B. A minor decrease in MABP and a trend towards PR interval increase were noted with co-administration treatment vs. propranolol alone. There were no episodes of second-degree atrioventricular blocks or sinus pauses>3 seconds. Baseline-corrected FEV1 was reduced by -0.07 L (95% CI: -0.17, 0.03) for group A and -0.05 L (-0.15, 0.05) for group B vs. propranolol alone. There were no cardiovascular adverse events during coadministration treatment. CONCLUSIONS: Coadministration of siponimod and propranolol was well tolerated. Bradyarrhythmic effects were less pronounced when propranolol was added to siponimod steady-state therapy compared with siponimod addition to propranolol.

Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study.

Lymphangioleiomyomatosis is a rare, progressive cystic lung disorder characterised by dysregulated activation of mammalian target of rapamycin (mTOR) signalling.This was a phase IIa, multicentre, open-label study of the mTOR inhibitor everolimus (2.5 mg·day(-1) escalated to 10 mg·day(-1)) in 24 women with lymphangioleiomyomatosis. Primary endpoints were safety, pharmacokinetics and serum vascular endothelial growth factor-D (VEGF-D) levels; secondary endpoints were measures of lung function.Following 26 weeks of everolimus treatment, forced vital capacity exhibited stability, while forced expiration volume in 1 s improved from baseline, with mean changes (95% confidence interval) of 10 mL (-111-132) and 114 mL (11-217), respectively; 6-min walk distance improved by 47 m. Median VEGF-D and collagen IV levels decreased from baseline, from 1730 pg·mL(-1) to 934.5 pg·mL(-1), and 103 ng·mL(-1) to 80.5 ng·mL(-1), respectively. Adverse events were mostly grade 1-2; mouth ulceration, headache, nausea, stomatitis and fatigue were common. Serious adverse events suspected to be treatment related included peripheral oedema, pneumonia, cardiac failure and Pneumocystis jirovecii infection. Everolimus blood levels increased dose proportionally.In this study, everolimus improved some measures of lung function and exercise capacity and reduced serum VEGF-D and collagen IV. Side effects were generally consistent with known toxicities of mTOR inhibitors, although some were severe.

Effect of oral siponimod (BAF312) on the pharmacokinetics and pharmacodynamics of a monophasic oral contraceptive in healthy female subjects.

OBJECTIVE: To evaluate the effects of siponimod (BAF312) on the pharmacokinetics (PK) and pharmacodynamics (PD) of a monophasic oral contraceptive (OC). MATERIALS AND METHODS: This was a phase 1, single-center, open-label, multipledose, single-sequence study in healthy females. Eligible subjects (n = 23) were exposed sequentially to two treatment periods: period 1 (OC alone) and period 2 (OC + siponimod) in two consecutive menstrual periods. PK parameters were assessed on day 21 of both treatment periods. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone concentrations were measured at baseline and days 3, 6, 8, 11, 14, 16, 19, 21, and 23 of each period. Largest ovarian follicle size and sex hormone-binding globulin (SHBG) concentration were measured and Hoogland score was calculated at baseline and day 21 of each period. Safety and tolerability of siponimod was also assessed. RESULTS: Co-administration (OC + siponimod) increased the AUC(τ,ss) and C(max,ss) of levonorgestrel by 28% and 18%, respectively, but had no effect on the PK of ethinylestradiol. No significant changes in estradiol, FSH, and LH were noted with co-administration vs. OC alone. Progesterone levels < 5 nmol/L, largest follicle size < 10 mm, and Hoogland score of 1 on day 21 indicated lack of ovulation in all subjects during co-administration. Co-administration was well tolerated. CONCLUSION: In conclusion, PK and PD of the OC were not altered to a clinically significant extent and contraceptive efficacy was maintained with co-administration. Hence, OC as a contraceptive measure can be safely co-administered with siponimod.

Bioavailability of valsartan oral dosage forms.

The oral bioavailability of valsartan from extemporaneous suspension and solution formulations were evaluated relative to tablet formulation in two separate open-label, randomized crossover studies in healthy adults. In both studies, the plasma concentrations of valsartan after oral administration were analyzed using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods, and the corresponding pharmacokinetic parameters were estimated using noncompartmental analysis. The peak plasma concentration (Cmax ) and area under the concentration time-curves (AUC(0-∞) ) of valsartan from the extemporaneous suspension were higher by 1.93- and 1.56-fold, respectively, relative to the tablet formulation (P < .001). The Cmax and AUC(0-∞) of valsartan from the oral solution were higher by 2.21- and 1.74-fold, respectively, relative to the tablet formulation (P < .001). These results indicate that both rate and extent of absorption of valsartan are higher in the two liquid dosage forms (extemporaneous suspension and solution formulations) relative to the solid oral dosage form (tablet formulation).

A single-dose, randomized, open-label, two-period crossover bioequivalence study of a fixed-dose pediatric combination of lamivudine 40-mg, nevirapine 70-mg, and stavudine 10-mg tablet for oral suspension with individual liquid formulations in healthy adult male volunteers.

BACKGROUND: Because of the lack of suitable pediatric antiretroviral (ARV) agents, adult fixed-dose ARVs are commonly used in children. This practice poses concerns about dose inaccuracy, which may lead to resistance or toxicity. OBJECTIVE: The objective of the present study was to evaluate the bioequivalence of a new pediatric fixed-dose combination (FDC) ARV tablet for oral suspension as compared with individual liquid formulations. METHODS: The FDC ARV tablet for oral suspension contained lamivudine 40 mg, nevirapine 70 mg, and stavudine 10 mg. This formulation was compared with 4 mL of lamivudine 10 mg/mL, 7 mL of nevirapine 50 mg/5 mL, and 10 mL of stavudine 1 mg/mL. This was an open-label, balanced, randomized, 2-treatment, 2-period, 2-sequence, single-dose crossover study in 36 Indian male volunteers under fasting conditions. Blood samples were collected before dosing and at 0.167, 0.25, 0.333, 0.5, 0.667, 0.833, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours after dosing in each period. RESULTS: The mean (SD) age, weight, and height of the Indian volunteers were 24.78 (5.31) years (range, 18-38 years), 57.06 (8.59) kg (range, 45-77 kg), and 165.14 (5.34) cm (range, 156-176 cm), respectively. The mean (SD) values for T(max), C(max), and AUC(0-t) for the FDC and the individual liquid formulations, respectively, were as follows: lamivudine, 0.71 (0.22) and 0.89 (0.50) hour, 594 (167) and 514 (139) ng/mL, 2382 (617) and 2227 (666) ng /mL per hour; nevirapine, 1.7 (1.1) and 2.5 (1.2) hours, 1248 (275) and 1185 (238) ng/mL, 70,372 (14,869) and 71,278 (17,435) ng/ mL per hour; and stavudine, 0.44 (0.11) and 0.43 (0.11) hour, 348 (82) and 395 (107) ng/mL, and 576 (113) and 631 (142) ng/mL per hour. The ratios and 90% CIs for the least-squares mean Cmax and AUC values were found to be within the prespecified range of 80% to 125% for each component. CONCLUSION: The FDC pediatric formulation of lamivudine, nevirapine, and stavudine was bioequivalent to the individual liquid formulations in these fasting, healthy Indian men.

Longterm efficacy of topical nonsteroidal antiinflammatory drugs in knee osteoarthritis: metaanalysis of randomized placebo controlled clinical trials.

OBJECTIVE: To evaluate the longterm efficacy of topical therapies for pain control in primary knee osteoarthritis (OA). METHODS: Systematic literature search was carried out from January 1, 1966, to December 31, 2004, in Pubmed, Medline, Embase, and Cochrane database. Manual searches of related journals in the National Medical Library (New Delhi, India), the library of our institute, and conference abstracts were also carried out. We included randomized controlled clinical trials of 4 weeks or more comparing any topical nonsteroidal antiinflammatory drug (NSAID) with placebo or vehicle. Effect size for pain control was estimated. RESULTS: Out of 172 citations, 4 studies fulfilled all the specified criteria. Four of them compared topical NSAID with placebo or vehicle. Pooled effect of topical NSAID measured at 4 weeks or beyond was superior to placebo/vehicle in pain relief (mean effect size -0.28, 95% CI -0.42 to -0.14). CONCLUSION: Topical NSAID are effective for pain relief in knee OA for a longer duration; however, this may not hold true for all the preparations.