Efficacy and safety of sitagliptin added to treatment of patients with type 2 diabetes inadequately controlled with premixed insulin.

To improve understanding of the safety and efficacy of adding sitagliptin to treatment of patients with type 2 diabetes taking premixed insulin, data from patients using premixed insulin ± metformin (screening HbA1c ≥7.5% and ≤11%) in either of two clinical trials in which sitagliptin 100 mg once-daily or placebo was added to various formulations of insulin treatment, were analysed. In both trials, insulin doses were to remain stable throughout the 24-week trial period. At week 24, the between-group difference (sitagliptin - placebo) in the least squares mean (95% confidence intervals) change from baseline in HbA1c in patients using premixed insulin was -0.43% (-0.58, -0.28), P <0.001. Adverse events were generally similar between the treatment groups. The incidence of symptomatic hypoglycaemia was slightly higher with sitagliptin, and the incidence of hypoglycaemia requiring medical attention was slightly higher with placebo; in both cases the difference was not statistically significant. The data from this pooled analysis confirm the utility of sitagliptin used in combination with premixed insulin in patients with type 2 diabetes.

A phase 3 randomized, open-label study evaluating the immunogenicity and safety of concomitant and staggered administration of a live, pentavalent rotavirus vaccine and an inactivated poliomyelitis vaccine in healthy infants in China.

This open-label, randomized, phase 3 study in China (V260-074; NCT04481191) evaluated the immunogenicity and safety of concomitant and staggered administration of three doses of an oral, live, pentavalent rotavirus vaccine (RV5) and three doses of an intramuscular, inactivated poliomyelitis vaccine (IPV) in 400 healthy infants. The primary objective was the non-inferiority of neutralizing antibody (nAb) responses in the concomitant- versus the staggered-use groups. Antibody responses were measured at baseline and 1-month post-dose 3 (PD3). Parents/legal guardians recorded adverse events for 30 or 15 d after study vaccinations in the concomitant-use or staggered-use groups, respectively. At PD3, >98% of participants seroconverted to all three poliovirus types, and the primary objective was met as lower bounds of the two-sided 95% CI for between-group difference in nAb seroconversion percentages ranged from - 4.3% to - 1.6%, for all poliovirus types, p < .001. At PD3, geometric mean titers (GMTs) of nAb responses to poliovirus types 1, 2, and 3 in the concomitant-use group and the staggered-use group were comparable; 100% of participants had nAb titers ≥1:8 and ≥1:64 for all poliovirus types. Anti-rotavirus serotype-specific IgA GMTs and participants with ≥3-fold rise in postvaccination titers from baseline were comparable between groups. Administration of RV5 and IPV was well tolerated with comparable safety profiles in both groups. The immunogenicity of IPV in the concomitant-use group was non-inferior to the staggered-use group and RV5 was immunogenic in both groups. No safety concerns were identified. These data support the concomitant use of RV5 and IPV in healthy Chinese infants.

Immunogenicity and safety of quadrivalent and 9-valent human papillomavirus vaccines in Indian clinical trial participants.

The quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) and 9-valent HPV (9vHPV; HPV6/11/16/18/31/33/45/52/58) vaccines have demonstrated efficacy, immunogenicity, and safety in international clinical trials. We report outcomes from three completed clinical trials in India: a single-arm study (V501-029 [NCT00380367]) in Indian girls (aged 9-15 years; N = 110) evaluating qHPV vaccine immunogenicity and safety; a subgroup analysis (n = 225) of Indian girls/boys (9-15 years) and women (16-26 years) from a global study (V503-002 [NCT00943722]) evaluating 9vHPV vaccine immunogenicity and safety; and a qHPV vaccine post-marketing safety surveillance study (V501-125) in Indian females (aged 9-45 years; N = 188) vaccinated during routine care. In V501-029 and V503-002, HPV vaccines were administered as 3 doses (Day 1, Month 2, Month 6). Serum HPV antibodies were evaluated by competitive Luminex immunoassays at Day 1 and Month 7 (both studies) and Months 12, 24, and 36 (V503-002 only). Adverse events (AEs) were collected by Vaccination Report Card. In V501-125, participants were actively surveilled for serious AEs (SAEs) within 30 days post-qHPV vaccination. In per-protocol analyses, qHPV and 9vHPV vaccines induced robust anti-HPV6/11/16/18 (V501-029) and HPV6/11/16/18/31/33/45/52/58 (V503-002) responses, respectively; ≥97% of participants seroconverted at Month 7 for each vaccine HPV type in both studies, and antibody responses persisted through 36 months in V503-002. The most common AEs were injection-site-associated. Most AEs were mild/moderate; no deaths, vaccine-related SAEs, or discontinuations due to AEs were reported. In V501-125, no SAE was reported. Overall, the qHPV and 9vHPV vaccines elicited robust antibody responses and were generally well tolerated in Indian participants.

Design of a phase III efficacy, immunogenicity, and safety study of 9-valent human papillomavirus vaccine in prevention of oral persistent infection in men.

BACKGROUND: Seven high-risk human papillomavirus (HPV) types (16/18/31/33/45/52/58) covered by the 9-valent HPV (9vHPV) vaccine cause >90% of HPV-related head and neck cancers (HNCs). An ongoing clinical trial (NCT04199689) was designed to evaluate 9vHPV vaccine efficacy against HPV oral persistent infection, a surrogate endpoint for HPV-related HNCs. METHODS: In this double-blind, placebo-controlled, international trial, men aged 20-45 years (N = 6000) are randomized 1:1 to receive 9vHPV vaccine or placebo on day 1, month 2, and month 6. The primary objective is to demonstrate whether 9vHPV vaccination reduces incidence of HPV16/18/31/33/45/52/58-related 6-month oral persistent infection. Incidence of HPV6/11-related 6-month oral persistent infection will be evaluated as a secondary endpoint. Oral rinse and gargle samples will be collected on day 1, month 7, month 12, and every 6 months thereafter for HPV detection by PCR. Primary analyses will be performed in per-protocol populations. Efficacy in this case-driven study will be analyzed upon accrual of ≥20 primary efficacy endpoint cases. Serum will be collected at day 1 and months 7, 12, 24, 36, and 42; anti-HPV antibody titers will be measured by competitive Luminex immunoassay. Data will be summarized as geometric mean titers and seropositivity rates. Injection-site and systemic adverse events (AEs) will be collected for 15 days post-any vaccination and serious AEs through 6 months after the last vaccination; deaths and vaccine-related serious AEs will be collected throughout the study. DISCUSSION: This trial is expected to generate important data regarding the potential for 9vHPV vaccine to prevent HPV-related head and neck disease.

Efficacy and tolerability of a single-pill combination of amlodipine/valsartan in Asian hypertensive patients not adequately controlled with valsartan monotherapy.

This randomized, double-blind study evaluated efficacy of a single-pill combination of amlodipine/valsartan (Aml/Val) in Asian patients with hypertension not responding to Val 80 mg. Patients with mean sitting diastolic blood pressure (DBP) ≥90-≤110 mmHg were randomized to Aml/Val 5/80, Val 80, or Val 160 mg for 8 weeks. At week-8 endpoint, significantly greater reductions in BP were seen with Aml/Val 5/80 mg than valsartan monotherapies (p < 0.0001). The BP control was greater with Aml/Val 5/80 (70.5%) than Val (44.1-58.6%) monotherapies. The combination was well tolerated. In conclusion, single-pill combination with Aml/Val provided significant additional BP reduction and control in hypertensive patients not responding to Val 80 mg.

Safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, followed by sequential PPSV23 vaccination in healthy adults aged ≥50 years: A randomized phase III trial (PNEU-PATH).

BACKGROUND: Streptococcus pneumoniae causes pneumococcal disease, and older adults are at an increased risk. Sequential vaccination of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for broad protection against pneumococcal disease in some countries. METHODS: This phase III trial evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 12 months later by PPSV23, in healthy adults aged ≥50 years (NCT03480763). A total of 652 participants were randomized 1:1 to receive either V114 or PCV13, followed by PPSV23. RESULTS: The most common solicited adverse events (AEs) following PCV vaccination included injection-site pain and fatigue. Higher proportions of participants with these events were observed in the V114 group following PCV; however, these differences were not clinically significant. Following PPSV23 vaccination, the most common solicited AEs were injection-site pain and injection-site swelling; the proportions of participants with these events were comparable between both groups. Incidence of serious AEs was low in both groups following PCV and PPSV23, and none were related to study vaccines. No deaths occurred during the study. Serum opsonophagocytic activity geometric mean titers and immunoglobulin G geometric mean concentrations were comparable between both groups for all 15 serotypes in V114 following PPSV23. Immune responses elicited by V114 persisted for at least 12 months. Immune responses at 30 days and 12 months post-vaccination with PCV were comparable between both groups for the 13 shared serotypes and higher in the V114 group for the V114-unique serotypes (22F and 33F). CONCLUSION: Administration of V114 followed by PPSV23 was well tolerated and induced comparable antibody levels to PCV13 followed by PPSV23 in healthy adults aged ≥50 years.

Differential HbA1c response in the placebo arm of DPP-4 inhibitor clinical trials conducted in China compared to other countries: a systematic review and meta-analysis.

BACKGROUND: It has been observed that the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors as compared to the placebo groups in some clinical trials conducted in China is weaker than that in trials conducted outside China, leading to the suspicion that this may be caused by differential Glycosylated Hemoglobin (HbA1c) response in the placebo arm of DPP-4 inhibitor clinical trials conducted in China compared to other countries. METHODS: We searched published articles and other documents related to phase III placebo-control trials of DPP-4 inhibitors in Type 2 diabetes mellitus (T2DM). We included studies from different countries and compared those conducted in China to those conducted in other countries. Meta-regression analysis was used to analyze the HbA1c response in the placebo arms. RESULTS: A total of 66 studies met the inclusion criteria and 10 were conducted within China. There were a total of 8303 participants (mean age 56, male 57 %) in placebo groups. The pooled change in HbA1c for the placebo groups of 10 trials conducted in patients with T2DM in China was 0.26 % (95 % CI [-0.36 %, -0.16 %], p-value < 0.001), compared to 0.015 % (95 % CI [-0.05 %, 0.08 %], p-value is 0.637) for 56 trials conducted outside of China. The difference of placebo effect between trials conducted in and outside China is -0.273 % (95 % CI [-0.42 %, -0.13 %], p-value is less than 0.001) while after excluding trials conducted in Japan, the difference is -0.203 % (95 % CI [-0.35 %, -0.06 %], p-value is 0.005). They are both statistically significant. CONCLUSIONS: The meta-analysis in the article demonstrates that there is statistically significant difference in the HbA1c response in the placebo arm of DPP-4 inhibitor clinical trials conducted in China compared to other countries. This differential HbA1c response in the placebo arm should be taken into consideration by both experimenters and medical decision makers when future DPP-4 studies are conducted in China.

Efficacy and safety of aliskiren, a direct renin inhibitor, compared with ramipril in Asian patients with mild to moderate hypertension.

This 8-week, randomized, double-blind, parallel-group study compared the efficacy and safety of aliskiren with ramipril in Asian patients with mild to moderate hypertension. Following a 2- to 3-week placebo run-in period, patients with mean sitting diastolic blood pressure (msDBP) ≥95 and <110 mm Hg were randomized to receive once daily dose of either aliskiren 75, 150, 300 mg or ramipril 5 mg for 8 weeks. Efficacy variables were the changes in msDBP and mean sitting systolic BP (msSBP) and BP control rates (<140/90 mm Hg). Safety was assessed by recording adverse events (AEs) and serious AEs (SAEs). Of 1316 randomized patients, 1160 (88.1%) completed the study. At the study endpoint, patients on aliskiren had greater mean BP reductions (14.39/11.63 mm Hg for 300 mg; 12.16/10.04 mm Hg for 150 mg; 12.24/10.66 mm Hg for 75 mg) than those on 5 mg ramipril (11.46/9.19 mm Hg). All aliskiren doses were statistically non-inferior (P<0.0001) to ramipril in reducing msDBP. The reduction in BP for aliskiren 300 mg was statistically superior vs. ramipril (P<0.002). Blood pressure control rates were higher for aliskiren (300 mg, 52.29%; 150 mg, 48.11%; 75 mg, 45.68%) than for ramipril (5 mg, 43.7%); the difference for aliskiren 300 mg vs. ramipril 5 mg was statistically significant (P<0.05). Aliskiren was well tolerated with a fourfold lower incidence of cough (0.6-1.2%) compared with ramipril (5.2%). SAEs were rare in this study (0.5%). Aliskiren produced greater BP reductions with a lower incidence of cough than ramipril in Asian patients with mild to moderate hypertension.