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We report the first analysis of an extended half‐life recombinant factor IX, nonacog beta pegol (N9‐GP), in previously untreated patients (PUPs) and minimally treated patients with hemophilia B. Paradigm 6 (Safety and Efficacy of Nonacog Beta Pegol [N9‐GP] in Previously Untreated Patients With Haemophilia B) is a multicenter, open‐label, single‐arm, phase 3 trial. Main inclusion criteria were males aged < 6 years, with hemophilia B with factor IX (FIX) activity ≤ 2%, who were previously untreated or with ≤ 3 exposure days (EDs) to FIX‐containing products. Patients received N9‐GP 40 IU/kg once weekly (prophylaxis) or individualized dosing (preprophylaxis). Bleeds were treated with N9‐GP 40 IU/kg (80 IU/kg if severe). The primary end point was incidence of anti‐FIX inhibitory antibodies (inhibitors). Secondary end points included safety outcomes and annualized bleeding rate (ABR). At data cutoff (August 31, 2018), 38 patients had been screened, and 37 had received N9‐GP (median age, 1.0 years [range, 0‐4]). Total in‐trial EDs amounted to 2833, representing ~ 65 patient‐years. Two (6.1%) of 33 “at‐risk” patients (patients with ≥ 10 EDs plus patients who developed inhibitors) developed high‐titer inhibitors and were withdrawn. No other safety concerns, including thromboembolic events, were identified. In the prophylaxis group (n = 28), 67.9% were bleed free; all bleeds (n = 15) were treated with one N9‐GP injection; and overall, spontaneous, and traumatic ABRs were low (median ABRs of 0.0, 0.0, and 0.0, respectively; modeled mean ABRs of 0.31, 0.08, and 0.23, respectively). Estimated mean FIX trough activity was 15.0%. We report an inhibitor incidence of 6.1%, which is within the expected range for PUPs with hemophilia B. No other safety concerns were identified; moreover, N9‐GP provided effective hemostatic coverage.

Regular factor XIII (FXIII) prophylaxis is standard treatment for congenital FXIII A‐subunit deficiency (FXIII‐A CD). Recombinant factor XIII‐A2 (rFXIII‐A2) was extensively evaluated in the mentor trials. To assess real‐world safety and treatment effectiveness of rFXIII‐A2 prophylaxis from the mentor 6 trial. mentor 6 was a noninterventional, postauthorization safety study investigating rFXIII‐A2 prophylaxis in FXIII‐A CD. rFXIII‐A2 treatment was observed for 2 to 6 years per patient. The primary end point was documentation of adverse drug reactions (including anti‐FXIII antibody development). Secondary end points were serious adverse events (SAEs), medical events of special interest (MESIs), and annualized bleeding rate (ABR). Among 30 patients (mean age, 25.5 years), there were 44 adverse events (AEs) (30 mild, 13 moderate, 1 severe). Eleven AEs were possibly/probably related to rFXIII‐A2. Of four MESIs, two were unlikely related to rFXIII‐A2 (accidental overdose, deep vein thrombosis), and two were possibly/probably related (nonneutralizing anti‐FXIII antibody, decreased therapeutic response). All 10 SAEs were unlikely related to rFXIII‐A2. Over a follow‐up of 75.4 patient‐years, there were six treatment‐requiring bleeds (all trauma‐related with no spontaneous bleeds), giving a treatment‐requiring ABR of 0.066; five bleeds were treated successfully with rFXIII‐A2. Eight of nine minor surgeries performed during rFXIII‐A2 prophylaxis reported successful hemostatic outcomes (one missing evaluation). These data confirm that rFXIII‐A2 prophylaxis is well tolerated as long‐term care. There were no spontaneous bleeds, ABR was low, and rFXIII‐A2 successfully treated bleeds in patients receiving rFXIII‐A2 prophylaxis.

ObjectiveThe current policy of measles vaccination at 9 months of age was decided in the mid-1970s. The policy was not tested for impact on child survival but was based on studies of seroconversion after measles vaccination at different ages. The authors examined the empirical evidence for the six underlying assumptions.DesignSecondary analysis.Data sources and methodsThese assumptions have not been research issues. Hence, the authors examined case reports to assess the empirical evidence for the original assumptions. The authors used existing reviews, and in December 2011, the authors made a PubMed search for relevant papers. The title and abstract of papers in English, French, Portuguese, Spanish, German and Scandinavian languages were assessed to ascertain whether the paper was potentially relevant. Based on cumulative measles incidence figures, the authors calculated how many measles cases had been prevented assuming everybody was vaccinated at a specific age, how many ‘vaccine failures’ would occur after the age of vaccination and how many cases would occur before the specific age of vaccination. In the combined analyses of several studies, the authors used the Mantel–Haenszel weighted RR stratifying for study or age groups to estimate common trends.Setting and participantsAfrican community studies of measles infection.Primary and secondary outcomesConsistency between assumptions and empirical evidence and the predicted effect on mortality.ResultsIn retrospect, the major assumptions were based on false premises. First, in the single study examining this point, seronegative vaccinated children had considerable protection against measles infection. Second, in 18 community studies, vaccinated measles cases (‘vaccine failures’) had threefold lower case death than unvaccinated cases. Third, in 24 community studies, infants had twofold higher case death than older measles cases. Fourth, the only study examining the assumption that ‘vaccine failures’ lead to lack of confidence found the opposite because vaccinated children had milder measles infection. Fifth, a one-dose policy was recommended. However, the two randomised trials of early two-dose measles vaccination compared with one-dose vaccination found significantly reduced mortality until 3 years of age. Thus, current evidence suggests that the optimal age for a single dose of measles vaccine should have been 6 or 7 months resulting in fewer severe unvaccinated cases among infants but more mild ‘vaccine failures’ among older children. Furthermore, the two-dose trials indicate that measles vaccine reduces mortality from other causes than measles infection.ConclusionsMany lives may have been lost by not determining the optimal age of measles vaccination. Since seroconversion continues to be the basis for policy, the current recommendation is to increase the age of measles vaccination to 12 months in countries with limited measles transmission. This policy may lead to an increase in child mortality.

Nonacog beta pegol (N9‐GP) and recombinant factor IX‐Fc fusion protein (rFIXFc) are extended half‐life rFIX compounds. We report the first single‐dose pharmacokinetic trial of N9‐GP and rFIXFc. Paradigm 7 was a multicenter, open‐label, randomized, crossover trial in previously treated (>150 exposure days) adults with congenital hemophilia B (FIX activity ≤2%). Patients received single intravenous injections (50 IU/kg) of N9‐GP and rFIXFc with at least 21 days between doses. Plasma FIX activity, predose, and at serial time points up to 240 hours postdose, was measured using validated one‐stage clotting assays (SynthAFax for N9‐GP; Actin FSL for rFIXFc) and a chromogenic assay (ROX factor IX) with normal human plasma as calibrator. The primary endpoint was area under the FIX activity–time curve from 0 to infinity, dose‐normalized to 50 IU/kg (AUC0‐inf,norm). Fifteen patients received study treatment. Based on FIX activity results from the one‐stage clotting assays, estimated AUC0‐inf,norm was significantly greater for N9‐GP than rFIXFc (ratio: 4.39; P<0.0001, based on a two‐sided test on 5% significance level). In addition, N9‐GP had a longer terminal half‐life, two times higher incremental recovery at 30 minutes and maximum FIX activity (dose‐normalized to 50 IU/kg) and six times higher FIX activity at 168 hours than rFIXFc. These findings were largely comparable with the chromogenic assay data and are consistent with published data for each compound. In this comparison, N9‐GP demonstrated favorable pharmacokinetic characteristics versus rFIXFc, helping clinicians to understand differences between N9‐GP and rFIXFc. This trial is registered with clinicaltrials.gov (NCT03075670) and the European Clinical Trials Database (EudraCT: 2016‐001149‐25).

Background: Recent studies have suggested that bacille Calmette-Guérin (BCG) immunization may have a nonspecific beneficial effect on infant survival and that the effect may be more pronounced among girls. In a prospective birth cohort, we examine whether a positive tuberculin skin test and BCG scar in response to BCG immunization were related to better overall survival in Guinea-Bissau and, if so, whether the effect was sex-specific. Methods: Skin tests and BCG scarring were monitored at ages 2 months (n = 2332) and 6 months (n = 1817) in children born from March 2000 to July 2002. A tuberculosis (TB) surveillance system allowed us to exclude from the analysis children with likely TB exposure. The children were followed for survival until 18 months of age. Results: Among children with a tuberculin skin test at 2 and 6 months of age, the mortality rate ratio for skin test reactors (>1 mm) versus nonreactors (0-1 mm) was 0.54 (95% confidence interval = 0.30-0.99). Comparing children with and without a BCG scar, the ratio was 0.55 (0.31-0.96). The effect of a skin test reaction or a BCG scar seemed stronger among girls; for those with positive reaction, the mortality ratio was 0.31 (0.11-0.88) among girls and 0.84 (0.39-1.82) among boys; and for BCG scar, the results were 0.41 (0.21-0.82) and 0.88 (0.34-2.30), respectively. Conclusions: A good response to BCG vaccination is related to lower child mortality. The effect seems most pronounced among girls. The findings may have implications for future vaccine trials and policy.

Background. Measles vaccine (MV) has a greater effect on child survival when administered in early infancy, when maternal antibody may still be present. Methods. To test whether MV has a greater effect on overall survival if given in the presence of maternal measles antibody, we reanalyzed data from 2 previously published randomized trials of a 2-dose schedule with MV given at 4–6 months and at 9 months of age. In both trials antibody levels had been measured before early measles vaccination. Results. In trial I (1993–1995), the mortality rate was 0.0 per 1000 person-years among children vaccinated with MV in the presence of maternal antibody and 32.3 per 1000 person-years without maternal antibody (mortality rate ratio [MRR], 0.0; 95% confidence interval [CI], 0–.52). In trial II (2003–2007), the mortality rate was 4.2 per 1000 person-years among children vaccinated in presence of maternal measles antibody and 14.5 per 1000 person-years without measles antibody (MRR, 0.29; 95% CI, .09–.91). Possible confounding factors did not explain the difference. In a combined analysis, children who had measles antibody detected when they received their first dose of MV at 4–6 months of age had lower mortality than children with no maternal antibody, the MRR being 0.22 (95% CI, .07–.64) between 4–6 months and 5 years. Conclusions. Child mortality in low-income countries may be reduced by vaccinating against measles in the presence of maternal antibody, using a 2-dose schedule with the first dose at 4–6 months (earlier than currently recommended) and a booster dose at 9–12 months of age. Clinical Trials Registration. NCT00168558.

Objective To investigate whether prophylactic antibiotics can prevent complications of measles. Design Community based, randomised, double blind, placebo controlled trial. Setting Bandim Health Project study area in Bissau, Guinea-Bissau, west Africa. Participants 84 patients with measles during a measles epidemic in Bissau in 1998 (fewer than originally planned owing to interruption by war). Interventions Sulfamethoxazole-trimethoprim (co-trimoxazole) or placebo for seven days. Main outcome measures Pneumonia and admission to hospital. Also weight change during the first month of infection, diarrhoea, severe fever, oral thrush, stomatitis, conjunctivitis, and otitis media. Results The median age of the patients with measles was 5.4 (range 0.49-24.8) years. One of 46 participants who received co-trimoxazole developed pneumonia, in contrast to six of 38 participants who received placebo (odds ratio 0.08 (95% confidence interval 0 to 0.56), adjusted for age group). The number needed to treat was 7 (4 to 48). All three participants admitted to hospital had received placebo (P=0.09). The weight gain during the first month after inclusion was 15 (2-29) g/day in the placebo group and 32 (23-42) g/day in the co-trimoxazole group (P=0.04, adjusted for age group, weight for age at inclusion, measles vaccination status, and duration of disease). Significantly less conjunctivitis occurred among recipients of co-trimoxazole than placebo, as well as a non-significant tendency to less diarrhoea, severe fever, oral thrush, and stomatitis. Complications of otitis media were the same in the two groups. Conclusions The group that received prophylactic antibiotics had less pneumonia and conjunctivitis and had significantly higher weight gains in the month after inclusion. The results indicate that prophylactic antibiotics may have an important role in the management of measles infection in low income countries. Trial registration Clinical trials NCT001168532.

Observational studies and trials from low-income countries indicate that measles vaccine has beneficial nonspecific effects, protecting against non-measles-related mortality. It is not known whether measles vaccine protects against hospital admissions. Between 2003 and 2007, 6417 children who had received the third dose of diphtheria, tetanus, and pertussis vaccine were randomly assigned to receive measles vaccine at 4.5 months or no measles vaccine; all children were offered measles vaccine at 9 months of age. Using hospital admission data from the national pediatric ward in Bissau, Guinea-Bissau, we compared admission rates between enrollment and the 9-month vaccination in Cox models, providing admission hazard rate ratios (HRRs) for measles vaccine versus no measles vaccine. All analyses were conducted stratified by sex and reception of neonatal vitamin A supplementation (NVAS). Before enrollment the 2 groups had similar admission rates. Following enrollment, the measles vaccine group had an admission HRR of 0.70 (95% confidence interval [CI], .52-. 95), with a ratio of 0.53 (95% CI, .32-. 86) for girls and 0.86 (95% CI, .58-1.26) for boys. For children who had not received NVAS, the admission HRR was 0.53 (95% CI, .34-. 84), with an effect of 0.30 (95% CI, .13-.70) for girls and 0.73 (95% CI, .42-1.28) for boys (P = .08, interaction test). The reduction in admissions was separately significant for measles infection (admission HRR, 0 [95% CI, 0-.24]) and respiratory infections (admission HRR, 0.37 [95% CI, .16-.89]). Early measles vaccine may have major benefits for infant morbidity patterns and healthcare costs.

The World Health Organization recommends administration of measles vaccine (MV) at age 9 months in low-income countries. We tested the measles virus antibody response at 4.5, 9, 18, and 24 months of age for children randomly assigned to receive standard-titer Edmonston-Zagreb MV at 4.5 and 9 months, at 9 months, or at 9 and 18 months of age. At 4.5 months of age, 75% had nonprotective measles virus antibody levels. Following receipt of MV at 4.5 months of age, 77% (316/408) had protective antibody levels at 9 months of age; after a second dose at 9 months of age, 97% (326/337) had protective levels at 24 months of age. In addition, the response at both 9 and 24 months of age was inversely correlated with the antibody level at receipt of the first dose of MV, and the second dose of MV, received at 9 months of age, provided a significant boost in antibody level to children who had low antibody levels. In the group of 318 children who received MV at 9 months of age, with or without a second dose at 18 months of age, 99% (314) had protective levels at 24 months of age. The geometric mean titer at 24 months of age was significantly lower in the group that received MV at 4.5 and 9 months of age than in the group that received MV at 9 months of age (P = .0001). In conclusion, an early 2-dose MV schedule was associated with protective measles virus antibody levels at 24 months of age in nearly all children. Clinical Trials Registration. NCT00168558.

Objective To examine in a randomised trial whether a 25% difference in mortality exists between 4.5 months and 3 years of age for children given two standard doses of Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age (current policy).Design Randomised controlled trial.Setting The Bandim Health Project, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area.Participants 6648 children aged 4.5 months of age who had received three doses of diphtheria-tetanus-pertussis vaccine at least four weeks before enrolment. A large proportion of the children (80%) had previously taken part in randomised trials of neonatal vitamin A supplementation.Intervention Children were randomised to receive Edmonston-Zagreb measles vaccine at 4.5 and 9 months of age (group A), no vaccine at 4.5 months and Edmonston-Zagreb measles vaccine at 9 months of age (group B), or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months of age (group C).Main outcome measure Mortality rate ratio between 4.5 and 36 months of age for group A compared with groups B and C. Secondary outcomes tested the hypothesis that the beneficial effect was stronger in the 4.5 to 9 months age group, in girls, and in the dry season, but the study was not powered to test whether effects differed significantly between subgroups.Results In the intention to treat analysis of mortality between 4.5 and 36 months of age the mortality rate ratio of children who received two doses of Edmonston-Zagreb vaccine at 4.5 and 9 months of age compared with those who received a single dose of Edmonston-Zagreb vaccine or Schwarz vaccine at 9 months of age was 0.78 (95% confidence interval 0.59 to 1.05). In the analyses of secondary outcomes, the intention to treat mortality rate ratio was 0.67 (0.38 to 1.19) between 4.5 and 9 months and 0.83 (0.83 to 1.16) between 9 and 36 months of age. The effect on mortality between 4.5 and 36 months of age was significant for girls (intention to treat mortality rate ratio 0.64 (0.42 to 0.98)), although this was not significantly different from the effect in boys (0.95 (0.64 to 1.42)) (interaction test, P=0.18). The effect did not differ between the dry season and the rainy season. As neonatal vitamin A supplementation is not WHO policy, the analyses were done separately for the 3402 children who did not receive neonatal vitamin A. In these children, the two dose Edmonston-Zagreb measles vaccine schedule was associated with a significantly lower mortality between 4.5 and 36 months of age (intention to treat mortality rate ratio 0.59 (0.39 to 0.89)). The effect was again significant for girls but not statistically significant from the effect in boys. When measles cases were censored, the intention to treat mortality rate ratio was 0.65 (0.43 to 0.99).Conclusions Although the overall effect did not reach statistical significance, the results may indicate that a two dose schedule with Edmonston-Zagreb measles vaccine given at 4.5 and 9 months of age has beneficial non-specific effects on children’s survival, particularly for girls and for children who have not received neonatal vitamin A. This should be tested in future studies in different locations.Trial registration Clinical trials NCT00168558.