Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: A Phase IV Open-Label Study (CrisADe CARE 1).

BACKGROUND: Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). OBJECTIVES: The aim of this study was to evaluate the safety, effectiveness, and pharmacokinetics (PK) of crisaborole in infants aged 3 to < 24 months with mild-to-moderate AD in an open-label study. METHODS: Infants (3 to < 24 months) with Investigator's Static Global Assessment (ISGA) of mild (2) or moderate (3) and percentage of treatable body surface area (%BSA) ≥ 5 received crisaborole twice daily for 28 days; a cohort with moderate AD per ISGA and %BSA ≥ 35 were included in a PK analysis. Endpoints included safety (primary), efficacy, and PK (exploratory). RESULTS: Included were 137 infants total (mean age [SD], 13.6 months [6.42]), with 21 in the PK cohort (12.7 months [6.58]). Treatment-emergent adverse events (TEAEs) were reported for 88 (64.2%) patients (98.9% rated as mild/moderate). TEAEs were considered treatment-related for 22 patients (16.1%); most frequently reported were application site pain (3.6%), application site discomfort (2.9%), and erythema (2.9%). ISGA clear/almost clear with ≥ 2-grade improvement at day 29 was achieved by 30.2% of patients. From baseline to day 29, mean percentage change in Eczema Area and Severity Index score was - 57.5%, and mean change in Patient-Oriented Eczema Measure total score was - 8.5. Crisaborole systemic exposures in infants were characterized and, based on nonlinear regression analysis, were comparable with that in patients aged ≥ 2 years. CONCLUSIONS: In this open-label study, crisaborole was well tolerated and effective in infants (3 to < 24 months) with mild-to-moderate AD with systemic exposures similar to patients aged ≥ 2 years. CLINICAL TRIAL REGISTRATION: NCT03356977.

Atopic dermatitis (AD) is a skin disease that causes inflamed and itchy skin. Crisaborole is an ointment that is approved to treat patients aged 2 years and older with mild-to-moderate AD. This clinical trial studied crisaborole in infants with mild-to-moderate AD who were 3 to under 24 months old. These infants were treated with crisaborole twice a day for 28 days. The trial studied crisaborole's safety, effectiveness, and absorption into the bloodstream. In total, 137 infants were treated. Although side effects of some sort occurred in about two-thirds of patients, only 1 in 6 patients experienced side effects that were attributed to crisaborole. When these side effects did occur, these were mainly pain, discomfort, or redness where crisaborole was applied. Fewer than 1 in 25 patients experienced each side effect where crisaborole was applied. The doctors saw improvement in the AD symptoms of some patients at day 29 of the study compared to the beginning of the study. Crisaborole blood-level measurements in this age group were consistent with those seen in patients aged 2 years and older. Overall, crisaborole was considered well tolerated and effective in infants (3 to under 24 months old) with mild-to-moderate AD. Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: An Open-Label, Phase 4 Study (MP4 40891 MB).

2'-Fucosyllactose Is Well Tolerated in a 100% Whey, Partially Hydrolyzed Infant Formula With Bifidobacterium lactis: A Randomized Controlled Trial.

Human milk oligosaccharides are important components of breast milk. We evaluated feeding tolerance of the human milk oligosaccharide 2'-fucosyllactose (2'FL) in a 100% whey, partially hydrolyzed infant formula with the probiotic Bifidobacterium animalis ssp lactis strain Bb12 (B lactis; Test) as compared with the same formula without 2'FL (Control) in a randomized controlled trial of healthy infants enrolled at 2 weeks of age (±5 days). After 6 weeks of feeding the assigned formula, the primary outcome of tolerance was assessed using the Infant Gastrointestinal Symptom Questionnaire. Stooling, vomiting, spit-up, crying, and fussing were compared between groups. Seventy-nine infants were enrolled and 63 completed the study per protocol (30 Test, 33 Control). Infant Gastrointestinal Symptom Questionnaire scores were similar between groups (Test 20.9 ± 4.8, Control 20.7 ± 4.3, P = .82). Partially hydrolyzed infant formula with 2'FL and B lactis is tolerated well, as confirmed by a validated multi-symptom index.

A double blind, randomized, active controlled study to assess the safety, tolerability and immunogenicity of measles, mumps rubella, and varicella vaccine (MMRV) manufactured using an alternative process.

Vaccination against measles, mumps, rubella, and varicella is recommended for all children in the US. Limitations manufacturing Oka/Merck strain varicella-zoster virus have hampered the availability of the combination vaccine (MMRV) against these 4 viruses, which drove the need to investigate an alternative manufacturing process. Healthy children 12-to-23 months of age at 71 US sites were randomized (1:1) to receive MMRV manufactured using an alternative process (MMRVAMP) or the currently licensed MMRV. Subjects received 2 0.5 mL doses 3 months apart. Sera were collected before and 6 weeks after Dose-1. Adverse experiences (AEs) were collected for 42 d after each dose and serious AEs and events of special interest for 180 d after Dose-2. Overall, 706 subjects were randomized to MMRVAMP and 706 to MMRV and 698 and 702 received at least 1 dose of study vaccine, respectively. The risk difference in response rates and geometric mean concentrations of antibody to measles, mumps, rubella, and varicella viruses 6 weeks after Dose-1 met non-inferiority criteria for MMRVAMP versus, MMRV. Response rates met acceptability criteria for each virus, and the seroconversion rate to varicella-zoster virus was 99.5% in both groups. Vaccine-related AEs were mostly mild-to-moderate in intensity and somewhat more common after MMRVAMP. Febrile seizures occurred at similar rates in both groups during the first 42 d after each vaccine dose. MMRVAMP is non-inferior to MMRV and represents an important advancement in maintaining an adequate supply of vaccines against these diseases.

Immunogenicity and Safety of a 3- and 4-dose Vaccination Series of a Meningococcal ACWY Conjugate Vaccine in Infants: Results of a Phase 3b, Randomized, Open-label Trial.

BACKGROUND: The quadrivalent meningococcal glycoconjugate vaccine MenACWY-CRM is licensed for children from 2 months of age as a 4-dose series. This study assessed the immunogenicity of a 3-dose MenACWY-CRM vaccination series in infants, compared with the 4-dose series, and evaluated the impact of MenACWY-CRM concomitant administration on immune responses to the 13-valent pneumococcal conjugate vaccine (PCV13). METHODS: Overall, 751 healthy infants (age: 55-89 days) were randomized to receive 3 or 4 doses of MenACWY-CRM (2/4/12 or 2/4/6/12 months of age, respectively) with PCV13 + routine vaccinations (ACWY3 and ACWY4 groups, respectively) or PCV13 + routine vaccinations only (routine group). Immunological noninferiority of the 3-dose versus 4-dose MenACWY-CRM vaccination series was evaluated at 13 months of age for serogroups CWY; noninferiority of immune responses to PCV13 serotypes for concomitant administration of MenACWY-CRM and PCV13 was evaluated at 7 and 13 months of age. RESULTS: At 13 months, 88%-100% of subjects in groups ACWY3 and ACWY4 achieved seroprotective bactericidal antibody titers against serogroups ACWY; noninferiority criteria for the 3-dose versus 4-dose MenACWY-CRM vaccination series were met. At 7 months, noninferiority criteria were met for all PCV13 serotypes except for serotypes 3 and 5 (group ACWY3) and 19A (group ACWY4). At 13 months, noninferiority criteria were met for all PCV13 serotypes for both ACWY groups. CONCLUSIONS: After completion of either MenACWY-CRM vaccination series, most subjects achieved seroprotective titers against serogroups ACWY, with the 3-dose series being noninferior to the 4-dose series for serogroups CWY, and no interference with immune responses against PCV13 serotypes was observed (NCT01214837).

Immunogenicity and safety of a CRM-conjugated meningococcal ACWY vaccine administered concomitantly with routine vaccines starting at 2 months of age.

BACKGROUND: Infants are at the highest risk for meningococcal disease and a broadly protective and safe vaccine is an unmet need in this youngest population. We evaluated the immunogenicity and safety of a 4-dose infant/toddler regimen of MenACWY-CRM given at 2, 4, 6, and 12 months of age concomitantly with pentavalent diphtheria-tetanus-acellular pertussis-Hemophilus influenzae type b-inactivated poliovirus-combination vaccine (DTaP-IPV/Hib), hepatitis B vaccine (HBV), 7- or 13-valent conjugate pneumococcal vaccine (PCV), and measles, mumps, and rubella vaccine (MMR). RESULTS: Four doses of MenACWY-CRM induced hSBA titers ≥8 in 89%, 95%, 97%, and 96% of participants against serogroups A, C, W-135, and Y, respectively. hSBA titers ≥8 were present in 76-98% of participants after the first 3 doses. A categorical linear analysis incorporating vaccine group and study center showed responses to routine vaccines administered with MenACWY-CRM were non-inferior to routine vaccines alone, except for seroresponse to the pertussis antigen fimbriae. The reactogenicity profile was not affected when MenACWY-CRM was administered concomitantly with routine vaccines. CONCLUSION: MenACWY-CRM administered with routine concomitant vaccinations in young infants was well tolerated and induced highly immunogenic responses against each of the serogroups without significant interference with the immune responses to routine infant vaccinations. METHODS: Healthy 2 month old infants were randomized to receive MenACWY-CRM with routine vaccines (n = 258) or routine vaccines alone (n = 271). Immunogenicity was assessed by serum bactericidal assay using human complement (hSBA). Medically attended adverse events (AEs), serious AEs (SAEs) and AEs leading to study withdrawal were collected throughout the study period.

Concomitant administration of hepatitis A vaccine with measles/mumps/rubella/varicella and pneumococcal vaccines in healthy 12- to 23-month-old children.

This open-label, multicenter, randomized, comparative study evaluated immunogenicity, safety and tolerability of concomitant (Group 1; n=330) vs. non-concomitant (Group 2; n=323) VAQTA™ (25U/0.5 mL) (hepatitis A vaccine; HAV) with ProQuad™ (measles/mumps/rubella/varicella; MMRV) and Prevnar™ (7-valent pneumococcal; PCV-7) in healthy, 12-23 mo old children. Group 1 received HAV/MMRV/PCV-7 concomitantly on Day 1 and second doses of HAV/MMRV at Week 24. Group 2 received MMRV/PCV-7 on Day 1, HAV at Weeks 6 and 30 and MMRV at Week 34. Hepatitis A seropositivity rate (SPR: ≥10 mIU/mL; 4 weeks postdose 2), varicella zoster-virus (VZV) SPR (≥5 gpELISA units/mL) and geometric mean titers (GMT) to S. pneumoniae were examined. Injection-site and systemic adverse experiences (AEs) and daily temperatures were collected. Hepatitis A SPR were 100% for Group 1 and 99.4% for Group 2 after two HAV doses; risk difference=0.7 (95%CI: -1.4,3.8, non-inferior) regardless of initial serostatus. VZV SPR was 93.3% for Group 1 and 98.3% for Group 2; risk difference=-5.1 (95%CI: -9.3, -1.4; non-inferior). S. pneumoniae GMT fold-difference (7 serotypes) ranged from 0.9 to 1.1; non-inferior. No statistically significant differences in the incidence of individual AEs were seen when HAV was administered concomitantly vs. non-concomitantly. Three (all Group 2 post-administration of MMRV/PCV-7) of 11 serious AEs were considered possibly vaccine-related: dehydration and gastroenteritis (same subject) on Day 52; febrile seizure on Day 9. No deaths were reported. Antibody responses to each vaccine given concomitantly were non-inferior to HAV given non-concomitantly with MMRV and PCV-7. Administration of HAV with PCV-7 and MMRV had an acceptable safety profile in 12- to 23-mo-old children.

Immunogenicity and safety of two tetravalent (measles, mumps, rubella, varicella) vaccines coadministered with hepatitis a and pneumococcal conjugate vaccines to children twelve to fourteen months of age.

BACKGROUND: This study compared single-dose tetravalent measles, mumps, rubella, varicella vaccine, Priorix-Tetra, stored refrigerated (GSK+4C) or frozen (GSK-20C), with ProQuad (Merck-20C), when coadministered with hepatitis A vaccine (HAV) and 7-valent pneumococcal conjugate vaccine (PCV7). METHODS: Multicenter, observer-blind phase 2 study in 1783 healthy 12-14 month olds randomized to: GSK+4C (n = 705), GSK-20C (n = 689) or Merck-20C (n = 389), administered concomitantly with HAV (Havrix) and PCV7 (Prevnar). Seroresponse rates and antibody geometric mean concentrations/titers were determined from enzyme-linked immunosorbent assay and neutralization assays. Reactogenicity and safety were assessed. RESULTS: Seroresponse rates (day 42) were >97% for measles and rubella viruses and >92% for mumps virus, in all groups. Noninferiority of both GSK+4C and GSK-20C vaccines versus Merck-20C was demonstrated for seroresponse rates to measles, mumps and rubella viruses (lower 97.5% confidence interval above -5%, -10% and -5%, respectively). For varicella-zoster virus, seroresponse rates were 57.1%, 69.8% and 86.7% in the GSK+4C, GSK-20C and Merck-20C groups, respectively. Noninferiority was not shown for either GSK vaccine (lower 97.5% confidence intervals <-15%). Geometric mean concentration ratios for anti-varicella-zoster virus demonstrated noninferiority (lower 97.5% confidence interval ≥ 0.5) versus Merck-20C for GSK-20C only. Geometric mean concentration ratios for antibodies to HAV and to PCV7 pneumococcal serotypes also met criteria for noninferiority for both GSK groups compared with Merck-20C. GSK vaccine safety was observed comparable to Merck-20C. Localized but not generalized measles/rubella-like rash and grade 3 fever was reported slightly more frequently with GSK vaccines, but antipyretic use was similar. The incidence of subjects experiencing at least 1 serious adverse event was 2.0%, 2.9% and 1.8% in the GSK+4C, GSK-20C and Merck-20C groups, respectively. CONCLUSIONS: Noninferiority of both GSK measles, mumps, rubella, varicella vaccines versus Merck-20C was demonstrated for responses to measles, mumps and rubella viruses but was not fully demonstrated for varicella-zoster virus. The vaccines showed acceptable reactogenicity/safety when coadministered with HAV and PCV7.

Immunogenicity and safety of a quadrivalent meningococcal conjugate vaccine administered concomitantly with measles, mumps, rubella, varicella vaccine in healthy toddlers.

BACKGROUND: Invasive meningococcal disease can have devastating outcomes, especially in high-risk groups such as infants. As infants are recommended to receive multiple vaccines during a single office visit, this phase 3 study assessed the safety and immune response to MenACWY-CRM at alternative visits in older infants and concomitant use with measles, mumps, rubella, varicella vaccine (MMRV) at 12 months of age. METHODS: Two age groups were concurrently enrolled: 7- to 9-month-old infants who received 2 doses of MenACWY-CRM at 7-9 and 12 months and were randomized 1:1 to receive MenACWY-CRM with or without MMRV at 12 months, and 12-month-old infants who received MMRV only at 12 months. Using predefined non-inferiority criteria, immune responses to the antigens in MMRV were compared between those who did and did not receive MenACWY-CRM; immune responses to MenACWY-CRM as measured by the percentage of subjects with human serum bactericidal activity (hSBA) titers ≥ 8, were compared between those who did and did not receive concomitant MMRV. Adequacy of the immune response to 2 doses of MenACWY-CRM administered at 7-9 and 12 months was also assessed. Local and systemic reactions, adverse events resulting in withdrawal or requiring medical attention and serious adverse events were monitored. RESULTS: Concomitant administration of MMRV with MenACWY-CRM did not affect the immune response to either vaccine. The 2-dose series of MenACWY-CRM induced adequate immune response to all 4 serogroups. No increased reactogenicity was observed with MenACWY-CRM+MMRV compared with MMRV alone, and there were no study-related serious adverse events. CONCLUSIONS: Concomitant administration of MenACWY-CRM with MMRV vaccinations at 12 months was well-tolerated, without safety concerns. Robust immune responses to all components of both vaccines were produced and all criteria for non-inferiority were met, supporting the use of a 2-dose regimen of MenACWY-CRM in this age group.

Repeat dosing of albuterol via metered-dose inhaler in infants with acute obstructive airway disease: a randomized controlled safety trial.

BACKGROUND: Airway obstruction and bronchial hyperactivity often times lead to emergency department visits in infants. Inhaled short-acting beta2-agonist bronchodilators have traditionally been dispensed to young children via nebulizers in the emergency department. Delivery of bronchodilators via metered-dose inhalers (MDIs) in conjunction with holding chambers (spacers) has been shown to be effective. STUDY OBJECTIVE: : Safety and efficacy evaluations of albuterol sulfate hydrofluoroalkane (HFA) inhalation aerosol in children younger than 2 years with acute wheezing caused by obstructive airway disease. METHODS: A randomized, double-blind, parallel group, multicenter study of albuterol HFA 180 microg (n = 43) or 360 microg (n = 44) via an MDI with a valved holding chamber and face mask in an urgent-care setting. Assessments included adverse events, signs of adrenergic stimulation, electrocardiograms, and blood glucose and potassium levels. Efficacy parameters included additional albuterol use and Modified Tal Asthma Symptoms Score ([MTASS] reduction in MTASS representing improvement). RESULTS: Overall, adverse events occurred in 4 (9%) and 3 (7%) subjects in the 180-microg and 360-microg groups, respectively. Drug-related tachycardia (360 microg) and ventricular extrasystoles (180 microg) were reported in 1 patient each. Three additional instances of single ventricular ectopy were identified from Holter monitoring. No hypokalemia or drug-related QT or QTc prolongation was seen; glucose values and adrenergic stimulation did not significantly differ between treatment groups. In the 180-microg and 360-microg groups, mean change from baseline in MTASS during the treatment period was -2.8 (-49.8%) and -2.9 (-48.4%), and rescue albuterol use occurred in 4 (9%) and 3 (7%) subjects, respectively. CONCLUSIONS: Cumulative dosing with albuterol HFA 180 microg or 360 microg via MDI-spacer and face mask in children younger than 2 years did not result in any significant safety issues and improved MTASS by at least 48%.