Karen Eves

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

Background Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. Methods We conducted two double‐blind, randomized, placebo‐controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard‐of‐care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention‐to‐treat population. Results In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, ‐10.1 percentage points; 95% confidence interval [CI], ‐15.9 to ‐4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, ‐9.9 percentage points; 95% CI, ‐15.5 to ‐4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, ‐11.6 percentage points; 95% CI, ‐17.4 to ‐5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, ‐10.7 percentage points; 95% CI, ‐16.4 to ‐5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. Conclusions Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.)

Safety and Immunogenicity of a Combination: Measles, Mumps, Rubella and Varicella Vaccine (ProQuad®)

Background: A combination measles, mumps, rubella, and varicella vaccine (ProQuad®, Merck & Co., Inc, West Point, PA) was evaluated in 5 clinical trials. Use of ProQuad® would result in fewer injections for children and would facilitate universal immunization against all 4 diseases. Objective: To describe the combined results obtained from the studies conducted during the clinical development program for ProQuad®. Methods: A total of 5833 healthy children, 12-23 months of age, and 399 healthy children, 4-6 years of age, received 1 or 2 doses of ProQuad® in 5 controlled clinical trials. M-M-R®II and VARIVAX® were used as the control for most studies. Safety was evaluated for 6 weeks postvaccination and immunogenicity was assessed 6 weeks after each dose by a sensitive assay (ELISA or gpELISA). Results: A single dose of ProQuad® in 12- to 23-month-old children was shown to be as immunogenic as a single dose of M-M-R®II and VARIVAX® and was generally well tolerated. ProQuad® can be used concomitantly with other vaccines (hepatitis B and Haemophilus influenzae b). A higher rate of fever was reported after 1 dose of ProQuad® compared to M-M-R®II and VARIVAX®, but fever episodes were transient without long-term sequelae. Both a 2-dose regimen of ProQuad® in 12- to 23-month-olds and use of ProQuad® in place of M-M-R®II at 4-6 years were shown to be immunogenic and well tolerated. The incidence of adverse experiences following a second dose of ProQuad® was lower than that following the initial dose. Conclusions: A single dose of ProQuad® is as immunogenic as M-M-R®II and VARIVAX® and is well tolerated in a 1- or 2-dose schedule. ProQuad® should easily fit into the routine immunization schedule.

An open randomized study of inactivated hepatitis A vaccine administered concomitantly with typhoid fever and yellow fever vaccines

BACKGROUND Concomitant administration of several vaccines is a common practice when travel clinics prepare persons for international travel. The purpose of the study was to compare the immunogenicity and safety of hepatitis A, typhoid fever, and yellow fever vaccines administered concomitantly with hepatitis A vaccine administered alone and typhoid fever and yellow fever vaccines administered alone. METHODS Healthy adults 18 to 55 years of age were randomized to receive either VAQTA, TyphimVi, and YF-VAX on day 0 and VAQTA at week 24 (Group 1); TyphimVi and YF-VAX on day 0 and an optional dose of VAQTA 1 month later (Group 2); or VAQTA at day 0 and week 24 (Group 3). RESULTS From March to December 1997, a total of 240 subjects were enrolled, 80 in each treatment group. Most were female and Caucasian, and the mean age was 29.4 years. Four weeks after vaccine dose 1, seroconversion to protective antibody levels against hepatitis A was 95.9% in Group 1 and 100% in Group 3. In Group 1, 93.4% of subjects demonstrated at least a 4-fold rise in neutralizing antibody levels against typhoid, compared with 90% in Group 2. Serum neutralizing antibody against yellow fever developed in 98.6% of subjects in Group 1 compared with 100% in Group 2. CONCLUSIONS These findings were consistent with similarity in the immune responses between treatment groups as defined a priori. The adverse experience (AE) profile did not appear to be substantially affected by concomitant administration of all three vaccines. Providing these three vaccines concomitantly can simplify the process of obtaining pretravel prophylaxis and may help ensure that all needed vaccines are administered.

A randomized study of a flexible booster dosing regimen of VAQTA® in adults: safety, tolerability, and immunogenicity

BACKGROUND VAQTA (hepatitis A vaccine inactivated, Merck & Co., Inc., West Point, PA) is licensed for use in healthy adults in a two-dose schedule at 0 and 6 months. OBJECTIVE to determine whether the responses to a booster dose of VAQTA administered to adults 12 or 18 months after the first dose were similar to the response when the booster dose was administered 6 months after the first dose. METHODS healthy adults were randomized to receive 50-U of VAQTA at 6 (Group I), 12 (Group II), or 18 months (Group III) following receipt of Dose 1 on Day 0. Blood samples were collected immediately prior to Doses 1 and 2 and then, 4 weeks following Dose 2. Seropositivity rates (SPRs), geometric mean titers (GMTs) in milli-international units per milliliter (mIU/ml) and booster response rates (BRRs) were compared among treatment groups. Safety data were collected on Vaccination Report Cards. RESULTS no serious adverse experiences were reported, and the vaccine was well-tolerated by subjects in the three treatment groups. One month following the booster dose, SPRs and GMTs for Groups I, II, and III, respectively, were, 100% (102/102) and 6726.4 mIU/ml; 97.9% (93/95) and 4863.8 mIU/ml; 100% (86/86) and 6068.3 mIU/ml. The BRRs were 88.2% (Group I), 90.2% (Group II) and 94.2% (Group III). CONCLUSION responses to the booster dose were comparable regardless of the timing (i.e. 6, 12, or 18 months following Dose 1). Flexibility in the timing of the booster dose of VAQTA in adults would allow the vaccination schedule to be the same for adults, adolescents, and children and may increase the likelihood that adults receive the booster dose.

Comparison of the Safety and Immunogenicity of a Refrigerator-Stable Versus a Frozen Formulation of ProQuad (Measles, Mumps, Rubella, and Varicella Virus Vaccine Live)

OBJECTIVE. A refrigerator-stable formulation of ProQuad has been developed to expand the utility of ProQuad to areas in which maintenance of a frozen cold chain (−15°C or colder) during storage and transport may not be feasible. The objective of this study was to demonstrate that the immunogenicity and safety profiles of a refrigerator-stable formulation of ProQuad are similar to the recently licensed frozen formulation. METHODS. In this double-blind, randomized, multicenter study, healthy 12- to 23-month-old children with negative vaccination and clinical histories for measles, mumps, rubella, varicella, and zoster were vaccinated with either the refrigerator-stable formulation of ProQuad (N = 1006) or the frozen formulation of ProQuad (N = 513). Patients were followed for 42 days after vaccination for adverse experiences. Immunogenicity was evaluated 6 weeks after vaccination. RESULTS. The refrigerator-stable formulation of ProQuad was generally well tolerated. The incidence of adverse experiences was similar between groups. No vaccine-related serious adverse experiences were reported. For both groups, the response rate was ≥97.7% for measles, mumps, and rubella, and the percentage of patients with a varicella zoster virus antibody titer of ≥5 U/mL glycoprotein antigen-based enzyme-linked immunosorbent assay after vaccination was ≥88.8%. The geometric mean titers for all antigens were numerically slightly higher in patients who received the refrigerator-stable formulation. CONCLUSIONS. The refrigerator-stable formulation of ProQuad is generally well tolerated, highly immunogenic, and noninferior in terms of postvaccination antibody responses. This refrigerator-stable formulation may improve ease of vaccine administration, increase use of the vaccine throughout the world because of its improved storage conditions, and replace the frozen formulation of ProQuad or any dose of M-M-RII and Varivax in routine practice.

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients at Increased Risk for Recurrence

Abstract Background Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B indicated to prevent C. difficile infection (CDI) recurrence (rCDI) in adults at high risk for rCDI. This post hoc analysis of pooled monocolonal antibodies for C.difficile therapy (MODIFY) I/II data assessed bezlotoxumab efficacy in participants with characteristics associated with increased risk for rCDI. Methods The analysis population was the modified intent-to-treat population who received bezlotoxumab or placebo (n = 1554) by risk factors for rCDI that were prespecified in the statistical analysis plan: age ≥65 years, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244. The proportion of participants with rCDI in 12 weeks, fecal microbiota transplant procedures, 30-day all cause and CDI-associated hospital readmissions, and mortality at 30 and 90 days after randomization were presented. Results The majority of enrolled participants (75.6%) had ≥1 risk factor; these participants were older and a higher proportion had comorbidities compared with participants with no risk factors. The proportion of placebo participants who experienced rCDI exceeded 30% for each risk factor compared with 20.9% among those without a risk factor, and the rCDI rate increased with the number of risk factors (1 risk factor: 31.3%; ≥3 risk factors: 46.1%). Bezlotoxumab reduced rCDI, fecal microbiota transplants, and CDI-associated 30-day readmissions in participants with risk factors for rCDI. Conclusions The risk factors prespecified in the MODIFY statistical analysis plan are appropriate to identify patients at high risk for rCDI. While participants with ≥3 risk factors had the greatest reduction of rCDI with bezlotoxumab, those with 1 or 2 risk factors may also benefit. Clinical Trials Registration NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).

Bezlotoxumab for Clostridium difficile Infection Complicating Inflammatory Bowel Disease

Bez, bezlotoxumab; CDI, Clostridium difficile infection; CI, confidence interval; IBD, inflammatory bowel disease; ICC, initial clinical cure; mITT, modified intent-to-treat; rCDI, recurrent CDI. Includes participants receiving bezlotoxumab or bezlotoxumab þ actoxumab. Includes participants receiving actoxumab or placebo. n, number of participants in the IBD subgroup analysis population meeting the endpoint criteria; m, total number of participants within the subgroup. mITT population; all randomized participants who received study infusion, had a positive baseline stool test for toxigenic C difficile and received antibacterial drug treatment for CDI. ICC; no diarrhea during the 2 consecutive days after completion of 16 calendar days of antibacterial drug treatment for CDI. rCDI; a new episode of diarrhea with a positive stool test for toxigenic C difficile, in participants that achieved ICC. Expanded ICC definition; no diarrhea during 2 consecutive days (regardless of the duration of antibacterial drug treatment for CDI and the timing of resolution of the initial episode). 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 Dear Editors: Individuals with inflammatory bowel disease (IBD) experience higher rates of Clostridium difficile infection (CDI) compared with the overall population, often lack typical CDI risk factors, and frequently experience recurrent episodes. Despite this, evidence-based management approaches for CDI complicating IBD are lacking. Bezlotoxumab (MK-6072), a fully human monoclonal antibody that binds to C difficile toxin B, is indicated to prevent recurrent CDI (rCDI) in at-risk adults. In the MODIFY I/II (NCT01241552/NCT01513239) phase III trials, bezlotoxumab resulted in a significantly lower rate of rCDI compared with placebo. Unlike other phase III CDI trials, individuals with IBD were eligible to participate. Using pooled data from MODIFY I/II, this post hoc analysis explored CDI-related outcomes in participants with IBD and CDI; initial clinical cure and rCDI (defined in Table 1). There were 2559 participants in the modified intent-to-treat population. In total, 44 participants had IBD: 23 (52.3%) had ulcerative colitis, 18 (40.9%) Crohn’s disease, and 3 (6.8%) noncharacterized IBD. Because the overall rCDI results were not different for the bezlotoxumab and the actoxumab þ bezlotoxumab groups, these groups were pooled (“bezlotoxumab” group); similarly, the actoxumab and placebo groups were pooled (“no bezlotoxumab” group). Of the 1554 participants randomized to the bezlotoxumab group, 28 had IBD and all completed the study. The 1005 remaining participants did not receive bezlotoxumab; 16 had IBD and 14 completed the study. The 2 remaining participants died (one due to stroke and the other due to septic shock). Baseline participant characteristics showed that, compared with those without IBD, participants with IBD were younger (mean age, 63.5 years vs 50.3 years, respectively), more frequently outpatients (32.0% vs 54.5%), more often immunocompromised (21.1% vs 40.9%), and less likely to have received a prior systemic antibiotic (55.2% vs 40.9%). There was a trend for a reduced rate of initial clinical cure in IBD participants in the bezlotoxumab group versus the no bezlotoxumab group (53.6% vs 81.3%, respectively; Table 1). During the 12-week follow-up period, there was a trend for rCDI to occur less frequently in the bezlotoxumab group (26.7% vs 53.8%), representing a 27.2% absolute reduction (95% confidence interval, -57.9 to 9.6) in the incidence of rCDI in IBD participants. A similar trend was observed in a sensitivity analysis using an expanded definition of initial clinical cure (Table 1).