The pediatric hydroxyurea phase III clinical trial (BABY HUG): Challenges of study design

Evidence of the laboratory benefits of hydroxyurea and its clinical efficacy in reducing acute vaso‐occlusive events in adults and children with sickle cell anemia has accumulated for more than 15 years. A definitive clinical trial showing that hydroxyurea can also prevent organ damage might support widespread use of the drug at an early age. BABY HUG is a randomized, double‐blind placebo‐controlled trial to test whether treating young children ages 9–17 months at entry with a liquid preparation of hydroxyurea (20 mg/kg/day for 2 years) can decrease organ damage in the kidneys and spleen by at least 50%. Creation of BABY HUG entailed unique challenges and opportunities. Although protection of brain function might be considered a more compelling endpoint, preservation of spleen and renal function has clinical relevance, and significant treatment effects might be discernable within the mandated sample size of 200. Concerns about unanticipated severe toxicity and burdensome testing and monitoring requirements were addressed in part by an internal Feasibility and Safety Pilot Study, the successful completion of which was required prior to enrolling a larger number of children on the protocol. Concerns over recruitment of potentially vulnerable subjects were allayed by inclusion of a research subject advocate, or ombudsman. Finally, maintenance of blinding of research personnel was aided by inclusion of an unblinded primary endpoint person, charged with transmitting endpoint data and monitoring blood work locally for toxicity (ClinicalTrials.gov number, NCT00006400). Pediatr Blood Cancer 2010;54:250–255. © 2009 Wiley‐Liss, Inc.     

Transitioning health care responsibility from caregivers to patient: a pilot study aiming to facilitate medication adherence during this process

Abstract:  Transition in pediatric transplant recipients consists of both a physical shift in medical care location as well as a transition in health care responsibilities from caregivers to patients. The purpose of the present study was to test the feasibility of a pilot intervention aiming to facilitate the transition in health care responsibilities from caregivers to patients while patients are still receiving pediatric services. Twenty-two patients were enrolled in a two-session educational protocol aiming to facilitate transition of responsibility. Patients were recruited from an outpatient transplant clinic. Ten were referred because of suspected difficulty in transitioning of care, and 12 were consecutively recruited without any specific a priori concerns. Medication adherence, measured through the use of standard deviations of tacrolimus blood levels, and ALT levels were the medical outcome measures. Complete data are available for 20 patients. Mean ALT levels improved after the follow-up period. For referred patients, adherence and ALT levels improved. Standard deviation of tacrolimus decreased from 3.33 to 2.23, t  =   2.52, p   = 0.04. Mean ALT decreased from 120.33 to 63.99, t  =   3.01, p   = 0.01. Maximal ALT values decreased overall from 284.10 to 101.20, t  =   2.61, p   = 0.03. Our findings suggest that targeted education regarding transition in responsibility for adolescents' own health care is feasible in the outpatient environment and may assist families who are facing this potentially challenging process. A randomized, controlled study with a substantial number of enrolled patients is needed to establish the efficacy of this or other approaches.     

Online participatory intervention to promote and support exclusive breastfeeding: Randomized clinical trial

The support offered to mothers after hospital discharge can be decisive in maintaining exclusive breastfeeding during the first 6 months post‐partum. The objective of this study was to assess the impact on the duration of exclusive breastfeeding of a participatory intervention using an online social network. A randomized clinical trial was performed involving 251 mother–child pairings in a university hospital in the Northeast of Brazil, 123 of which assigned to the intervention group and 128 to the control group. After hospital discharge, the intervention group was followed through a closed group of an online social network, where weekly posters were published on topics related to breastfeeding and an active communication was established with the mothers. The groups were interviewed monthly over the phone until the child reached 6 months of age. The duration of exclusive breastfeeding was calculated through survival analysis, and the effect of the intervention was estimated through the Cox regression model. The exclusive breastfeeding frequencies were higher in the intervention group in all follow‐up months, reaching 33.3% in the sixth month versus 8.3% in the control group. The median exclusive breastfeeding duration was 149 days (95% CI [129.6, 168.4]) in the intervention group and 86 days (95% CI [64.9, 107.1]) in the control group (P < 0.0001). The proportional risk of early interruption of exclusive breastfeeding was 0.38 (95% CI [0.28, 0.51], P < 0.0001). This intervention had a positive impact on the duration and frequency of exclusive breastfeeding.     

Pediatric oncology clinical trial participation where the geography is vast: Development of a clinical research system for tertiary and satellite centers in Ontario,Canada

Opportunities for participation in clinical trials are a core component of the care of children with cancer. In Ontario, many pediatric patients live long distances from their cancer center. This paper describes the work that was done in order to allow patients participating in Children's Oncology Group trials to receive care, including research protocol related care, jointly between the tertiary pediatric cancer center and the closer‐to‐home satellite center. The system is a pragmatic risk‐based model, supporting excellence in care while ensuring good conduct of the research in compliance with applicable regulations and guidelines, including ethics oversight.     

Identification of educational and infrastructural barriers to prompt antibiotic delivery in febrile neutropenia: a quality improvement initiative

Background

Antibiotic administration within 60 minutes of presentation for medical care may be used as a treatment target for febrile neutropenia (FN); however, anecdotal evidence suggests this target is often missed. Few studies have examined the prevalence or causes of delay. We describe the median time to antibiotic administration at our institution, predictors of delay, and barriers to prompt administration to inform quality improvement strategies.

Procedure

A random sample of 50 episodes of FN presenting to the emergency department (ED) between 2008 and 2009 were reviewed. Times between triage, MD assessment, lab results, and antibiotic administration were recorded. Patient and ED variables were examined as possible predictors of delay. In parallel, lean methodology was used to identify system inefficiencies. A trained moderator conducted group interviews with interdisciplinary representatives involved in the emergency care of neutropenic patients to identify process barriers to prompt antibiotics.

Results

The median time from triage to antibiotics was 216 minutes (interquartile range [IQR] = 151–274 minutes). The greatest delay occurred following the reporting of lab results (152 minutes, IQR = 84–210 minutes). Only fall season predicted a longer time to antibiotics (P = 0.03). The lean process identified unnecessary areas of delay between departments.

Conclusions

Time to antibiotic administration exceeded 1 hour. The chart review and lean process suggested targets for educational and infrastructural interventions, including an ED pre‐printed order sheet, targeted combined subspecialty education between emergency and hematology/oncology staff, and family education. A mixed methodology approach represents a model for improving process efficiency and meeting “best‐practice” targets in medicine. Pediatr Blood Cancer 2012;59:431–435. © 2011 Wiley Periodicals, Inc.     

First-day step-down to oral outpatient treatment versus continued standard treatment in children with cancer and low-risk fever in neutropenia. A randomized controlled trial within the multicenter SPOG 2003 FN study

Background

The standard treatment of fever in chemotherapy‐induced neutropenia (FN) includes emergency hospitalization and empirical intravenous antimicrobial therapy. This study determined if first‐day step‐down to oral outpatient treatment is not inferior to continued standard regarding safety and efficacy in children with low‐risk FN.

Procedure

In a randomized controlled non‐blinded multicenter study, pediatric patients with FN after non‐myeloablative chemotherapy were reassessed after 8–22 hours of inpatient intravenous antimicrobial therapy. Low‐risk patients were randomized to first‐day step‐down to experimental (outpatient, oral amoxicillin plus ciprofloxacin) versus continued standard treatment. Exact non‐inferiority tests were used for safety (no serious medical complication; non‐inferiority margin of difference, 3.5%) and efficacy (resolution of infection without recurrence, no modification of antimicrobial therapy, no adverse event; 10%).

Results

In 93 (26%) of 355 potentially eligible FN episodes low‐risk criteria were fulfilled, and 62 were randomized, 28 to experimental (1 lost to follow‐up) and 34 to standard treatment. In intention‐to‐treat analyses, non‐inferiority was not proven for safety [27 of 27 (100%) vs. 33 of 34 (97%; 1 death) episodes; 95% upper confidence border, 6.7%; P = 0.11], but non‐inferiority was proven for efficacy [23 of 27 (85%) vs. 26 of 34 (76%) episodes; 95% upper confidence border, 9.4%; P = 0.045]. Per‐protocol analyses confirmed these results.

Conclusions

In children with low‐risk FN, the efficacy of first‐day step‐down to oral antimicrobial therapy with amoxicillin and ciprofloxacin in an outpatient setting was non‐inferior to continued hospitalization and intravenous antimicrobial therapy. The safety of this procedure, however, was not assessable with sufficient power. Pediatr Blood Cancer 2012;59:423–430. © 2012 Wiley Periodicals, Inc.     

Promoting medication adherence from the perspective of adolescent and young adult kidney transplant recipients,parents, and health care professionals: A TAKE‐IT TOO study

Medication non‐adherence is an important factor limiting allograft survival after kidney transplantation in AYA. Some interventions, including the TAKE‐IT, showed some success in promoting adherence but the potential for scalability and use in routine clinical practice is limited. We applied user‐centered design to gather the perspectives of recipients, parents, and health professionals concerning their needs, challenges, and potential intervention strategies to design an optimal, multi‐component medication adherence intervention. The qualitative study was conducted at four Canadian and three American kidney transplant programs. Separate focus groups for recipients, parents, and health professionals were convened to explore these stakeholders' perspectives. Directed content analysis was employed to identify themes that were shared vs distinct across stakeholders. All stakeholder groups reported challenges related to taking medications on time in the midst of their busy schedules and the demands of transitioning toward independence during adolescence. The stakeholders also made suggestions for the multi‐component behavioral intervention, including an expanded electronic pillbox and companion website, education materials, and customized digitized features to support shared responsibility and communication among recipients, parents, and health professionals. Several suggestions regarding the functionality and features of the potential intervention reported in this early stage will be explored in more depth as the iterative process unfolds. Our approach to actively involve all stakeholders in the process increases the likelihood of designing an adherence intervention that is truly user‐informed and fit for the clinical setting.     

OFF-LABEL USE OF GRANULOCYTE COLONY-STIMULATING FACTOR IN NONCONGENITAL NEUTROPENIA: Retrospective Data from the Italian Neutropenia Registry

This paper reviews a series of 70 consecutive children with rhabdomyosarcoma (RMS) diagnosed during 1971-1978 and treated in five Italian institutions. Thirteen were classified as group I, 12 as group II, 37 as group III, and 8 as group IV according to the Intergroup RMS Study staging system. Survival was influenced by tumor extension at diagnosis, primary site, and response to therapy. The 5-year-survival rate was 92% for group I patients, 67% for group II, 44% for group HI, and 0% for group IV. Thirty-four children had all therapy stopped after 12-32 months of complete remission, 7 had late recurrences, and 3 died from disease. Musculoskeletal sequelae were diagnosed in 11 children, short stature in 3, corneal opacity in 2, and cardiac failure in 1.