Recombinant von Willebrand factor and tranexamic acid for heavy menstrual bleeding in patients with mild and moderate von Willebrand disease in the USA (VWDMin): a phase 3, open-label, randomised, crossover trial.

BACKGROUND: Heavy menstrual bleeding occurs in 80% of women with von Willebrand disease and is associated with iron deficiency and poor response to current therapies. International guidelines indicate low certainty regarding effectiveness of hormonal therapy and tranexamic acid. Although von Willebrand factor (VWF) concentrate is approved for bleeds, no prospective trials guide its use in heavy menstrual bleeding. We aimed to compare recombinant VWF with tranexamic acid for reducing heavy menstrual bleeding in patients with von Willebrand disease. METHODS: VWDMin, a phase 3, open-label, randomised crossover trial, was done in 13 haemophilia treatment centres in the USA. Female patients aged 13-45 years with mild or moderate von Willebrand disease, defined as VWF ristocetin cofactor less than 0·50 IU/mL, and heavy menstrual bleeding, defined as a pictorial blood assessment chart (PBAC) score more than 100 in one of the past two cycles were eligible for enrolment. Participants were randomly assigned (1:1) to two consecutive cycles each of intravenous recombinant VWF, 40 IU/kg over 5-10 min on day 1, and oral tranexamic acid 1300 mg three times daily on days 1-5, the order determined by randomisation. The primary outcome was a 40-point reduction in PBAC score by day 5 after two cycles of treatment. Efficacy and safety were analysed in all patients with any post-baseline PBAC scores. The trial was stopped early due to slow recruitment on Feb 15, 2022, by a data safety monitoring board request, and was registered at ClinicalTrials.gov, NCT02606045. FINDINGS: Between Feb 12, 2019, and Nov 16, 2021, 39 patients were enrolled, 36 of whom completed the trial (17 received recombinant VWF then tranexamic acid and 19 received tranexamic acid then recombinant VWF). At the time of this unplanned interim analysis (data cutoff Jan 27, 2022), median follow-up was 23·97 weeks (IQR 21·81-28·14). The primary endpoint was not met, neither treatment corrected PBAC score to the normal range. Median PBAC score was significantly lower after two cycles with tranexamic acid than with recombinant VWF (146 [95% CI 117-199] vs 213 [152-298]; adjusted mean treatment difference 46 [95% CI 2-90]; p=0·039). There were no serious adverse events or treatment-related deaths and no grade 3-4 adverse events. The most common grade 1-2 adverse events were mucosal bleeding (four [6%] patients during tranexamic acid treatment vs zero during recombinant VWF treatment) and other bleeding (four [6%] vs two [3%]). INTERPRETATION: These interim data suggest that recombinant VWF is not superior to tranexamic acid in reducing heavy menstrual bleeding in patients with mild or moderate von Willebrand disease. These findings support discussion of treatment options for heavy menstrual bleeding with patients based on their preferences and lived experience. FUNDING: National Heart Lung Blood Institute (National Institutes of Health).

Comparing the effectiveness of Family Support for Health Action (FAM-ACT) with traditional community health worker-led interventions to improve adult diabetes management and outcomes: study protocol for a randomized controlled trial.

BACKGROUND: Diabetes self-management education and support (DSMES) programs have struggled to deliver sustainable, effective support for adults with diabetes (AWDs) to improve self-management behaviors, achieve glycemic goals, and reduce risk for complications. One largely untapped resource for this support is AWDs' social networks. Fifty to 75% of AWDs have an unpaid family member or friend ("support person") who provides ongoing help with diabetes management. However, DSMES interventions to date lack structured and effective approaches to directly engage support persons in AWDs' diabetes management. METHODS: This parallel arm randomized trial is designed to determine the effectiveness of Family Support for Health Action (FAM-ACT), a novel community health worker (CHW)-delivered program focused on educating and supporting patients with type 2 diabetes (T2D) and their support persons (SPs), relative to an established, CHW-delivered, individual patient-focused DSMES and care management (I-DSMES) intervention. Both interventions were developed using a community-based participatory research (CBPR) approach. The study will be conducted in partnership with an urban Federally Qualified Health Center (FQHC) serving a low-income, Latino/a community, with target enrollment of 268 dyads consisting of an FQHC patient with T2D with high HbA1c and an SP. Patient-SP dyads will be randomized to receive FAM-ACT or I-DSMES over 6 months. The primary outcome is change in patient HbA1c from baseline to 6 months. Secondary patient outcomes include 12-month change in HbA1c, changes in patient blood pressure, diabetes self-management behaviors, diabetes distress, patient activation, diabetes self-efficacy, and perceptions of and satisfaction with SP support for diabetes. Secondary SP outcomes include self-efficacy for helping the patient with diabetes management and SP distress about the patient's diabetes. We also will assess the effect of the COVID-19 pandemic on patient's ability to manage diabetes. DISCUSSION: This study will inform scalable, evidence-based approaches that leverage family support to help AWDs improve and sustain self-management strategies that underpin optimal management of multiple diabetes complication risk factors. The protocol is designed for and evaluated with a low-income and predominantly Latino/a community, which may increase applicability to other similar communities. The COVID-19 pandemic presented several challenges to study protocol and intervention delivery; modifications made to address these challenges are described. TRIAL REGISTRATION: ClinicalTrials.gov NCT03812614. Registered on 18 January 2019.

Creating an academic research organization to efficiently design, conduct, coordinate, and analyze clinical trials: The Center for Clinical Trials & Data Coordination.

When properly executed, the randomized controlled trial is one of the best vehicles for assessing the effectiveness of one or more interventions. However, numerous challenges may emerge in the areas of study startup, recruitment, data quality, cost, and reporting of results. The use of well-run coordinating centers could help prevent these issues, but very little exists in the literature describing their creation or the guiding principles behind their inception. The Center for Clinical Trials & Data Coordination (CCDC) was established in 2015 through institutional funds with the intent of 1) providing relevant expertise in clinical trial design, conduct, coordination, and analysis; 2) advancing the careers of clinical investigators and CCDC-affiliated faculty; and 3) obtaining large data coordinating center (DCC) grants. We describe the organizational structure of the CCDC as well as the homegrown clinical trial management system integrating nine crucial elements: electronic data capture, eligibility and randomization, drug and external data tracking, safety reporting, outcome adjudication, data and safety monitoring, statistical analysis and reporting, data sharing, and regulatory compliance. Lastly, we share numerous lessons that can be taken from our experience. Specifically, we focus on 1) funding for DCCs, 2) the importance of DCCs to clinical researchers, 3) the expertise of DCC personnel, and 4) continually striving to improve. In conclusion, the CCDC strives to provide high-quality support for the design, conduct, coordination, and analyses of clinical trials, and we hope this paper will serve as a blueprint for future clinical trialists involved in DCCs.

Design of a randomized controlled trial of zinc supplementation to improve markers of mortality and HIV disease progression in HIV-positive drinkers in St. Petersburg, Russia.

Background Russia continues to have an uncontrolled HIV epidemic and its per capita alcohol consumption is among the highest in the world. Alcohol use among HIV-positive individuals is common and is associated with worse clinical outcomes. Alcohol use and HIV each lead to microbial translocation, which in turn results in inflammation. Zinc supplementation holds potential for lowering levels of biomarkers of inflammation, possibly as a consequence of its impact on intestinal permeability. This paper describes the protocol of a double-blinded randomized placebo-controlled trial of zinc supplementation in St. Petersburg, Russia. Methods Participants (n = 254) were recruited between October 2013 and June 2015 from HIV and addiction clinical care sites, and non-clinical sites in St. Petersburg, Russia. Participants were randomly assigned, to receive either zinc (15 mg for men; 12 mg for women) or placebo, daily for 18 months. The following outcomes were assessed at 6, 12, and 18 months: (1) mortality risk (primary outcome at 18 months); (2) HIV disease progression; (3) cardiovascular risk; and (4) microbial translocation and inflammation. Adherence was assessed using direct (riboflavin) and indirect (pill count, self-report) measures. Conclusion Given the limited effectiveness of current interventions to reduce alcohol use, zinc supplementation merits testing as a simple, low-cost intervention to mitigate the consequences of alcohol use in HIV-positive persons despite ongoing drinking.

MENSTRUAL AND REPRODUCTIVE FUNCTION IN WOMEN WITH TYPE 1 DIABETES.

OBJECTIVE: Menstrual irregularities, reproductive abnormalities, and androgen excess are reported to be more prevalent in women with type 1 diabetes (T1D). The objective of this study was to investigate the prevalence of menstrual irregularities, reproductive abnormalities, and androgen excess among women with T1D and their age-matched controls. METHODS: A survey requesting information regarding menstrual and reproductive histories was administered to all participants. Results were stratified according to age (18 to 40, 40 to 50, and >50 years). RESULTS: There were no significant differences between women with and without diabetes in age at menarche, cycle length, or androgen excess in any group. Women who self-reported difficulty with glycemic control were more likely to report irregular menses than controls (P = .04). Among women who reported ever being pregnant, there were fewer pregnancies (P = .02) and live births (P = .002) in women with T1D. Women with T1D reported a lower frequency of oral contraceptive use (P = .003), despite being less likely to smoke (P = .016). CONCLUSION: Menstrual and reproductive abnormalities were not observed more frequently in women with T1D in this study. Subtle but measurable differences in menstrual and reproductive function were confined to the subgroup of women who perceived poor control of their diabetes. Additional prospective studies of T1D and menstrual and reproductive function would be useful.

Pilot trial of diabetes self-management education in the hospital setting.

AIMS: Diabetes self-management education (DSME) is recommended for all patients with diabetes. Current estimates indicate that <50% of patients receive DSME, increasing risk for hospitalization which occurs more frequently with diabetes. Hospitalization presents opportunities to provide DSME, potentially decreasing readmissions. To address this, we investigated the feasibility of providing DSME to inpatients with diabetes. METHODS: Patients hospitalized on four medicine units were randomized to receive DSME (Education Group) (n=9) prescribed by a certified diabetes educator and delivered by a registered nurse, or Usual Care (n=12). Participants completed Diabetes Knowledge Tests (DKT), Medical Outcomes Short Form (SF-36), Diabetes Treatment Satisfaction Questionnaire (DTSQ), and the DTSQ-inpatient (DTSQ-IP). Bedside capillary blood glucoses (CBG) on day of admission, randomization and discharge were compared. RESULTS: There were no group differences in demographics, diabetes treatment, admission CBG (186±93 mg/dL vs. 219±84 mg/dL, p=0.40), DKT scores (Education vs. Usual Care 48±25 vs. 68±19, p=0.09), SF-36, and DTSQ scores (28±6 vs. 25±7, p=0.41). Patients receiving education reported more satisfaction with inpatient treatment (83±13 vs. 65±19, p=0.03), less hyperglycemia prior to (2.7±4.5 vs. 4.5±1.4, p=0.03) and during hospitalization (3.9±1.9 vs. 5.5±1.2, p=0.04); and had lower mean discharge CBG (159±38 mg/dL vs. 211±67 mg/dL, p=0.02). CONCLUSIONS: Inpatient diabetes education has potential to improve treatment satisfaction, and reduce CBG.

Effect of a targeted glycemic management program on provider response to inpatient hyperglycemia.

OBJECTIVE: To report the results of implementation of a Targeted Glycemic Management (TGM) Service pilot, with the goals of improving clinician awareness of available inpatient glycemic management protocols and improving responsiveness to and frequency of severe hyperglycemia. METHODS: Patients with a blood glucose (BG) level ≥300 mg/dL who were hospitalized on a general medicine unit during three 12-week periods before, during, and after the TGM pilot were compared for responsiveness by the primary team, percentage of subsequent BG measurements between 80 and 180 mg/dL, and frequency of subsequent severe hyperglycemia (BG levels ≥300 mg/dL) and hypoglycemia (BG values <70 mg/dL). RESULTS: In comparison with pre-TGM and post-TGM periods, more patients during the TGM pilot had a modification of their glycemic regimen in response to severe hyperglycemia (49% versus 73% versus 50%, before, during, and after TGM, respectively; P = .044), and the percentage of patients with ≥50% of subsequent BG measurements in the desired range (27% versus 53% versus 32%; P = .035) was greatest during the TGM period. The incidence of subsequent severe hyperglycemia (20% versus 9% versus 16%; P = .0004) was lowest during the TGM period; however, the incidence of hypoglycemia was similar in all 3 periods (3.9% versus 3.7% versus 3.7%). CONCLUSION: These results indicate that a TGM Service can favorably influence glycemic management practices and improve glycemic control, but ongoing intervention is necessary for maintenance of these results.

Patient outcomes after implementation of a protocol for inpatient insulin pump therapy.

OBJECTIVE: To determine the safety and the results of use of an inpatient insulin pump protocol (IIPP). METHODS: In this quality improvement initiative, review of medical records of bedside capillary blood glucose (CBG) levels and pump-related adverse events was performed on 50 consecutive inpatients admitted to the hospital with continuous subcutaneous insulin infusion (CSII) after implementation of our IIPP. Patients were categorized in 3 groups on the basis of evidence in the medical records for IIPP in combination with inpatient diabetes service consultation (group 1; n = 34), for IIPP alone (group 2; n = 12), or for usual care (group 3; n = 4). Patients identified during hospital admission as using CSII therapy were invited to complete a satisfaction questionnaire for inpatient CSII use. RESULTS: Mean CBG levels were similar among the 3 groups (groups 1, 2, and 3: 173 +/- 43 mg/dL versus 187 +/- 62 mg/dL versus 218 +/- 46 mg/dL, respectively). Although there were more patient-days with blood glucose >300 mg/dL in group 3 (P = .02), there were no significant group differences in the frequency of hypoglycemia (CBG <70 mg/dL). Only 1 pump malfunction and 1 infusion site problem were reported among all study patients. No serious adverse events related to CSII therapy occurred. The majority of patients (86%) reported satisfaction with their ability to continue CSII use in the hospital. CONCLUSION: Patients using CSII as outpatients are candidates for inpatient diabetes self-management. Inexperience with these devices on the part of hospital personnel together with the limited studies of patient experience with CSII in the hospital contributes to inconsistencies in management of these patients. An IIPP provides a standardized and safe approach to the use of CSII in the hospital.

Insulin therapy and glycemic control in hospitalized patients with diabetes during enteral nutrition therapy: a randomized controlled clinical trial.

OBJECTIVE: To compare two subcutaneous insulin strategies for glycemic management of hyperglycemia in non-critically ill hospitalized patients with diabetes during enteral nutrition therapy (ENT). RESEARCH DESIGN AND METHODS: Fifty inpatients were prospectively randomized to receive sliding-scale regular insulin (SSRI) alone (n = 25) or in combination with insulin glargine (n = 25). NPH insulin was added for persistent hyperglycemia in the SSRI group (glucose >10 mmol/l). RESULTS: Glycemic control was similar in the SSRI and glargine groups (mean +/- SD study glucose 8.9 +/- 1.6 vs. 9.2 +/- 1.6 mmol/l, respectively; P = 0.71). NPH insulin was added in 48% of the SSRI group subjects. There were no group differences in frequency of hypoglycemia (1.3 +/- 4.1 vs. 1.1 +/- 1.8%; P = 0.35), total adverse events, or length of stay. CONCLUSIONS: Both insulin strategies (SSRI with the addition of NPH for persistent hyperglycemia and glargine) demonstrated similar efficacy and safety in non-critically ill hospitalized patients with type 2 diabetes during ENT.