Integration of mHEALTH Into the Care of Patients With Sickle Cell Disease to Increase Hydroxyurea Utilization

• ClinicalTrials.gov Identifier: NCT04080167
• Recruitment Status: Completed
• First Posted: September 6, 2019
• Last Update Posted: February 28, 2023
• Sponsor: St. Jude Children's Research Hospital
• Collaborators: RTI International; National Heart, Lung, and Blood Institute (NHLBI); University of Memphis
• Information provided by (Responsible Party): St. Jude Children's Research Hospital

Tracking Information

• First Submitted Date: August 15, 2019
• First Posted Date: September 6, 2019
• Last Update Posted Date: February 28, 2023
• Actual Study Start Date: November 11, 2019
• Actual Primary Completion Date: April 6, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 24, 2023)

Mean change in PDC from baseline through 24 weeks [ Time Frame: baseline (prior to the intervention), week 24 ]

The primary outcome is the change in the percentage of days covered (PDC) of hydroxyurea, measured by comparing PDC during the 24-week baseline interval (i.e. prior the intervention) with PDC during the 24-week follow-up interval. PDC is calculated as the number of days covered (i.e., days of prescription refill dates and supply of each prescription) divided by the number of days in a treatment time point then multiply by 100 to obtain the PDC as a percentage.

Original Primary Outcome Measures (submitted: September 3, 2019)

Measure of the association between InCharge Health app to patient hydroxyurea adherence [ Time Frame: baseline (prior to the intervention), week 12, week 24 ]

The primary outcome is the change in proportion of days covered (PDC) of hydroxyurea from baseline (prior the intervention) to week 24. PDC is calculated as the number of days covered (i.e., days of prescription refill dates and supply of each prescription) divided by the number of days in a treatment time point then multiple by 100 to obtain the PDC as a percentage.

Current Secondary Outcome Measures (submitted: February 24, 2023)

• Implementation of InCharge Health app. [ Time Frame: baseline, 24 weeks ]
  Proportion and representativeness of patients. Patients participating/enrolled in the study (numerator) among all patients who receive hydroxyurea treatment and were screened and eligible (denominator) at each site.
• Change in mean corpuscular volume (MCV) [ Time Frame: baseline, 24 weeks ]
  Mean difference between MCV during the baseline interval and during the follow-up interval
• Change in fetal hemoglobin [ Time Frame: baseline, 24 weeks ]
  Mean difference between fetal hemoglobin during the baseline interval and during the follow-up interval
• Change in hemoglobin concentration [ Time Frame: baseline, 24 weeks ]
  Mean difference between hemoglobin during the baseline interval and during the follow-up interval
• Change in reticulocyte percentage [ Time Frame: baseline, 24 weeks ]
  Mean difference between reticulocyte percentage during the baseline interval and during the follow-up interval
• Change in absolute neutrophil percentage [ Time Frame: baseline, 24 weeks ]
  Mean difference between neutrophil percentage during the baseline interval and during the follow-up interval
• Change bilirubin [ Time Frame: baseline, 24 weeks ]
  Mean difference between total bilirubin during the baseline interval and during the follow-up interval
• Change in mean plasma lactate dehydrogenase (LDH) [ Time Frame: baseline, 24 weeks ]
  Mean difference between LDH during the baseline interval and during the follow-up interval
• Change in rate of emergency room visits per patient in the last 24 weeks [ Time Frame: baseline, 24 weeks ]
  Mean difference between number of emergency room visits during the baseline interval and during the follow-up interval.
• Change in rate of hospitalization per patient in the last 24 weeks [ Time Frame: baseline, 24 weeks ]
  Mean difference between number of hospitalizations during the baseline interval and during the follow-up interval.
• Change in patient reported pain quality [ Time Frame: baseline, 24 weeks ]
  Mean difference between scores on the Patient Reported Outcomes Information System (PROMIS) Pain Quality Scale during baseline and follow-up when the responses, never, rarely, sometimes, often, and always are coded 0 through 4.
• Change in patient reported pain impact: ASCQ-Me Pain Impact scale [ Time Frame: baseline, 24 weeks ]
  Mean difference between scores on the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Pain Episode Frequency and Severity Scale during baseline and follow-up when the responses, never, rarely, sometimes, often, and always are coded 0 through 4.
• Change in patient reported pain frequency and severity [ Time Frame: baseline, 24 weeks ]
  Mean difference between scores on the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Pain Episode Frequency and Severity scale during baseline and follow-up when the responses, never, rarely, sometimes, often, and always are coded 0 through 4.
• Change in healthy literacy [ Time Frame: baseline, 24 weeks ]
  Mean difference between responses to the Single item literacy screener (SILS) during baseline and follow-up when the responses, Never, rarely, sometimes, often, and always are coded 0 through 4; score is the sum of responses to 8 questions (score range: 0-32).
• Change in perceived self-efficacy [ Time Frame: baseline, 24 weeks ]
  Mean difference between responses to the Patient reported outcomes information system (PROMIS) medication self-efficacy short form during baseline and follow-up when the responses, I am not at all confident, I am a little confident, I am somewhat confident, I am quite confident, and I am very confident are coded 0 to 4.
• Change in provider knowledge of hydroxyurea (HU) prescription guidelines [ Time Frame: baseline, 9 months ]
  Mean difference between responses during baseline and follow-up to the 5 questions on the Hydroxyurea Knowledge Scale regarding knowledge of correctly prescribing hydroxyurea. Each question was scored 0 (incorrect response) or 1 (correct) and the 5 scores were summed to produce totals of 0 to 5.
• Change is provider self-efficacy of hydroxyurea (HU) prescription guidelines [ Time Frame: baseline, 9 months ]
  Hydroxyurea self-efficacy scale (comfort level and perceived effectiveness in prescribing hydroxyurea) with responses scored 0 to 4.
• Mean change in PDC from baseline through 36 weeks [ Time Frame: baseline (prior to the intervention), week 36 ]
  This outcome is the change in the percentage of days covered (PDC) of hydroxyurea, measured by comparing PDC during the 24-week baseline interval (i.e. prior the intervention) with PDC during the 36-week follow-up interval. PDC is calculated as the number of days covered (i.e., days of prescription refill dates and supply of each prescription) divided by the number of days in a treatment time point then multiply by 100 to obtain the PDC as a percentage.

Original Secondary Outcome Measures (submitted: September 3, 2019)

• Implementation of InCharge Health app. [ Time Frame: baseline, 24 weeks, 36 weeks ]
  Proportion and representativeness of patients participating/enrolled in the study (numerator) among all patients who receive hydroxyurea treatment and were eligible (denominator) at each site.
• Change in mean corpuscular volume (MCV) [ Time Frame: baseline, 24 weeks ]
  Mean MCV
• Change in fetal hemoglobin [ Time Frame: baseline, 24 weeks ]
  Mean fetal hemoglobin
• Change in hemoglobin [ Time Frame: baseline, 24 weeks ]
  Mean hemoglobin
• Change in absolute reticulocyte count [ Time Frame: baseline, 24 weeks ]
  Mean absolute reticulocyte count
• Change in absolute neutrophil count (ANC) [ Time Frame: baseline, 24 weeks ]
  Mean ANC
• Change in bilirubin (indirect) [ Time Frame: baseline, 24 weeks ]
  Mean indirect bilirubin
• Change in lactate dehydrogenase (LDH) [ Time Frame: baseline, 24 weeks ]
  Mean LDH
• Change in patients emergency room visits [ Time Frame: baseline, 24 weeks ]
  Frequency of emergency room visits per patient.
• Change in incidence of hospitalization [ Time Frame: baseline, 24 weeks ]
  Frequency of hospitalizations per patient.
• Change in patient reported pain quality [ Time Frame: baseline, 24 weeks ]
  PROMIS pain quality scale
• Change in patient reported pain impact: ASCQ-Me Pain Impact scale [ Time Frame: baseline, 24 weeks ]
  The ASCQ-Me Pain Episode Frequency and Severity Scale
• Change in patient reported pain frequency and severity [ Time Frame: baseline, 24 weeks ]
  The ASCQ-Me Pain Episode Frequency and Severity scale
• Change in healthy literacy [ Time Frame: baseline, 24 weeks ]
  The Newest Vital Sign scale
• Change in perceived self-efficacy [ Time Frame: baseline, 24 weeks ]
  PROMIS medication self-efficacy short form
• Change in provider knowledge of hydroxyurea (HU) prescription guidelines [ Time Frame: baseline, 9 months ]
  HU knowledge scale
• Change is provider self-efficacy of hydroxyurea (HU) prescription guidelines [ Time Frame: baseline, 9 months ]
  HU self-efficacy scale
• Implementation of the HU Toolbox [ Time Frame: baseline, 36 weeks, 48 weeks ]
  Mean change in provider satisfaction and proportion of providers that use the toolbox app at least once a week based on monthly clicks.
• Combined effects of the patient and provider mHealth interventions [ Time Frame: baseline, 36 weeks ]
  Patients' proportion of daily coverage and hospitalizations and emergency department visits per patient.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Integration of mHEALTH Into the Care of Patients With Sickle Cell Disease to Increase Hydroxyurea Utilization
• Official Title: Integration of mHEALTH Into the Care of Patients With Sickle Cell Disease to Increase Hydroxyurea Utilization- mESH Study

Brief Summary

This project proposes to develop, test and evaluate targeted interventions to improve clinical provider prescribing of and patient adherence to hydroxyurea (HU). Using a stepped-wedge design, The investigators will test two innovative interventions utilizing mobile health to address both patients' and providers' needs: 1) an mHealth application for patients (InCharge Health app) that includes multi-component features to address the memory, motivation, and knowledge barriers to hydroxyurea use, and 2) an mHealth toolbox application for providers (HU Toolbox app) that addresses clinical knowledge barriers in prescribing and monitoring hydroxyurea use. These two interventions will be tested through the following aims:

Aim 1. Improve Patient Adherence to Hydroxyurea: Addressing Memory, Motivation, and Knowledge Barriers to Hydroxyurea Use. Primary hypothesis: The investigators hypothesize that among adolescents and adults with SCD, the adherence to hydroxyurea, as measured by percentage of days covered (PDC), will increase by at least 20% at 24 weeks after receiving the InCharge Health app, compared to their hydroxyurea adherence at baseline.

Sub-aim 1.a. To examine and assess both patient engagement and behaviors related to use of the InCharge Health app, the investigators will evaluate consistent use of the app among enrolled patients, patient satisfaction, and continued use of the app beyond the study period.

Sub-Aim 1.b. To examine the clinical influence of the use of the InCharge Health app on PDC, patients' clinical outcomes, perceived health literacy, health related quality of life, and perceived self-efficacy between baseline and 24 weeks.

Aim 2. Improve Provider Hydroxyurea Awareness, Prescribing and Monitoring Behaviors.

Sub-Aim 2.a. To examine and assess provider engagement and behaviors related to use of the HU Toolbox, the investigators will evaluate consistent use of the app among enrolled providers, providers' satisfaction, and continued use of the app beyond the study period.

Sub-Aim 2.b. To assess the combined effects of the patient and provider mHealth interventions on hydroxyurea and health care utilization, the investigators will examine if the changes in hydroxyurea adherence are enhanced by the use of both provider and patient interventions compared to those not exposed to one or both interventions.

Aim 3. Identify and Evaluate the Barriers and Facilitators to the use of mHealth Interventions.

Detailed Description

The National Heart, Lung, and Blood Institute (NHLBI) created the Sickle Cell Disease Implementation Consortium (SCDIC) to apply implementation science methods to identify and address barriers to guideline-based care in sickle cell disease (SCD) and promote evidence-based treatment for SCD patients between ages 15 to 45 years. The SCDIC conducted a systematic literature review and a comprehensive needs assessment among the eight participating centers. A major conclusion was that care redesign to support better hydroxyurea utilization would likely improve clinical outcomes for patients with SCD. Hydroxyurea therapy has been shown to improve patient outcomes and reduce disease complications and is endorsed by the NHLBI. SCDIC now proposes to develop, test and evaluate targeted interventions to improve clinical provider prescribing of and patient adherence to hydroxyurea.

The overall purpose of this proposed project is to address barriers identified by the needs assessment to improve adherence with hydroxyurea therapy. Multiple approaches for improving adherence with pharmaceutical regimens have been studied and demonstrate a need to address barriers that both providers and patients face. This project aims, via a stepped-wedge design, to test two innovative interventions utilizing mobile health (mHealth), to address both patients' and providers' needs: 1) an mHealth application for patients (InCharge Health app) that includes multi-component features to address the memory, motivation, and knowledge barriers to hydroxyurea use, and 2) an mHealth toolbox application for providers (HU Toolbox app) that addresses the clinical knowledge barriers in prescribing and monitoring hydroxyurea use. These two interventions will be tested through the following aims:

Aim 1. Improve Patient Adherence to Hydroxyurea: Addressing Memory, Motivation, and Knowledge Barriers to Hydroxyurea Use. Primary hypothesis: The investigators hypothesize that among adolescents and adults with SCD, the adherence to hydroxyurea, as measured by percentage of days covered (PDC), will increase by at least 20% at 24 weeks after receiving the InCharge Health app, compared to their hydroxyurea adherence at baseline.

Sub-aim 1.a. To examine and assess both patient engagement and behaviors related to use of the InCharge Health app, the investigators will evaluate consistent use of the app among enrolled patients, patient satisfaction, and continued use of the app beyond the study period.

Sub-Aim 1.b. To examine the clinical influence of the use of the InCharge Health app on PDC, patients' clinical outcomes, perceived health literacy, health related quality of life, and perceived self-efficacy between baseline and 24 weeks.

Aim 2. Improve Provider Hydroxyurea Awareness, Prescribing and Monitoring Behaviors. The investigators will examine among providers using the HU Toolbox App if there is an increase in reported awareness of hydroxyurea benefits and risks, accurate prescribing of hydroxyurea, and perceived self-efficacy to correctly administer hydroxyurea therapy between baseline and after 9 months of using the HU Toolbox app.

Sub-Aim 2.a. To examine and assess provider engagement and behaviors related to use of the HU Toolbox, the investigators will evaluate consistent use of the app among enrolled providers, providers' satisfaction, and continued use of the app beyond the study period.

Sub-Aim 2.b. To assess the combined effects of the patient and provider mHealth interventions on hydroxyurea and health care utilization, the investigators will examine if the changes in hydroxyurea adherence are enhanced by the use of both provider and patient interventions compared to those not exposed to one or both interventions.

Aim 3. Identify and Evaluate the Barriers and Facilitators to the use of mHealth Interventions. The investigators will evaluate the strategies used by participating sites in supporting the implementation of mHealth interventions via a mixed-method evaluation of the facilitators and barriers in adopting and implementing the mHealth interventions from multiple stakeholder perspectives: patient, provider, and organization.

Both mHealth interventions will be tested concurrently and because the investigators are using a stepped-wedge design, each site will enter the study at different times. Provider participants will receive the HU Toolbox intervention for 9 months with a lagged but overlapping introduction of the InCharge Health intervention patient participants for 24 weeks. The implementation evaluation will be guided by RE-AIM to assess the Reach, Effectiveness, Adoption, Implementation and Maintenance of the interventions. All sites will also complete follow-on needs assessment and medical record abstractions that will provide data to evaluate other patient and provider outcomes, barriers and enablers to hydroxyurea prescribing, use, and monitoring.

mHealth technology can be leveraged to support more effective use of hydroxyurea and eventually improved SCD clinical outcomes. If the mHealth applications tested in this study show preliminary efficacy, both apps could be scaled up within SCDIC centers and expanded to other institutions outside the SCDIC.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

nonrandomized, closed cohort, stepped-wedge cluster trial

Masking: None (Open Label)
Primary Purpose: Health Services Research

• Condition: Sickle Cell Disease

Intervention

• Behavioral: InCharge Health mobile application
  The InCharge Health app features include: Daily reminders; Ability to customize content of message and time of day when the message comes; Symptom tracker to monitor daily pain and mood; 7-day streak that tracks daily adherence; Graphing adherence against pain symptoms; Communication feature allowing the patient to connect to the clinic and a "health partner"; Link to discussion forum where communication to other patients can occur; Education bank that provides information about SCD and hydroxyurea. Participants can delay daily push notifications. If hospitalized, participants may stop notifications. A special feature of the app is to set up a "health partner", who may be a person the participant may choose from his/her contact list and who will receive notifications if it had been <4 hours since not documenting the use of hydroxyurea. The "app healthy partner" will be encouraged to message the participant to remind him/her to take the medication.
• Behavioral: HU Toolbox mobile application
  The HU Toolbox app includes algorithms for hydroxyurea use and is ready for immediate use on Apple and Android operating systems. In addition, it has the NHLBI guidelines adapted for pediatrics (guidelines/recommendations separated by age) and for adults (guidelines/ recommendations separated by organ system, laboratory, or physical exam finding). The HU Toolbox app includes the ability to search guidelines for key words and add notes. Algorithms are also included as PDF documents that can be printed out or emailed. Finally, a contact list of local SCD specialists and important contacts is included, so providers can easily contact SCD experts and expect an answer in 24 hours or less. The HU Toolbox app is easily updated with all data and resources stored on a cloud-based server that can provide instant up-to-date information to those using the app.

Study Arms

• Arm 1 (InCharge Health app)
  Patient receives the InCharge Health app for 6 months
  Intervention: Behavioral: InCharge Health mobile application
• Arm 2 (HU Toolbox app)
  Provider receives the HU Toolbox app for 9 months
  Intervention: Behavioral: HU Toolbox mobile application

Publications *

• Badawy SM, DiMartino L, Brambilla D, Klesges L, Baumann A, Burns E, DeMartino T, Jacobs S, Khan H, Nwosu C, Shah N, Hankins JS; Sickle Cell Disease Implementation Consortium. Impact of the COVID-19 Pandemic on the Implementation of Mobile Health to Improve the Uptake of Hydroxyurea in Patients With Sickle Cell Disease: Mixed Methods Study. JMIR Form Res. 2022 Oct 14;6(10):e41415. doi: 10.2196/41415.
• Hankins JS, Shah N, DiMartino L, Brambilla D, Fernandez ME, Gibson RW, Gordeuk VR, Lottenberg R, Kutlar A, Melvin C, Simon J, Wun T, Treadwell M, Calhoun C, Baumann A, Potter MB, Klesges L, Bosworth H; Sickle Cell Disease Implementation Consortium. Integration of Mobile Health Into Sickle Cell Disease Care to Increase Hydroxyurea Utilization: Protocol for an Efficacy and Implementation Study. JMIR Res Protoc. 2020 Jul 14;9(7):e16319. doi: 10.2196/16319.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 22, 2021): 293
• Original Estimated Enrollment (submitted: September 3, 2019): 368
• Actual Study Completion Date: August 31, 2022
• Actual Primary Completion Date: April 6, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age 15 years up to and including 45 years
• Treated at or affiliated with one of the SCDIC sites
• English speaking
• Confirmed Sickle Cell Disease (SCD) diagnosis. An SCD diagnosis is defined as Hb fractionation test (e.g., high- performance liquid chromatography or another technique) that is diagnostic of one the following: Hb SS, Hb SC, Hb Sβ-thalassemia, Hb SO, Hb SD, Hb SG, Hb SE, or Hb SF.
• Willing and cognitively able to give informed consent
• Access to a cellular/mobile smart phone (either Android or IPhone are acceptable)
• Hydroxyurea therapy: Already receiving hydroxyurea therapy: defined as at least one prior prescription to hydroxyurea in the past 3 months and no plans to escalate the dose by more than 5 mg/kg/day. Initiating hydroxyurea therapy: defined as at least one prescription written at the time of study enrollment (the first prescription must be written on the same day as study enrollment). Patients who initiate hydroxyurea on the same day of study enrollment will not contribute to the total of 46 patients target accrual for the site. A max of 30 patients who are initiating hydroxyurea can be enrolled per site.

Exclusion Criteria:

• Current pregnancy
• On a chronic transfusion program in which they receive more than 8 erythrocyte transfusions in a 12-month period.
• A red blood cell transfusion in the past 60 days
• Currently using another phone application or an online-based tool (e-health tool) to increase hydroxyurea adherence

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 15 Years to 45 Years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04080167
• Other Study ID Numbers: mESH; 5U01HL133996 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified patient-level data will be available to researchers outside the SCDIC through an application and approval process through BIOLINCC. To protect the confidentiality and privacy of the participants, investigators granted access to the limited access data must adhere to strict requirements incorporated into a standard Data Use Agreement. In accordance with NHLBI policy, outside researchers may also be required to submit an approval to BIOLINCC from their IRB.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: Data will be made available by BIOLINCC for the study, upon request.
• Access Criteria: Access to the data must be requested through BIOLINCC by first creating an account and submitting a request for the data through the BIOLINCC website.
• URL: http://biolincc.nhlbi.nih.gov/register

• Current Responsible Party: St. Jude Children's Research Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: St. Jude Children's Research Hospital
• Original Study Sponsor: Same as current

Collaborators

• RTI International
• National Heart, Lung, and Blood Institute (NHLBI)
• University of Memphis

Investigators

• Principal Investigator: Jane Hankins, MD; St. Jude Children's Research Hospital

• PRS Account: St. Jude Children's Research Hospital
• Verification Date: February 2023