Use of Mobile Devices and the Internet to Streamline an Asthma Clinical Trial (MICT)

Asthma is an inflammatory disease that imposes a significant burden affecting an estimated 300 million persons and 20% of all children worldwide. It is one of the most common chronic diseases of childhood and is a leading cause of school absenteeism. There continues to be a great need for clinical trials in asthma but traditional clinical trials are expensive and reasons cited by patients for non-participation are extra inconvenience and logistical barriers. Study designs which are patient centered and reduce trial costs are needed. The long-range goal of this application is to transform the paradigm of clinical research into a more efficient and cost-effective enterprise by capitalizing upon current widely used mobile electronic means of communication and information transfer. This innovative project is a streamlined clinical trial that will run concurrently with a nearly identical traditional clinical trial, "Long-acting Beta Agonist Step Down Study" (LASST) which will allow for direct comparison of processes and outcomes between the streamlined and traditional approach. Children 12 to 17 years old with asthma will be randomized to participate in this project (streamlined trial) or LASST (traditional trial). In this proposal we will: measure comprehension of study information using an original questionnaire, Research Participant Assessment (developed at Nemours), following a parental permission/assent process delivered over the internet in a dynamic interactive multi-media format (Specific Aim 1); measure the efficiency of participant driven data entry from home into a Research Electronic Data Capture (REDCap) online database using the iPad, and quality of spirometry with the EasyOne Plus handheld meter with remote coaching using the iPad (Specific Aim 2); test whether the streamlined approach has a "trial effect" by comparing the differences in Asthma Control Test (ACT) scores following 12 weeks of study drug treatment in children randomized to this project compared to LASST. We will collect effort reporting data to compare personnel costs between the trials. If this streamlined project lacks a "trial effect" and reduces costs compared to LASST, the methodologies would be generalizable to studies which include adults and other diseases.

Introduction Phase III / IV clinical trials are expensive and time consuming and often suffer from poor enrollment and retention rates. Pediatric trials are particularly difficult because scheduling around the parent, participant and potentially other sibling schedules can be burdensome. We are evaluating using the internet and mobile devices to conduct the consent process and study visits in a streamlined pediatric asthma trial. Our hypothesis is that these study processes will be noninferior and will be less expensive compared to a traditional pediatric asthma trial. Materials/Methods Parents and participants, aged 12 through 17 years, complete the informed consent process by viewing a multi-media website containing a consent video and study material in the streamlined trial. Participants are provided an iPad with WiFi (wireless internet) and EasyOne spirometer for use during FaceTime visits and online twice daily symptom reporting during an 8-week run-in followed by 12-week study period. Outcomes are compared with participants completing a similarly designed traditional trial comparing the same treatments within the same pediatric health-system. After 8 weeks of open-label Advair 250/50 twice daily, participants in both trial types are randomized to Advair 250/50, Flovent 250, or Advair 100/50 given 1 inhalation twice daily. Study staff track time spent to determine study costs. Results Participants have been enrolled in the streamlined and traditional trials and recruitment is ongoing. Conclusions This project will provide important information on both clinical and economic outcomes for a novel method of conducting clinical trials. The results will be broadly applicable to trials of other diseases.

Participants randomized to MICT will complete study procedures using an iPad for data entry and FaceTime visits rather than coming into the study site for onsite visits. Participants will perform spirometry at home using a handheld spirometer, EasyOne Plus. Randomized to one of 3 study treatments: fluticasone/salmeterol 250/50 Dry Powder Inhaler one inhalation twice daily, or fluticasone/salmeterol 100/50 Dry Powder Inhaler one inhalation twice daily, or fluticasone 100mcg Dry Powder Inhaler one inhalation twice daily

Participants randomized to LASST will complete study procedures in the traditional format in which all study visits are conducted at the study site, all questionnaires are completed by pen/paper, and all spirometry is performed at the clinic site. Randomized to one of 3 study treatments: fluticasone/salmeterol 250/50 Dry Powder Inhaler one inhalation twice daily, or fluticasone/salmeterol 100/50 Dry Powder Inhaler one inhalation twice daily, or fluticasone 100mcg Dry Powder Inhaler one inhalation twice daily.

Participants will receive Advair Diskus 250/50 Dry Powder Inhaler, administered twice daily for 12 weeks after randomization

Participants will receive Advair Diskus 100/50 Dry Powder Inhaler administered twice daily for 12 weeks after randomization

Participants will receive Flovent Diskus 100mcg Dry Powder Inhaler administered twice daily for 12 weeks after randomization

The Research Participant Assessment Score (RPA Comprehension) was a 17-item questionnaire designed to assess comprehension of study information at screening (Visit 1, week -8) between MICT and LASST trial designs. The same 17-item questionnaire was administered to the adolescent participant and to the caregiver participant. The items were scored as 1=incorrect, 2=partially correct, 3=correct (minimum possible score=17 and maximum possible score=51). Scores were assigned by two trained coders who independently listed to audio recordings of the RPA Comprehension questionnaire administration. Scores from the two coders were averaged for a final score. Higher scores indicate better comprehension. Mean (95% Confidence Interval) are the outcome measure reported.

The Research Participant Assessment Score (RPA Comprehension) was a 17-item questionnaire designed to assess comprehension of study information at screening (Visit 1, week -8) between MICT and LASST trial designs. The same 17-item questionnaire was administered to the adolescent participant and to the caregiver participant. The items were scored as 1=incorrect, 2=partially correct, 3=correct (minimum possible score=17 and maximum possible score=51). Scores were assigned by two trained coders who independently listed to audio recordings of the RPA Comprehension questionnaire administration. Scores from the two coders were averaged for a final score. Higher scores indicate better comprehension. Mean (95% Confidence Interval) are the outcome measure reported.

The Research Participant Assessment Score (RPA Comprehension) was a 17-item questionnaire designed to assess comprehension of study information at screening (Visit 6, week 12) between MICT and LASST trial designs. The same 17-item questionnaire was administered to the adolescent participant and to the caregiver participant. The items were scored as 1=incorrect, 2=partially correct, 3=correct (minimum possible score=17 and maximum possible score=51). Scores were assigned by two trained coders who independently listed to audio recordings of the RPA Comprehension questionnaire administration. Scores from the two coders were averaged for a final score. Higher scores indicate better comprehension. Mean (95% Confidence Interval) are the outcome measure reported.

The Research Participant Assessment Score (RPA Comprehension) was a 17-item questionnaire designed to assess comprehension of study information at screening (Visit 6, week 12) between MICT and LASST trial designs. The same 17-item questionnaire was administered to the adolescent participant and to the caregiver participant. The items were scored as 1=incorrect, 2=partially correct, 3=correct (minimum possible score=17 and maximum possible score=51). Scores were assigned by two trained coders who independently listed to audio recordings of the RPA Comprehension questionnaire administration. Scores from the two coders were averaged for a final score. Higher scores indicate better comprehension. Mean (95% Confidence Interval) are the outcome measure reported.

The Asthma Control Test is a 5-item Likert scale questionnaire; Scaling of items 5-point scale (for symptoms and activities: 1=all the time to 5= not at all; for asthma control rating: 1=not controlled at all to 5=completely controlled); The score for each item is summed to generate a total score. The scores range from 5 (poor control of asthma) to 25 (complete control of asthma), with higher scores reflecting greater asthma control. An ACT score >19 indicates well-controlled asthma. The study was powered to have greater than 90% power to detect a clinically meaningful difference of 3 in the ACT score between the MICT Trial Design and the LASST trial Design , assuming a mean score of 19 with a standard deviation of 4 (data from a previous ALA-ACRC trial).

The Asthma Control Test is a 5-item Likert scale questionnaire; Scaling of items 5-point scale (for symptoms and activities: 1=all the time to 5= not at all; for asthma control rating: 1=not controlled at all to 5=completely controlled); The score for each item is summed to generate a total score. The scores range from 5 (poor control of asthma) to 25 (complete control of asthma), with higher scores reflecting greater asthma control. An ACT score >19 indicates well-controlled asthma. The study was powered to have greater than 90% power to detect a clinically meaningful difference of 3 in the ACT score between the MICT Trial Design and the LASST trial Design , assuming a mean score of 19 with a standard deviation of 4 (data from a previous ALA-ACRC trial).

Spirometry grade scores in MICT participants (who performed spirometry at home) were compared with spirometry grade scores in LASST participants (who performed spirometry at the study sites). Spirometry grade scores were only available for LASST participants at Visit 3 (week 0), therefore only spirometry grade scores from Visit 3 were compared between MICT and LASST participants. Per the LASST trial no scoring was performed on the LASST participants for any other visit; the scoring for the LASST trial was for quality control only and was not a pre-specified trial outcome. Spirometry grade score scale was: 4.00 (highest=best possible score), 3.00, 2.00, 1.00, 0.00 (lowest=worst possible score). The maximum score was 4.00, the minimum score was 0.00. Higher scores indicate better spirometry score and therefore better quality.

This outcome was to measure differences in timeliness and completeness of forms completed at home through REDCap in MICT participants compared with LASST participants. No data were collected for this outcome. This is because in designing the REDCap database used to send questionnaires to the MICT trial participants and to store the responses from the completed questionnaires, data checks were put into place to prevent incomplete forms. We did this by requiring all fields to be completed before the questionnaire could be submitted. If a questionnaire was not submitted, the study coordinator re-sent the questionnaire to the participant and the questionnaire was completed during the FaceTime visit. For the LASST participants, the study coordinator reviewed all forms the participant completed at the study site visit and any incomplete fields were completed at the time of the study site visit.

This outcome was to measure differences in timeliness and completeness of forms completed at home through REDCap in MICT participants compared with LASST participants. No data were collected for this outcome. This is because in designing the REDCap database used to send questionnaires to the MICT trial participants and to store the responses from the completed questionnaires, data checks were put into place to prevent incomplete forms. We did this by requiring all fields to be completed before the questionnaire could be submitted. If a questionnaire was not submitted, the study coordinator re-sent the questionnaire to the participant and the questionnaire was completed during the FaceTime visit. For the LASST participants, the study coordinator reviewed all forms the participant completed at the study site visit and any incomplete fields were completed at the time of the study site visit.

This outcome was to measure differences in timeliness and completeness of forms completed at home through REDCap in MICT participants compared with LASST participants. No data were collected for this outcome. This is because in designing the REDCap database used to send questionnaires to the MICT trial participants and to store the responses from the completed questionnaires, data checks were put into place to prevent incomplete forms. We did this by requiring all fields to be completed before the questionnaire could be submitted. If a questionnaire was not submitted, the study coordinator re-sent the questionnaire to the participant and the questionnaire was completed during the FaceTime visit. For the LASST participants, the study coordinator reviewed all forms the participant completed at the study site visit and any incomplete fields were completed at the time of the study site visit.

This outcome was to measure differences in timeliness and completeness of forms completed at home through REDCap in MICT participants compared with LASST participants. No data were collected for this outcome. This is because in designing the REDCap database used to send questionnaires to the MICT trial participants and to store the responses from the completed questionnaires, data checks were put into place to prevent incomplete forms. We did this by requiring all fields to be completed before the questionnaire could be submitted. If a questionnaire was not submitted, the study coordinator re-sent the questionnaire to the participant and the questionnaire was completed during the FaceTime visit. For the LASST participants, the study coordinator reviewed all forms the participant completed at the study site visit and any incomplete fields were completed at the time of the study site visit.

This outcome was to measure differences in timeliness and completeness of forms completed at home through REDCap in MICT participants compared with LASST participants. No data were collected for this outcome. This is because in designing the REDCap database used to send questionnaires to the MICT trial participants and to store the responses from the completed questionnaires, data checks were put into place to prevent incomplete forms. We did this by requiring all fields to be completed before the questionnaire could be submitted. If a questionnaire was not submitted, the study coordinator re-sent the questionnaire to the participant and the questionnaire was completed during the FaceTime visit. For the LASST participants, the study coordinator reviewed all forms the participant completed at the study site visit and any incomplete fields were completed at the time of the study site visit.

This outcome was to measure differences in timeliness and completeness of forms completed at home through REDCap in MICT participants compared with LASST participants. No data were collected for this outcome. This is because in designing the REDCap database used to send questionnaires to the MICT trial participants and to store the responses from the completed questionnaires, data checks were put into place to prevent incomplete forms. We did this by requiring all fields to be completed before the questionnaire could be submitted. If a questionnaire was not submitted, the study coordinator re-sent the questionnaire to the participant and the questionnaire was completed during the FaceTime visit. For the LASST participants, the study coordinator reviewed all forms the participant completed at the study site visit and any incomplete fields were completed at the time of the study site visit.

Main Trial Inclusion Criteria: Age 12-17 years Physician diagnosed asthma (without any other co-morbid pulmonary disease) that is well-controlled on medium dose inhaled corticosteroid and long-acting β2-agonist given twice daily [Advair Diskus (fluticasone propionate/salmeterol) 250/50mcg; Advair HFA (hydrofluoroalkane) (fluticasone propionate/salmeterol hydrofluoroalkane) 115/21mcg; Symbicort (budesonide/formoterol) 160/4.5mcg; Dulera (mometasone/formoterol) 100/4.5mcg] based on an ACT score > 20, and the absence of unscheduled visits or use of rescue prednisone for 4 weeks prior to enrollment Pre-bronchodilator forced expiratory volume in the first second > 70% predicted < 10 pack/year history of tobacco use and abstinence for at least 1 year Exclusion Criteria: Chronic oral steroid therapy Hospitalization or urgent care visit within 4 weeks of the screening visit Near fatal asthma within 2 years of enrollment or high risk of near fatal or fatal asthma 125-127 Women who are pregnant or lactating Parallel MICT and Parallel LASST Inclusion Criteria: Age 12-17 years Physician diagnosed asthma (without any other co-morbid pulmonary disease) that is well-controlled on medium dose inhaled corticosteroid and long-acting β2-agonist given twice daily [Advair Diskus (fluticasone propionate/salmeterol) 250/50mcg; Advair HFA (hydrofluoroalkane) (fluticasone propionate/salmeterol hydrofluoroalkane) 115/21mcg; Symbicort (budesonide/formoterol) 160/4.5mcg; Dulera (mometasone/formoterol) 100/4.5mcg] based on an ACT score > 20, and the absence of unscheduled visits or use of rescue prednisone for 4 weeks prior to enrollment < 10 pack/year history of tobacco use and abstinence for at least 1 year Exclusion Criteria: Chronic oral steroid therapy Hospitalization or urgent care visit within 4 weeks of the screening visit Near fatal asthma within 2 years of enrollment or high risk of near fatal or fatal asthma 125-127 Women who are pregnant or lactating

Deidentified datasets, study forms, study protocol, study manual of procedures will be deposited into BioLINCC.

Data will be deposited in BioLINCC after the primary manuscript is published which is expected to be by January 2019.

Blake K, Holbrook JT, Antal H, Shade D, Bunnell HT, McCahan SM, Wise RA, Pennington C, Garfinkel P, Wysocki T. Use of mobile devices and the internet for multimedia informed consent delivery and data entry in a pediatric asthma trial: Study design and rationale. Contemp Clin Trials. 2015 May;42:105-18. doi: 10.1016/j.cct.2015.03.012. Epub 2015 Apr 3.

Antal H, Bunnell HT, McCahan SM, Pennington C, Wysocki T, Blake KV. A cognitive approach for design of a multimedia informed consent video and website in pediatric research. J Biomed Inform. 2017 Feb;66:248-258. doi: 10.1016/j.jbi.2017.01.011. Epub 2017 Jan 19.