A multi-site pilot randomized clinical trial of the Treatment and Education Approach for Childhood-onset Lupus (TEACH) program: study design and COVID-19 adaptations

This two-arm, international multi-site RCT will examine the feasibility and effect of a remotely delivered TEACH protocol in reducing symptoms in youth with cSLE. Six children’s hospitals (five in the United States [US], one in Canada [CAN]) plan to recruit participants. The anticipated participating sites expanded to this total number following the onset of the COVID-19 pandemic. All sites have established pediatric rheumatology programs with a substantial referral base. Two primary locations in the US (Michigan State University [MSU], led by NRC) and CAN (The Hospital for Sick Children, led by AMK) will coordinate study activities. Each primary location houses site PIs, interventionists, and research coordinators. MSU will receive referrals from the US-based sites: Helen DeVos Children’s Hospital, Seattle Children’s Hospital), Montefiore Medical Center/The Children’s Hospital at Montefiore), University of Alabama-Birmingham/Children’s of Alabama), and Cincinnati Children’s Hospital and Medical Center (see Fig. 1).

Seventy-five participants ages 12–22 years diagnosed with cSLE from participating rheumatology clinics will be enrolled.

Inclusion criteria will include patients who must: be diagnosed with cSLE, meeting the revised American College of Rheumatology Classification Criteria for SLE by age 18 [19]; be between the ages of 12 and 22 years; have clinical elevations in fatigue or depressive symptoms, or pain (see Measures section); have English language proficiency; and those under age 18 must be accompanied by a primary caregiver with English language proficiency willing to participate.

Exclusion criteria include patients with: other chronic medical conditions (e.g., juvenile idiopathic arthritis); a documented developmental delay, severe cognitive impairment, thought disorder; or an untreated major psychiatric illness (e.g., bipolar disorder, psychosis, severe depression, or active suicidal ideation (see Measures section)). In cases where patient safety is a concern, study staff will be notified immediately and a risk assessment will be conducted with oversight from a study psychologist. Parents will be informed for youth under 18 years, and appropriate safety measures (e.g., outpatient referrals, hospitalization) will be taken. Of note, the depressive symptom exclusionary criterion was adjusted by the study team given increased depressive symptoms in the cSLE population following the onset of COVID-19 [6]. Specifically, cut-off scores on the depression inventory were adjusted from T-score > 80 to T-score > 90 in August of 2021.

Physicians will identify youth who meet criteria for cSLE, introduce the study, and then study staff will speak with the family to obtain consent/assent. If study staff are not physically present, virtual consent procedures will be conducted via phone and REDCap’s eConsent Framework to minimize patient risk. After consent, study staff will conduct a psychosocial screening to determine eligibility (~ 5 min), as well as a baseline assessment with qualifying youth (see Fig. 1). Eligible patients will then be randomized to receive TEACH + TAU or TAU alone (See Fig. 2). Approximately eight and 20 weeks later, all subjects will be re-assessed on study outcomes. If significant symptom levels remain (or if family requests additional care), participants will be offered appropriate referrals. Following the post assessment, those randomized to TAU will then be eligible to receive TEACH+TAU (see Fig. 2). Subjects will receive up to $100 in Amazon gift cards ($50 at baseline and $50 at the eight-week assessment; no compensation is offered for 20-week assessment). Participants at the CAN site will receive research volunteer hours at the 20-week visit.

Eligible participants will be randomized to receive either TEACH + TAU or TAU alone in this open trial. Randomization scheduling will be computer-generated by a biostatistician at MSU and stratified based on the two main study sites and two age groups (< 18, 18 +), with a 1:1 ratio for each condition. We will also use blocking to keep the ratio of TEACH + TAU vs. TAU approximately equal throughout the trial. The study team including the site recruiters will be masked to the block size(s). Post assessment and follow up measures will be collected autonomously using online methods, allowing for blinded collection of outcome data irrespective of group assignment.

Study assessments will occur at baseline, eight weeks, and 20-weeks following the baseline assessment. Psychometrically validated instruments (self-report unless otherwise indicated) sensitive to change in pediatric health studies will be used to explore secondary and additional outcomes (see below). All online assessments will be delivered directly to participants, caregivers, and referring rheumatologists and collected via autonomous self-report in REDCap. The lead research coordinators will oversee data collection to ensure data is complete and collected in a timely manner.

Daily diaries will be completed by participants during the TEACH program to assess pain, mood, and fatigue. Each domain is assessed on a VAS, with qualitative end anchors (e.g., Pain = No pain to Worst possible pain; Mood = Great to The worst; Fatigue = Not tired at all to Extremely tired).

The Negative Effects Questionnaire, a 20-item questionnaire to examine adverse/unwanted events experienced during TEACH [39]. Participants will indicate whether they experienced the event and if it was related to TEACH. The degree of negativity is also measured on a 4-point Likert scale ranging from minimum to maximum.

Interventionists will receive individual training from the PI (NRC) or other trained interventionists either in person or via Zoom conference. The protocol will be reviewed and practiced by interventionists, with direct feedback provided during training. Continued feedback/monitoring will be provided throughout. Interventionists will meet periodically via Zoom to discuss barriers and tips learned to ensure best practices.

All participants across both conditions will continue standard medical treatment by their pediatric rheumatology team (TAU), either alone or in combination with TEACH.

Data will be managed and stored using REDCap, a secure software designed exclusively to support data capture for research studies. Considerable efforts (e.g., electronic data capture, standardized data checking strategies) will be made to limit missing data. Rates of missing data will be reported and addressed statistically if over 10%. If missing data are considered to be missing at random, multiple imputation or inverse probability weighting will be implemented at the time of final analysis. Given the modest sample size of this study, every effort will be made to minimize missing data.

Recruitment/retention rates and qualitative analysis of the semi-structured interview will assess feasibility, tolerability, and acceptability of TEACH. Evidence of feasibility is demonstrated by > 65% of patients/families approached will agree to participate (H1) and > 80% of recruits will complete the TEACH protocol (H2). Participant feedback about TEACH will be solicited and will support program feasibility (H3). Recorded qualitative interviews will be transcribed for the team to identify and code themes and key content domains. Discrepancies between reviewers will be discussed at length until a consensus is reached. Members of the research team (NRC, AMK) are experts in qualitative data analysis [18, 44‐48].

A repeated measures ANOVA will evaluate the hypotheses outlined in Aim 2. Participants will be allocated to the TEACH + TAU or TAU group. The mean change in fatigue (main secondary outcome), depressive symptoms, and pain from baseline to eight-week post will be analyzed separately to determine the effect of TEACH on these symptoms in comparison to the control group.