Lupus PROGRESS is enrolling 150 individuals with SLE and chronic pain from 3 study sites. Consistent with the pragmatic design, enrollment reflects site-specific patient populations and recruitment capacity: Humana Healthcare Research is part of the national Medicare Advantage plan (anticipated n=120), Stanford Medicine is an academic medical center (anticipated n=15), and Intermountain Health is an integrated care network (anticipated n=15). Recruitment at Humana involves mailed advertising sent to individuals identified through database diagnostic codes (International Classification of Diseases). Stanford recruitment involves direct-to-participant email outreach (n=645) through an opt-in institutional pain research registry where patients self-identify as having SLE. Intermountain Health recruits patients with SLE via study advertisements mailed to patients with chronic pain–related International Classification of Diseases codes.

Inclusion criteria are age ≥18 years, receipt of medical care through a Lupus PROGRESS study site, experience of chronic pain for 3 or more months with past-month average severity of 3 or more on a 10-point scale [23], and diagnosis of SLE. To enhance SLE diagnostic accuracy, we are applying criteria based on the work by Falasinnu et al [23] to increase the likelihood of true idiopathic SLE rather than drug-induced lupus or other secondary lupus conditions more common in older adults and to align with typical SLE onset and disease patterns. Patients must be actively and continuously enrolled in a commercial or Medicare Advantage plan for at least 6 months to ensure that all outcome measures are available. Following the work by Falasinnu et al [3], patients are required to have 2 or more lupus diagnostic codes from Textbox 1 on different dates separated by 7 to 365 days during the data period, with at least one code from a rheumatologist, dermatologist, or nephrologist. Per Humana institutional policies, members enrolled in administrative services–only insurance, Medicaid, and other research-excluded groups will be excluded. Other exclusion criteria are inability to consent, complete study measures (online or paper based), or participate in internet-based treatment groups. Past-3-month receipt of Empowered Relief or CBT and active suicidal ideation at screening are also exclusionary. Concomitant pain care of other types is allowed, self-reported throughout the trial, and will be reported in the study.

Study information, including recruitment materials and screening survey links, is available via the study website [24], where interested individuals can click on a screening survey link to complete initial screening and eligibility verification. Participants complete online eligibility screening and e-consent through the online study informatics platform, called CHOIR [16], with health care use derived from linked electronic health record and claims data where available.

Study data are collected and managed using the CHOIR platform, with secure, password-protected storage and built-in data quality checks (eg, range and completeness checks) to support data integrity. Participant-reported level of depression symptoms are continuously monitored through the platform, with predefined clinical thresholds triggering alerts to study staff and escalation procedures, including follow-up and referral to appropriate care as needed.

After completing the study screener to ensure initial eligibility, randomization occurs using CHOIR’s randomization functionality to ensure balanced 1:1 allocation (ie, 75 per arm). Informed consent takes place with a study coordinator via phone. However, group assignment (Empowered Relief or CBT) is only disclosed to participants after completion of the baseline survey. To maintain study integrity, treatment allocation remains concealed from investigators and biostatisticians until database closure after the 6-month follow-up, whereas site personnel and treatment providers necessarily remain unblinded for operational execution. Figure 1 details the study recruitment methods and participant flow.

The study is guided by a multilevel patient-centered engagement infrastructure, including a 76-member national patient advisory panel, a 17-member local patient advisory board, and a central 10-member patient engagement and diversity board with a patient representative with lupus, which collaboratively inform study design, recruitment strategies, patient-facing materials, and implementation processes to ensure accessibility and inclusivity [22]. These advisory boards prioritize diverse representation across demographic and lived experience domains and are actively engaged throughout the study life cycle [22]. Additionally, condition-specific advisory input contributes to tailoring study procedures and materials to enhance inclusivity for specific patient populations.

CHOIR [25] is used as the study informatics platform to confirm eligibility, obtain electronic consent, distribute automated emails, and collect self-report data. The study uses a hybrid workflow combining automated processes with strategic coordinator touchpoints developed in response to local regulatory requirements and informed by patient advisor feedback, emphasizing the value of coordinator interaction for participant engagement and retention.

Lupus PROGRESS compares 2 evidence-based online skill-based pain treatments that have common and distinct elements and differ in treatment duration and intensity.

The study primary aims were selected based on patient preference surveys administered in the parent PROGRESS study.

Primary aim 1 is to compare treatment groups for multiple primary outcomes (pain intensity and pain interference) at 3 months after treatment. We hypothesize that Empowered Relief will be noninferior to 8-session CBT for reducing pain intensity or pain interference.

Primary aim 2 is to compare treatment groups for 4 priority secondary outcomes (sleep disturbance, pain catastrophizing, pain bothersomeness, and anxiety), treatment completion and adherence, and treatment burden. We hypothesize that Empowered Relief will be noninferior to 8-session CBT for improving priority secondary outcomes at 3 months after treatment and that Empowered Relief will have superior treatment completion and adherence (number and percentage of those attending Empowered Relief or at least 5 sessions of CBT) and lower burden ratings than 8-session CBT.

Primary aim 3 is to compare treatment groups for other secondary outcomes (satisfaction with social roles and responsibilities, patient global impression of change, anger, fatigue, and depression). We hypothesize that Empowered Relief will be noninferior to CBT for improving secondary outcomes at 3 months after treatment.

Primary aim 4 is to compare the durability of treatment effects at 6 months after treatment. We hypothesize that Empowered Relief will be noninferior to 8-session CBT for multiple primary outcomes and priority secondary outcomes at 6 months after treatment.

The exploratory aim is to compare health care use and opioid use through electronic health record and Centers for Medicare & Medicaid Services (CMS) data 3 months prior to enrollment to the last 3 study months. We will assess medication status (eg, stable dose, voluntary tapering, or involuntary tapering), as well as medication access (eg, no access problems or difficulty with medication access). We hypothesize that both groups will show reduced use during the final 3 study months.

We will also investigate the trajectory of both treatments individually (within-group treatment outcomes).

Self-reported demographic data are collected at baseline and include age, gender identity, sex at birth, race and ethnicity, household composition, educational attainment, veteran status, disability status, employment status, annual household income, and pregnancy status. Additional baseline variables include pain history, prior behavioral pain treatment, current pain treatments, and barriers to pain care. Substance use is assessed using the National Institute on Drug Abuse 4-item quick screen, pain distribution is assessed using the Stanford CHOIR visual body map [31], treatment expectancy is assessed after treatment assignment is revealed to participant using the 6-item Stanford Expectations of Treatment Scale [32], and immediately after treatment, satisfaction and perceived utility are assessed using study-specific items [9].

Participants complete validated measures at baseline; immediately before treatment; and at 1, 2, 3, and 6 months after treatment, with Table 1 showing each outcome, the specific measure used, and the time points of administration. Additional posttreatment measures include treatment burden and satisfaction; engagement is assessed via session attendance. Health care use is evaluated using electronic medical record or claims data comparing the 3 months prior to enrollment with the final 3 months of follow-up.

SLE-specific measures include the Brief Index of Lupus Damage (BILD) [58], a validated patient-reported and dichotomous (yes or no) measure of cumulative organ damage in SLE, and the Systemic Lupus Activity Questionnaire (SLAQ) [59], a patient-reported instrument that uses a mixed-response format to assess lupus disease activity and recent symptom burden. The BILD assesses cumulative organ damage across 12 organ systems, capturing damage attributable to SLE that has been present for at least 6 months since disease onset. Each item is recorded as present or absent, yielding total scores ranging from 0 to 30, with higher scores reflecting greater accumulated organ damage. The SLAQ comprises 24 items assessing symptoms and signs of disease activity (eg, fatigue, fever, cutaneous manifestations, and arthritis) over the preceding 3 months. Each item is rated on a 4-point scale (“no problem,” “mild,” “moderate,” or “severe”), corresponding to scores from 0 to 3. Total scores range from 0 to 44, with higher values indicating greater SLE-related disease activity. Both measures are administered at baseline and at 3 and 6 months after treatment.

Harms are defined as adverse events, including participant-reported distress or other negative experiences, and are assessed through both structured study assessments and spontaneous participant report, with ongoing monitoring by study staff. Adverse events will be summarized by comparator and included in the final trial report.

Table 2 describes the study power to assess noninferiority across multiple primary outcomes, priority secondary outcomes, and other secondary outcomes at 3 months after treatment.

The sample size of 75 patients per group was selected to support noninferiority testing for 2 primary outcomes (pain intensity and pain interference) at a 1-sided significance level of 10%/2=5%, and all secondary outcomes (sleep disturbance, pain bothersomeness, pain catastrophizing, anxiety, satisfaction with social roles and responsibilities, patient global impression of change, anger, fatigue, and depression) at a 1-sided significance level of 10%. Different significance levels were selected to account for multiple testing and reflecting the priority of the outcomes. Table 2 shows the power for the primary, priority secondary, and other secondary outcomes, with sufficient power (>70%) achieved for most outcomes except pain intensity, and satisfaction with roles and responsibilities; the study is not powered to detect changes in SLE-related activity and disease burden outcomes.

Primary analyses will evaluate the noninferiority of Empowered Relief compared with 8-session CBT for pain intensity and pain interference at 3 months after treatment based on estimated treatment effects from a mixed model for repeated measures (MMRM) with an unstructured covariance matrix under an intention-to-treat framework. We will conduct 2 separate MMRMs analyses for pain intensity and pain interference; for addressing missing data, MMRM is considered superior over other options such as multiple imputation or least observation carried forward. Specifically, treatment effects at month 3 will be estimated through the treatment-by-time interaction at the 3-month time point. Secondary analysis will similarly evaluate the noninferiority of Empowered Relief compared with CBT for 4 priority secondary outcomes and 5 other secondary outcomes at the month 3 visit. We will also evaluate the noninferiority of all the aforementioned outcomes at the month 6 visits. Exploratory analyses will evaluate within-group change trajectories and compare treatment completion, patient burden, and exploratory health care use outcomes between the 2 groups. Exploratory analyses will examine changes in the BILD and SLAQ for both groups.

Power calculations for multiple primary end points, priority secondary measures, and additional outcomes are shown in Table 2; adequate statistical power was achieved for general pain outcomes, although lupus-specific measures are exploratory given sample constraints. Enrolling 150 participants provides sufficient power to assess noninferiority between treatments for pain intensity and interference (multiple primary outcomes) applying a 1-sided α of .05 and priority secondary end points applying a 1-sided α of .10.

The primary analytic strategy tests whether Empowered Relief demonstrates noninferiority to CBT on pain intensity and interference at the 3-month primary end point. We will use MMRMs with unstructured variance-covariance matrices, analyzing all participants as randomized (intention to treat). Between-group differences will be quantified via treatment-by-time interaction terms evaluated at 3 months after the intervention.

Additional analyses address several secondary objectives: persistence of treatment gains at the 6-month follow-up, longitudinal symptom trajectories within each intervention arm, rates of treatment engagement and participant-reported burden, and patterns of health care service use. SLE-specific end points, including BILD [58] and SLAQ [59], will also be examined to characterize how interventions perform within this disease population, although these analyses are exploratory.

Exploratory heterogeneous treatment effect subgroup analyses will assess whether treatment effects differ by pain type, number of pain conditions, race and ethnicity, socioeconomic status, disability status, and insurance type—factors associated with pain burden and treatment access. Analyses will use the Tukey method for multiple comparison adjustment.

For both groups, we will summarize data on treatment burden, satisfaction, and completion; online ease; and missing data. We will examine effects by site, therapist, and insurance type. We will also examine CBT attendance as a continuous variable and baseline predictors for attrition.

Lupus PROGRESS is conducted in compliance with all participating site institutional review boards, with the coordinating approval provided by the Stanford University School of Medicine Institutional Review Board (65439). The study is conducted in accordance with the Declaration of Helsinki and adheres to Patient-Centered Outcomes Research Institute regulatory standards [66]. The study is overseen by an independent data safety and monitoring board meeting twice annually and reported in accordance with SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines and sponsor regulatory standards. The study has been registered on ClinicalTrials.gov (NCT05612750).

Participant identification is protected with a unique study identification number. All data will be received electronically, immediately locked in the database, and stored with double password protection. The project manager and treatment instructors will be unblinded to individual group assignment; coinvestigators will be blinded until 6-month data are received. Statisticians will remain blinded to group assignment until the database is locked. Participant blinding is not possible given the obvious difference in treatment duration (1 vs 8 sessions), with treatment assignment revealed only after completion of the baseline survey. In advertisements and consent forms, both treatments are described as expert-led evidence-based group treatments for chronic pain that involve learning, experiences, pain relief skills, and creating a personalized plan for pain relief.

Participants may discontinue their participation in the study at any time in response to distress, adverse experiences, or personal preference, with study staff available to provide support as needed. For 8-session CBT, personal information may be shared among the group. At the start of each treatment cohort, the instructor explains group confidentiality, requests that members adhere to it, and also outlines the “honor system” limits of confidentiality. A similar, briefer explanation is provided at the outset of Empowered Relief given its brief time frame and limited opportunities to share personal information. Participants assigned to Empowered Relief may take part anonymously if they wish.

All study participants may receive up to US $195 for completing all study assessments.