Systemic Lupus Erythematosus
Conditions
Keywords
SLE, lupus, biomarkers, depomedrol, flare, disease activity
Brief summary
Hypothesis: A reason for repeated disappointing outcomes of clinical trials testing targeted immune biologics for lupus may be the heterogeneity of the disease, exacerbated by the variable effects on immune homeostasis of the background medications that must be continued, in most study designs, in these flare-prone patients. Purpose of Study: This study was designed to purposefully study a population equivalent to the placebo group of typical trials in SLE. In Group A patients entered the trial in mild-moderate flare, were treated with depomedrol, and any background immune suppressants withdrawn. Biomarkers at entry on various medications can be compared to biomarkers after steroid efficacy with background immune suppressants withdrawn. Depomedrol usually wears off over one to three months. Patients were closely observed, with serial biomarkers drawn at monthly intervals or immediately at the time of a new flare. Those patients developing new flares donated blood samples, were immediately treated as deemed appropriate, exiting the study. Group A was designed for up to 50 patients and recruited a total of 41. An additional group of 62 SLE patients donated blood once without additional interventions in order to increase the power of exploratory cross-sectional biomarker analysis on different immune suppressants (Group B). A control population of matched, healthy individuals donated blood twice for the same biomarker studies to validate these assays (Group C).
Detailed description
Original Protocol for Group A: Patients with at least a SLEDAI score of 6 or a BILAG score of B in at least two organ systems or A in at least one organ system were immediately entered into this study once informed consent was obtained. Background immune suppressants (if any) were stopped and in about half of the patients hydroxychloroquine was also stopped. All patients immediately received a shot of depomedrol 160 mg IM. Over the next two weeks they could elect up to three more shots of depomedrol for a total of four shots by the two week visit period. A complete battery of blood tests to assess lupus disease was drawn at the screening visit, and monthly thereafter. Exploratory biomarker studies were drawn as often as weekly for some markers and as often as three times in the study (landmark visits) for others. Protocol Changes during course of study: Biomarkers were drawn at Day zero, week 2 week 4 and monthly thereafter until flare. Patients who did not improve with protocol steroid treatments were withdrawn from Group A and immediately treated as warranted. Since there was no protocol-defined improving visit, they could not continue the protocol until flare. However their baseline samples were appropriate for study as part of Group B (see below). Landmark visits for Group A are defined as: 1.) screening (pre-dose, on background meds with active disease) 2.) two weeks or four weeks after screening as optimal to assess a patient who has stopped background meds and is now maximally improved (but at least one grade drop in BILAG scores in all organs entered at A or B or a four point drop in SLEDAI, otherwise the participant is deemed a treatment failure and could not participate further in Group A. 3.) Flare visit on no background immune suppression defined as an increase in SLEDAI of 4 points from maximal improvement or one new BILAG moderate (B) score AND the investigator considers the condition to be a significant flare with intent to treat. Patients were (whenever possible) seen within 3 days for the flare visit if flare occured between monthly scheduled visits. The primary purpose of this study was to evaluate the time to flare and safety of a treatment withdrawal protocol in patients with active, but non-organ threatening SLE. The following biomarkers were obtained for exploratory analysis: cytokine panel, B Cell studies, T Cell studies, autoantibody profiles, epigenetic and gene expression studies and flow cytometry studies.
Interventions
OTHERGroup B SLE one blood donation
Blood drawing, history, physical examination,medical record review, questionnaires, completion of disease activity measures including SLEDAI,BILAG, CLASI,PGA,PROs,LFA investigational systems, BICLA, SRI
OTHERBlood drawing only Group C
Blood drawing and Brief medical history to ensure status of healthy control
DRUGGroup A SLE prospective study
Patients have history and physical exmamination at each visit. Blood is drawn at each visit. At baseline, any background immune suppressant is stopped and patients given depomedrol up to 160 mg IM which can be repeated up to four times in the first two weeks. Patients are seen again at week 2, 4 and monthly until the final flare visit at which time they donate blood, receive appropriate treatments and exit study. Patients may elect to continue in study for up to one year. The following disease activity measures are included: SLEDAI, BILAG, CLASI, PGA, PROs (including lupus PRO and SF-36 ant ptGA), joint counts, exploratory outcome measures,BICLA,SRI
Sponsors
Pfizer
Oklahoma Medical Research Foundation
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
SLE Groups (Group A and B): 1. ACR criteria for SLE. 2. At least two organ systems moderately active to a minimum of BILAG B or SLEDAI score of 6. Control group (Group C): 1. Age, ethnicity and gender matched (2:1) with an SLE study participant. 2. Free of active or major chronic disease as determined by brief history.
Exclusion criteria
1\. Safety or circumstantial reasons why volunteer cannot comply with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Flare Comparing Patients With Moderate vs Severe Disease Activity at Baseline | 12 months | Group A only: patients on immunosuppressive treatments had them withdrawn at baseline. All patients were allowed up to 160 mg depomedrol at baseline which could be repeated within two weeks up to a total of 4 shots maximum or until satisfactory improvement. Time to flare was calculated from baseline. moderate disease at baseline was defined as up to 3 BILAG B (moderate disease) organ scores, no BILAG A (severe disease) score and a SLEDAI \</= 10. Severe disease required \>3 BILAG B, OR at least one BILAG A OR SLEDAI \> 10 or meeting criteria for a severe flare on the SELENA SLEDAI flare index. At baseline 25 patients with moderate disease. 16 patients had severe disease. Note: severe rash with A on BILAG is only SLEDAI=2, explaining some discrepancies in measures |
Countries
United States
Participant flow
Recruitment details
The final recruitment tally is as follows: 41 SLE patients entered the prospective serial blood donation study. 62 SLE patients gave one time blood sample and 52 controls gave two blood samples each
Pre-assignment details
All patients in Group A (prospective study) had any immune suppressive (e.g. MMF, MTX, AZA) withdrawn at the time of entry and all received between 1-3 depomedrol shots up to 160 mg each. Those who did not improve were immediately withdrawn from prospective study but the original sample was retained, in all cases, for the cross sectional arm.
Participants by arm
| Arm | Count |
|---|---|
| Group A Medication Withdrawal, Depomedrol, Prospective Follow- When depomedrol was given, any immune suppressant being taken (e.g. aza, mmf, mtx) was stopped and biomarkers studied before and after this change. Depomedrol was expected to last 1-3 months, serial biomarkers were drawn until time of any flare, designated as end of study. Patients could elect to continue to donate blood samples per protocol up to one year. Of 41 patients who improved after depomedrol and could complete Group A, 40 flared at or before the six month visit. One patient continued for one year and did not flare. This study design allowed the comparison of 40 patients flaring at baseline on or not on background immune suppresion vs themselves serving as their own control flaring later....not on immune suppression. | 41 |
| Group C Healthy Controls Healthy controls, age, sex and ethnicity matched to SLE study participants were recruited for two time blood donation as controls for the biomarker studies
Blood drawing and brief history only : No treatments given | 55 |
| Group B SLE One Time Donation We amended protocol with IRB approval to include more patients in this group and ended up recruiting a total of 62. This was to allow enrichment of a cross sectional study of biomarkers related to the different background immune suppressants used in Group A at baseline. By combining baseline samples from Group A and Group B data we had a total of 103 lupus samples to study cross sectionally comparing impact of methotrexate, mmf, azathioprine or no IS on a range of biomarkers. | 62 |
| Total | 158 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 3 | 0 |
| Overall Study | Never flared in 12 months | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Group C Healthy Controls | Group B SLE One Time Donation | Group A Medication Withdrawal, Depomedrol, Prospective Follow- | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 55 Participants | 62 Participants | 40 Participants | 157 Participants |
| Age, Continuous | 40.8 years STANDARD_DEVIATION 12.1 | 41.6 years STANDARD_DEVIATION 11.3 | 42.3 years STANDARD_DEVIATION 11.9 | 41.1 years STANDARD_DEVIATION 11.7 |
| Region of Enrollment United States | 55 participants | 62 participants | 41 participants | 158 participants |
| Sex: Female, Male Female | 53 Participants | 55 Participants | 39 Participants | 147 Participants |
| Sex: Female, Male Male | 2 Participants | 7 Participants | 2 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 29 / 41 | 0 / 55 | 0 / 62 |
| serious Total, serious adverse events | 1 / 41 | 0 / 55 | 0 / 62 |
Outcome results
Primary
Time to Flare Comparing Patients With Moderate vs Severe Disease Activity at Baseline
Group A only: patients on immunosuppressive treatments had them withdrawn at baseline. All patients were allowed up to 160 mg depomedrol at baseline which could be repeated within two weeks up to a total of 4 shots maximum or until satisfactory improvement. Time to flare was calculated from baseline. moderate disease at baseline was defined as up to 3 BILAG B (moderate disease) organ scores, no BILAG A (severe disease) score and a SLEDAI \</= 10. Severe disease required \>3 BILAG B, OR at least one BILAG A OR SLEDAI \> 10 or meeting criteria for a severe flare on the SELENA SLEDAI flare index. At baseline 25 patients with moderate disease. 16 patients had severe disease. Note: severe rash with A on BILAG is only SLEDAI=2, explaining some discrepancies in measures
Time frame: 12 months
Population: This prespecified primary outcome was restricted to Group A only. This was an exploratory proof of concept study, not powered for the primary endpoint
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Severe Disease Activity at Baseline | Time to Flare Comparing Patients With Moderate vs Severe Disease Activity at Baseline | 45 days to flare |
| Moderate Disease Activity at Baseline | Time to Flare Comparing Patients With Moderate vs Severe Disease Activity at Baseline | 71 days to flare |
p-value: 0.273895% CI: [5, 95]Log Rank
Post Hoc
Time to Flare Comparing Patients With (at Baseline) British Isles Lupus Assessment Group Index (BILAG) >/= 17 (Severe Disease) to Those With BILAG < 17 (Moderate Disease Activity).
Time frame: 12 months
Population: Only 40/41 entered patients completed the study by the definition of the endpoint which was flare.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Severe Disease Activity at Baseline | Time to Flare Comparing Patients With (at Baseline) British Isles Lupus Assessment Group Index (BILAG) >/= 17 (Severe Disease) to Those With BILAG < 17 (Moderate Disease Activity). | 40 days to flare |
| Moderate Disease Activity at Baseline | Time to Flare Comparing Patients With (at Baseline) British Isles Lupus Assessment Group Index (BILAG) >/= 17 (Severe Disease) to Those With BILAG < 17 (Moderate Disease Activity). | 72.5 days to flare |