Biomarkers of Lupus Disease: Serial Biomarker Sampling in Patients With Active Systemic Lupus Erythematosus (SLE)

Phase 1

Completed

• Conditions: Systemic Lupus Erythematosus
• Interventions: Drug: Group A SLE prospective study; Other: Blood drawing only Group C; Other: Group B SLE one blood donation

• Registration Number: NCT00987831
• Lead Sponsor: Oklahoma Medical Research Foundation

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patients entered the trial in mild-moderate flare, were treated with depomedrol, and any background immune suppressants withdrawn.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entry on various medications can be compared to biomarkers after steroid efficacy with background immune suppressants withdrawn.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.

Study Timeline

• Study Start: 2009-05
• Study First Submitted: 2009-09-30
• Study First Submitted QC: 2009-09-30
• Study First Posted: 2009-10-01
• Primary Completion: 2012-12
• Study Completion: 2012-12
• Results First Submitted: 2013-08-28
• Status Verified: 2014-10
• Results First Submitted QC: 2014-10-17
• Last Update Submitted: 2014-10-17
• Results First Posted: 2014-10-20
• Last Update Posted: 2014-10-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 158

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.

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Exclusion Criteria

1. Safety or circumstantial reasons why volunteer cannot comply with the protocol.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A SLE prospective study	Group A SLE prospective study	In Group A SLE patients enter with active disease. Any immune suppressant (e.g. methotrexate, azathioprine or mmf) is withdrawn and after blood drawing, depomedrol up to 160 mg IM is given. This may be repeated for a maximum of 160mg up to four times total in the first two weeks. Depomedrol is expected to last 1-3 months, serial biomarkers will be drawn until time of flare, at which time biomarkers will be drawn, patient is defined as meeting endpoint and new treatment initiated. Patients may elect to continue to donate blood samples per protocol up to one year.
Blood drawing only Group C	Blood drawing only Group C	Healthy controls, age, sex and ethnicity matched to the active study participants were recruited for two time blood donation as controls for the biomarker studies
Group B SLE one blood donation	Group B SLE one blood donation	SLE patients who meet the same entry criteria as Group A could elect to donate blood one time and not to continue in the prospective protocol. No extra intervention was performed other than blood draw and medical records review. This allowed an extension of cross sectional comparisons between biomarker changes related to background treatments by combining Group A baseline data with Group B data.

Primary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (2)

Oklahoma Medical Research Foundation; 🇺🇸 Oklahoma City, Oklahoma, United States

Pfizer Inc; 🇺🇸 Collegeville, Pennsylvania, United States