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

October 17, 2014 updated by: Joan Merrill, MD, Oklahoma Medical Research Foundation

Biomarkers of Lupus Disease: Study of Biomarker Changes Before and After Treatment With Depomedrol and Background Medication Withdrawal in Patients With Mild to Moderate SLE Disease Activity

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entered the trial in mild-moderate flare, were treated with depomedrol, and any background immune suppressants withdrawn.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entry on various medications can be compared to biomarkers after steroid efficacy with background immune suppressants withdrawn.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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

158

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • Oklahoma Medical Research Foundation
    • Pennsylvania
      • Collegeville, Pennsylvania, United States, 19426
        • Pfizer Inc

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 70 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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
Other: Blood drawing only Group C
Blood drawing and Brief medical history to ensure status of healthy control
Experimental: 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.
Drug: Group 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
Other Names:
  • methylprednisolone
  • medrol
  • depomedrol
Experimental: 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.
Other: Group 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to Flare Comparing Patients With Moderate vs Severe Disease Activity at Baseline
Time Frame: 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
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Oklahoma Medical Research Foundation

Collaborators

Pfizer

Investigators

  • Principal Investigator: Joan T Merrill, Oklahoma Medical Research Foundation

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2009

Primary Completion (Actual)

December 1, 2012

Study Completion (Actual)

December 1, 2012

Study Registration Dates

First Submitted

September 30, 2009

First Submitted That Met QC Criteria

September 30, 2009

First Posted (Estimate)

October 1, 2009

Study Record Updates

Last Update Posted (Estimate)

October 20, 2014

Last Update Submitted That Met QC Criteria

October 17, 2014

Last Verified

October 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • OMRF 09-02
  • Pfizer Inc (Pfizer investigator initiated study)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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