BOLD: Biomarkers of Lupus Disease: Serial Biomarker Sampling in Patients With Active Systemic Lupus Erythematosus (SLE)
Study Details
Study Description
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patients entered the trial in mild-moderate flare, were treated with depomedrol, and any background immune suppressants withdrawn.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entry on various medications can be compared to biomarkers after steroid efficacy with background immune suppressants withdrawn.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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
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 Design
Arms and Interventions
| 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:
|
| 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
|
Outcome Measures
Primary Outcome Measures
- 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
Eligibility Criteria
Criteria
Inclusion Criteria:
SLE Groups (Group A and B):
-
ACR criteria for SLE.
-
At least two organ systems moderately active to a minimum of BILAG B or SLEDAI score of 6.
Control group (Group C):
-
Age, ethnicity and gender matched (2:1) with an SLE study participant.
-
Free of active or major chronic disease as determined by brief history.
Exclusion Criteria:
- Safety or circumstantial reasons why volunteer cannot comply with the protocol.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Oklahoma Medical Research Foundation | Oklahoma City | Oklahoma | United States | 73104 |
| 2 | Pfizer Inc | Collegeville | Pennsylvania | United States | 19426 |
Sponsors and Collaborators
- Oklahoma Medical Research Foundation
- Pfizer
Investigators
- Principal Investigator: Joan T Merrill, Oklahoma Medical Research Foundation
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- OMRF 09-02
- Pfizer Inc
Study Results
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 Detail | 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. |
| Arm/Group Title | Group A Medication Withdrawal, Depomedrol, Prospective Follow- | Group C Healthy Controls | Group B SLE One Time Donation |
|---|---|---|---|
| Arm/Group Description | 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 suppression vs themselves serving as their own control flaring later....not on immune suppression. | 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 | 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. |
| Period Title: Overall Study | |||
| STARTED | 41 | 55 | 62 |
| COMPLETED | 40 | 52 | 62 |
| NOT COMPLETED | 1 | 3 | 0 |
Baseline Characteristics
| Arm/Group Title | Group A Medication Withdrawal, Depomedrol, Prospective Follow- | Group C Healthy Controls | Group B SLE One Time Donation | Total |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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 | 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. | Total of all reporting groups |
| Overall Participants | 41 | 55 | 62 | 158 |
| Age (Count of Participants) | ||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
40
97.6%
|
55
100%
|
62
100%
|
157
99.4%
|
| >=65 years |
1
2.4%
|
0
0%
|
0
0%
|
1
0.6%
|
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
42.3
(11.9)
|
40.8
(12.1)
|
41.6
(11.3)
|
41.1
(11.7)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
39
95.1%
|
53
96.4%
|
55
88.7%
|
147
93%
|
| Male |
2
4.9%
|
2
3.6%
|
7
11.3%
|
11
7%
|
| Region of Enrollment (participants) [Number] | ||||
| United States |
41
100%
|
55
100%
|
62
100%
|
158
100%
|
Outcome Measures
| Title | Time to Flare Comparing Patients With Moderate vs Severe Disease Activity at Baseline |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Severe Disease Activity at Baseline | Moderate Disease Activity at Baseline |
|---|---|---|
| Arm/Group Description | This is fully explained above. Severe disease activity is defined as > 3 BILAG B, OR at least one BILAG A or SLEDAI > 10 OR Meets Definition for severe Flare on SELENA SLEDAI | this is fully explained above. Moderate disease activity is defined as up to 3 BILAG B, no A, and SLEDAI </= 10. |
| Measure Participants | 16 | 25 |
| Median (95% Confidence Interval) [days to flare] |
45
|
71
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Severe Disease Activity at Baseline, Moderate Disease Activity at Baseline |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2738 |
| Comments | Definition of Moderate Disease was </= 3 BILAG B (moderate) organ scores, no A (severe) scores and SLEDAI </=10. Severe disease was > 3 BILAG B or >/= BILAG A or SLEDAI > 10 or meets definition for severe flare on the SELENA SLEDAI Flare Index | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Median Difference (Final Values) |
| Estimated Value | 30 | |
| Confidence Interval |
(2-Sided) 95% 5 to 95 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | 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). |
|---|---|
| Description | |
| Time Frame | 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only 40/41 entered patients completed the study by the definition of the endpoint which was flare. |
| Arm/Group Title | Severe Disease Activity at Baseline | Moderate Disease Activity at Baseline |
|---|---|---|
| Arm/Group Description | This is fully explained above. Severe disease is now defined as total cumulative BILAG score >/= 17 | this is fully explained above. Moderate disease is now defined as BILAG < 17 in cumulative score |
| Measure Participants | 11 | 29 |
| Median (95% Confidence Interval) [days to flare] |
40
|
72.5
|
Adverse Events
| Time Frame | Adverse events were collected until end of study participation (ranging one visit to 12 months) Note all patients in Group A who flared were treated and followed up within six weeks and all improved again on new treatments initiated at the time of flare. | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | This was an interventional study using depomedrol which is a commonly used treatment in our clinic. The main safety issue in the study was the withdrawal of background immune suppressants. | |||||
| Arm/Group Title | Group A Medication Withdrawal, Depomedrol, Prospective Follow- | Group C Healthy Controls | Group B SLE One Time Donation | |||
| Arm/Group Description | 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 suppression vs themselves serving as their own control flaring later....not on immune suppression. | 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 | 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. | |||
All Cause Mortality |
||||||
| Group A Medication Withdrawal, Depomedrol, Prospective Follow- | Group C Healthy Controls | Group B SLE One Time Donation | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Group A Medication Withdrawal, Depomedrol, Prospective Follow- | Group C Healthy Controls | Group B SLE One Time Donation | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/41 (2.4%) | 0/55 (0%) | 0/62 (0%) | |||
| Gastrointestinal disorders | ||||||
| Bleeding Peptic Ulcer | 1/41 (2.4%) | 1 | 0/55 (0%) | 0 | 0/62 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
| Group A Medication Withdrawal, Depomedrol, Prospective Follow- | Group C Healthy Controls | Group B SLE One Time Donation | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 29/41 (70.7%) | 0/55 (0%) | 0/62 (0%) | |||
| Endocrine disorders | ||||||
| cushingoid face | 2/41 (4.9%) | 2 | 0/55 (0%) | 0 | 0/62 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| gastroenteritis | 8/41 (19.5%) | 8 | 0/55 (0%) | 0 | 0/62 (0%) | 0 |
| Immune system disorders | ||||||
| seasonal allergy | 2/41 (4.9%) | 2 | 0/55 (0%) | 0 | 0/62 (0%) | 0 |
| Infections and infestations | ||||||
| Upper Respiratory Infection | 3/41 (7.3%) | 3 | 0/55 (0%) | 0 | 0/62 (0%) | 0 |
| sinusitis | 4/41 (9.8%) | 4 | 0/55 (0%) | 0 | 0/62 (0%) | 0 |
| oral candidiasis | 2/41 (4.9%) | 2 | 0/55 (0%) | 0 | 0/62 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Musculoskeletal pain | 2/41 (4.9%) | 2 | 0/55 (0%) | 0 | 0/62 (0%) | 0 |
| Nervous system disorders | ||||||
| insomnia | 4/41 (9.8%) | 4 | 0/55 (0%) | 0 | 0/62 (0%) | 0 |
| Renal and urinary disorders | ||||||
| urinary tract infection | 2/41 (4.9%) | 2 | 0/55 (0%) | 0 | 0/62 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Joan T Merrill, M.D |
|---|---|
| Organization | Oklahoma Medical Research Foundation |
| Phone | 405-271-7805 |
| JTMmail@aol.com |
- OMRF 09-02
- Pfizer Inc