DARE: Dipyridamole Assessment for Flare Reduction in Systemic Lupus Erythematosus (SLE)
Study Details
Study Description
Brief Summary
Dipyridamole, a medication extensively used in combination with aspirin for stroke prevention, is a promising new treatment for lupus. Dipyridamole has been shown to inhibit certain lymphocyte populations that are over-reactive in lupus and to delay the emergence of lupus-related pathology in mice with lupus. The investigators are interested in investigating the efficacy of dipyridamole in preventing flares in patients with lupus and its impact on biomarkers of disease activity.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
T cells in systemic lupus erythematosus (SLE) express an abnormal phenotype characterized by increased effector functions and deficient regulatory responses. Dipyridamole, a phosphodiesterase inhibitor extensively used in combination with low dose aspirin in secondary stroke prevention, has been proposed as a specific T cell directed treatment for SLE. Dipyridamole inhibits the calcium/calcineurin/NF-AT pathway in SLE T cells in vitro and abrogates expression of cytokines and costimulatory molecules, eventually also affecting B cell responses. Dipyridamole delays the emergence of lupus related pathology in lupus prone mice, but has not yet been studied in humans with SLE. The investigators aim to investigate the efficacy of dipyridamole in the prevention of flares in SLE patients after withdrawal of background immunosuppressive medications. The investigators will additionally evaluate the safety and tolerability of dipyridamole and its impact on quality of life measures in this population. Furthermore, the effect of dipyridamole on T and B cell biomarkers will be examined.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: extended release dipyridamole/aspirin extended release dipyridamole 200mg/aspirin 25mg twice daily for 24 weeks |
Drug: extended release dipyridamole 200mg/aspirin 25mg
one tablet twice daily for 24 weeks
Other Names:
|
| Active Comparator: aspirin half a tablet of a 81mg aspirin twice daily for 24 weeks |
Drug: 81mg aspirin
half a tablet twice daily for 24 weeks
Other Names:
|
Outcome Measures
Primary Outcome Measures
- British Isles Lupus Assessment Group Index-based Combined Lupus Assessment (BICLA) [24 weeks]
This is a landmark measure of percentage of patients who meet response criteria. To meet the BICLA response measure a patient must, compared to baseline, have a decrease in all moderate or severe scores on the British Isles Lupus Assessment Group (BILAG) index by at least one severity grade (Severe disease (BILAG A score) must drop to at least moderate (B or better) and B must drop to at least mild (C or not present). Also, there must be no increase in any other BILAG organ scores, no increase in The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and no increase in the physician's global assessment (PGA) by more than 10% of the scale. Furthermore, there may no off protocol medication increases. Note on all scales mentioned a higher score signifies greater disease activity. Ranges on BILAG could be 0-108 but are rarely greater than 36. SLEDAI could range 0-105 but is rarely greater than 20. PGA 0-100 but rarely greater than 76.
Secondary Outcome Measures
- Systemic Lupus Erythematosus Responder Index (SRI) 4 [24 weeks]
This is a landmark analysis of percentage of patients who meet the following response criteria: Compared to baseline there must be a 4 point decrease in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), no increase in The British Isles Lupus Assessment Group (BILAG) Index score and no more of an increase in Physician's Global Assessment (PGA) than 10% of the scale. As assessed here, there must also be no off protocol increase in medications. All scales signify worsening disease when scores increase. Ranges on BILAG could be 0-108 but are rarely greater than 36. SLEDAI could range 0-105 but is rarely greater than 20. PGA 0-100 but rarely greater than 76.
- SRI Component Analyses: 4 Point Drop in SLEDAI [24 weeks]
This is a landmark analysis of percentage of patients who, compared to baseline, have a 4 point drop in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). A 4 point decrease signifies a clinically significant decrease in disease activity as reported in many studies and as commonly used as a clinical endpoint in trials. SLEDAI could range 0-105 but is rarely greater than 20.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patients with SLE meeting the 1997 ACR Classification Criteria
-
Evidence of positive ANA or anti-dsDNA within one year of screening
-
SLEDAI ≥4 or ≥1 BILAG A or B at screening, despite standard of care
Exclusion Criteria:
-
Leukopenia (WBC <2.000/mm3) or lymphopenia (lymphocytes < 300/mm3)
-
AST or ALT >3 times above normal cut off values
-
Acute lupus nephritis defined as class II, IV or V nephritis diagnosed within 6 months or prot/creat > 1.5 gm/gm due to active lupus or in process of receiving induction therapy for nephritis
-
Active CNS lupus affecting mental status
-
Pregnancy or breast feeding
-
Current requirement for anticoagulation
-
Contraindication to aspirin or dipyridamole, including history of recent or severe GI bleeding, hemoglobin <9 mg/dL, platelet count of <30,000 /mm3 or unstable platelet count
-
Any other medical condition, whether or not related to lupus which, in the opinion of the investigator would render the patient inappropriate or too unstable to complete the study protocol
-
Inability or unwillingness to understand and/or sign informed consent
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Oklahoma Medical Research Foundation | Oklahoma City | Oklahoma | United States | 73104 |
Sponsors and Collaborators
- Oklahoma Medical Research Foundation
Investigators
- Principal Investigator: Katherine Thanou, MD, Oklahoma Medical Research Foundation
Study Documents (Full-Text)
More Information
Publications
- IRB# 12-10
Study Results
Participant Flow
| Recruitment Details | All patients were recruited from the Oklahoma Medical Research Foundation clinic after a full informed consent process. |
|---|---|
| Pre-assignment Detail | There were no pre-assignment restrictions or procedures. |
| Arm/Group Title | Extended Release Dipyridamole/Aspirin | Aspirin |
|---|---|---|
| Arm/Group Description | extended release dipyridamole 200mg/aspirin 25mg twice daily for 24 weeks extended release dipyridamole 200mg/aspirin 25mg: one tablet twice daily for 24 weeks | half a tablet of a 81mg aspirin twice daily for 24 weeks 81mg aspirin: half a tablet twice daily for 24 weeks |
| Period Title: Overall Study | ||
| STARTED | 13 | 5 |
| COMPLETED | 9 | 5 |
| NOT COMPLETED | 4 | 0 |
Baseline Characteristics
| Arm/Group Title | Extended Release Dipyridamole/Aspirin | Aspirin | Total |
|---|---|---|---|
| Arm/Group Description | extended release dipyridamole 200mg/aspirin 25mg twice daily for 24 weeks extended release dipyridamole 200mg/aspirin 25mg: one tablet twice daily for 24 weeks | half a tablet of a 81mg aspirin twice daily for 24 weeks 81mg aspirin: half a tablet twice daily for 24 weeks | Total of all reporting groups |
| Overall Participants | 13 | 5 | 18 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
44.5
(12.0)
|
43.8
(12.9)
|
44.3
(11.9)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
12
92.3%
|
5
100%
|
17
94.4%
|
| Male |
1
7.7%
|
0
0%
|
1
5.6%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
1
7.7%
|
0
0%
|
1
5.6%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
2
15.4%
|
1
20%
|
3
16.7%
|
| White |
9
69.2%
|
4
80%
|
13
72.2%
|
| More than one race |
1
7.7%
|
0
0%
|
1
5.6%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
13
100%
|
5
100%
|
18
100%
|
| Mean BILAG Score at Entry (units on a scale) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [units on a scale] |
11.2
(4.4)
|
10
(4.9)
|
10.9
(4.4)
|
Outcome Measures
| Title | British Isles Lupus Assessment Group Index-based Combined Lupus Assessment (BICLA) |
|---|---|
| Description | This is a landmark measure of percentage of patients who meet response criteria. To meet the BICLA response measure a patient must, compared to baseline, have a decrease in all moderate or severe scores on the British Isles Lupus Assessment Group (BILAG) index by at least one severity grade (Severe disease (BILAG A score) must drop to at least moderate (B or better) and B must drop to at least mild (C or not present). Also, there must be no increase in any other BILAG organ scores, no increase in The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and no increase in the physician's global assessment (PGA) by more than 10% of the scale. Furthermore, there may no off protocol medication increases. Note on all scales mentioned a higher score signifies greater disease activity. Ranges on BILAG could be 0-108 but are rarely greater than 36. SLEDAI could range 0-105 but is rarely greater than 20. PGA 0-100 but rarely greater than 76. |
| Time Frame | 24 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full Analysis Set was analyzed including all randomized patients |
| Arm/Group Title | Extended Release Dipyridamole/Aspirin | Aspirin |
|---|---|---|
| Arm/Group Description | extended release dipyridamole 200mg/aspirin 25mg twice daily for 24 weeks extended release dipyridamole 200mg/aspirin 25mg: one tablet twice daily for 24 weeks | half a tablet of a 81mg aspirin twice daily for 24 weeks 81mg aspirin: half a tablet twice daily for 24 weeks |
| Measure Participants | 13 | 5 |
| Count of Participants [Participants] |
3
23.1%
|
2
40%
|
| Title | Systemic Lupus Erythematosus Responder Index (SRI) 4 |
|---|---|
| Description | This is a landmark analysis of percentage of patients who meet the following response criteria: Compared to baseline there must be a 4 point decrease in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), no increase in The British Isles Lupus Assessment Group (BILAG) Index score and no more of an increase in Physician's Global Assessment (PGA) than 10% of the scale. As assessed here, there must also be no off protocol increase in medications. All scales signify worsening disease when scores increase. Ranges on BILAG could be 0-108 but are rarely greater than 36. SLEDAI could range 0-105 but is rarely greater than 20. PGA 0-100 but rarely greater than 76. |
| Time Frame | 24 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set of all randomized patients |
| Arm/Group Title | Extended Release Dipyridamole/Aspirin | Aspirin |
|---|---|---|
| Arm/Group Description | extended release dipyridamole 200mg/aspirin 25mg twice daily for 24 weeks extended release dipyridamole 200mg/aspirin 25mg: one tablet twice daily for 24 weeks | half a tablet of a 81mg aspirin twice daily for 24 weeks 81mg aspirin: half a tablet twice daily for 24 weeks |
| Measure Participants | 13 | 5 |
| Count of Participants [Participants] |
3
23.1%
|
2
40%
|
| Title | SRI Component Analyses: 4 Point Drop in SLEDAI |
|---|---|
| Description | This is a landmark analysis of percentage of patients who, compared to baseline, have a 4 point drop in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). A 4 point decrease signifies a clinically significant decrease in disease activity as reported in many studies and as commonly used as a clinical endpoint in trials. SLEDAI could range 0-105 but is rarely greater than 20. |
| Time Frame | 24 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full Analysis Set of all randomized patients |
| Arm/Group Title | Extended Release Dipyridamole/Aspirin | Aspirin |
|---|---|---|
| Arm/Group Description | extended release dipyridamole 200mg/aspirin 25mg twice daily for 24 weeks extended release dipyridamole 200mg/aspirin 25mg: one tablet twice daily for 24 weeks | half a tablet of a 81mg aspirin twice daily for 24 weeks 81mg aspirin: half a tablet twice daily for 24 weeks |
| Measure Participants | 13 | 5 |
| Count of Participants [Participants] |
4
30.8%
|
2
40%
|
Adverse Events
| Time Frame | 6 months | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | All adverse events were recorded in the medical record and compiled for analysis. | |||
| Arm/Group Title | Extended Release Dipyridamole/Aspirin | Aspirin | ||
| Arm/Group Description | extended release dipyridamole 200mg/aspirin 25mg twice daily for 24 weeks extended release dipyridamole 200mg/aspirin 25mg: one tablet twice daily for 24 weeks | half a tablet of a 81mg aspirin twice daily for 24 weeks 81mg aspirin: half a tablet twice daily for 24 weeks | ||
All Cause Mortality |
||||
| Extended Release Dipyridamole/Aspirin | Aspirin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/13 (0%) | 0/5 (0%) | ||
Serious Adverse Events |
||||
| Extended Release Dipyridamole/Aspirin | Aspirin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/13 (0%) | 1/5 (20%) | ||
| Reproductive system and breast disorders | ||||
| Hysterectomy | 0/13 (0%) | 0 | 1/5 (20%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| Extended Release Dipyridamole/Aspirin | Aspirin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 13/13 (100%) | 5/5 (100%) | ||
| Gastrointestinal disorders | ||||
| Gastroenteritis | 8/13 (61.5%) | 12 | 3/5 (60%) | 3 |
| Colitis | 1/13 (7.7%) | 1 | 0/5 (0%) | 0 |
| General disorders | ||||
| weight loss | 1/13 (7.7%) | 1 | 0/5 (0%) | 0 |
| Immune system disorders | ||||
| herpes zoster | 1/13 (7.7%) | 1 | 0/5 (0%) | 0 |
| neuralgia | 1/13 (7.7%) | 1 | 0/5 (0%) | 0 |
| urticaria | 2/13 (15.4%) | 2 | 0/5 (0%) | 0 |
| Infections and infestations | ||||
| Upper Respiratory Infection | 1/13 (7.7%) | 2 | 3/5 (60%) | 3 |
| Urinary Tract Infection | 3/13 (23.1%) | 3 | 2/5 (40%) | 2 |
| Pneumonia | 1/13 (7.7%) | 1 | 1/5 (20%) | 1 |
| Chlamydia infectoin | 1/13 (7.7%) | 1 | 0/5 (0%) | 0 |
| Paronychia | 1/13 (7.7%) | 1 | 0/5 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||
| Spider Bite | 0/13 (0%) | 0 | 2/5 (40%) | 2 |
| Musculoskeletal and connective tissue disorders | ||||
| Chest Pain | 1/13 (7.7%) | 1 | 0/5 (0%) | 0 |
| Muscle Cramp | 1/13 (7.7%) | 1 | 0/5 (0%) | 0 |
| sprained ankle | 1/13 (7.7%) | 1 | 0/5 (0%) | 0 |
| Nervous system disorders | ||||
| Headache | 4/13 (30.8%) | 4 | 1/5 (20%) | 1 |
| Dizziness | 0/13 (0%) | 0 | 1/5 (20%) | 4 |
| Sleep Disorder | 1/13 (7.7%) | 2 | 0/5 (0%) | 0 |
| Renal and urinary disorders | ||||
| Bladder Outlet Obstruction | 1/13 (7.7%) | 1 | 0/5 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Joan T. Merrill, M.D. |
|---|---|
| Organization | Oklahoma Medical Research Foundation |
| Phone | 405-822-2336 |
| joan-merrill@omrf.org |
- IRB# 12-10