Systemic Lupus Erythematosus
Conditions
Keywords
lupus, dipyridamole
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.
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.
Interventions
DRUGextended release dipyridamole 200mg/aspirin 25mg
one tablet twice daily for 24 weeks
DRUG81mg aspirin
half a tablet twice daily for 24 weeks
Sponsors
Oklahoma Medical Research Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Pilot study
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
All patients were recruited from the Oklahoma Medical Research Foundation clinic after a full informed consent process.
Pre-assignment details
There were no pre-assignment restrictions or procedures.
Participants by arm
| Arm | Count |
|---|---|
| Extended Release Dipyridamole/Aspirin extended release dipyridamole 200mg/aspirin 25mg twice daily for 24 weeks
extended release dipyridamole 200mg/aspirin 25mg: one tablet twice daily for 24 weeks | 13 |
| Aspirin half a tablet of a 81mg aspirin twice daily for 24 weeks
81mg aspirin: half a tablet twice daily for 24 weeks | 5 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 0 |
Baseline characteristics
| Characteristic | Extended Release Dipyridamole/Aspirin | Aspirin | Total |
|---|---|---|---|
| Age, Continuous | 44.5 years STANDARD_DEVIATION 12 | 43.8 years STANDARD_DEVIATION 12.9 | 44.3 years STANDARD_DEVIATION 11.9 |
| Mean BILAG Score at Entry | 11.2 units on a scale STANDARD_DEVIATION 4.4 | 10 units on a scale STANDARD_DEVIATION 4.9 | 10.9 units on a scale STANDARD_DEVIATION 4.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 4 Participants | 13 Participants |
| Region of Enrollment United States | 13 participants | 5 participants | 18 participants |
| Sex: Female, Male Female | 12 Participants | 5 Participants | 17 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 5 |
| other Total, other adverse events | 13 / 13 | 5 / 5 |
| serious Total, serious adverse events | 0 / 13 | 1 / 5 |
Outcome results
Primary
British Isles Lupus Assessment Group Index-based Combined Lupus Assessment (BICLA)
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
Population: Full Analysis Set was analyzed including all randomized patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Extended Release Dipyridamole/Aspirin | British Isles Lupus Assessment Group Index-based Combined Lupus Assessment (BICLA) | 3 Participants |
| Aspirin | British Isles Lupus Assessment Group Index-based Combined Lupus Assessment (BICLA) | 2 Participants |
Secondary
SRI Component Analyses: 4 Point Drop in SLEDAI
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
Population: Full Analysis Set of all randomized patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Extended Release Dipyridamole/Aspirin | SRI Component Analyses: 4 Point Drop in SLEDAI | 4 Participants |
| Aspirin | SRI Component Analyses: 4 Point Drop in SLEDAI | 2 Participants |
Secondary
Systemic Lupus Erythematosus Responder Index (SRI) 4
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
Population: Full analysis set of all randomized patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Extended Release Dipyridamole/Aspirin | Systemic Lupus Erythematosus Responder Index (SRI) 4 | 3 Participants |
| Aspirin | Systemic Lupus Erythematosus Responder Index (SRI) 4 | 2 Participants |