Arthritis, Rheumatoid, Atherosclerosis
Conditions
Keywords
Arthritis, Rheumatoid, Atherosclerosis
Brief summary
The purpose of this study is to determine whether sildenafil improves parameters of vascular function and blood markers involved in development of heart disease in patients with rheumatoid arthritis.
Detailed description
Rheumatoid arthritis (RA) is associated with a 2-fold increased risk of cardiovascular disease (CVD), which is not explained by traditional cardiovascular (CV) risk factors alone; this risk is likely mediated in part through systemic inflammation. Indeed, RA itself is deemed to impart a CV risk equivalent to diabetes mellitus (DM). However, unlike in DM, optimal CV management strategies in RA are lacking. Despite improved anti-inflammatory therapies for RA, the mortality gap in RA compared to the general population is still widening, in part due to suboptimal primary and secondary CV preventive care in RA. To date, there have been no published controlled intervention trials for primary CV prevention in RA, despite this clearly urgent unmet need. One of the early stages of atherogenesis is endothelial dysfunction, and drugs that target improvement in this are promising novel strategies for CVD prevention. The fundamental feature of endothelial dysfunction is impaired nitric oxide (NO) bioavailability. Sildenafil improves endothelial function by increasing NO signaling by inhibition of phosphodiesterase-5 (PDE5). PDE5 inhibitors improve endothelial function in pulmonary hypertension and DM, and were safe and well tolerated in patients with erectile dysfunction and other CV comorbidities. Furthermore, PDE inhibitors have immunomodulatory properties that may be utilized to treat autoimmune conditions like RA. The investigators' central hypothesis is that sildenafil is a uniquely suited agent targeting endothelial dysfunction as a novel adjunctive CV prevention strategy and immunomodulatory agent in RA. Specifically, their goal is to determine if sildenafil use in RA improves endothelial dysfunction and atherosclerosis biomarkers. The proposed study is a phase II, randomized double-blind placebo-controlled crossover efficacy trial of 60 RA patients, with no known history of CVD but at least one traditional CV risk factor, on stable baseline doses of RA medications; randomized 1:1 to receive either sildenafil 50 mg or placebo orally once daily for 3 months, with a 2-week washout before the crossover phase for another 3 months. Vascular studies validated in assessing endothelial dysfunction and laboratory studies for selected atherosclerosis biomarkers will be performed at baseline, 3 months pre- and post-washout, and 6 months. Adverse events will be collected to assess safety. The Specific Aims are: 1. To determine whether sildenafil use in RA leads to improvement in parameters of vascular function; and to confirm its safety profile. 2. To determine whether sildenafil use in RA is associated with improvement in atherosclerosis biomarkers. The results of this study will serve as preliminary data for future larger trials evaluating sildenafil as a CV prevention strategy by reducing endothelial dysfunction in RA. It will provide needed data on potential benefits of sildenafil for immunomodulation and CV prevention in this high-risk population.
Interventions
DRUGSildenafil
Sildenafil 50 mg once daily
OTHERPlacebo
Placebo once daily with same size, shape, color, and texture as Sildenafil 50 mg pill
Sponsors
Kimberly Liang
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Meets 2010 American College of Rheumatology (ACR) classification criteria for diagnosis of RA * Aged 18 years or older * No known history of CVD (see
Exclusion criteria
) * At least one traditional CV risk factor (i.e., older age \[men ≥45 years, women ≥55 years\], obesity \[defined as body mass index (BMI) \>30 kg/m2\], smoking, hypertension, hyperlipidemia, diabetes mellitus, family history of premature \[defined as diagnosed at \<65 years old\] CVD in first-degree relative) * On stable baseline doses of RA medications, defined as no change in dose within past 4 weeks and no anticipated changes over the next 6 months * On no higher than 10 mg per day of prednisone or prednisone-equivalent within past 4 weeks * RA disease duration (from symptom onset) of more than 6 months * Having clinical disease activity index (CDAI) of \>2.8 but ≤22 (i.e., either low or moderate disease activity), within 30 days of study enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Brachial Artery Flow Mediated Dilation (FMD) Without Nitroglycerin at 3 Months | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) | The methods of assessment of endothelial function via FMD will be performed following guidelines. Using Duplex ultrasound with a high-resolution linear array transducer, the difference between the maximum brachial artery diameter (BAD) postocclusion and the baseline diameter will be calculated, expressed as a percentage (%BAD). Generally, %BAD values below 5-7% represent endothelial dysfunction, which is associated with CV risk factors, future CVD and mortality. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in hsCRP at 3 Months | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) | High-sensitivity CRP (hsCRP) measured using standard clinical laboratory protocols |
| Change From Baseline in ESR at 3 Months | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) | Erythrocyte sedimentation rate (ESR) measured using standard clinical laboratory protocols |
| Change From Baseline in Number of Participants With Detectable IL-6 at 3 Months | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) | Interleukin (IL)-6 measured using enzyme linked immunosorbent assay (ELISA) (pg/mL). Since very few subjects had detectable IL-6 levels, the outcome measure reports the number of participants with detectable IL-6 rather than mean levels. |
| Change From Baseline in RF at 3 Months | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) | Rheumatoid factor (RF) measured using standard clinical laboratory protocols |
| Change From Baseline in CCP at 3 Months | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) | Anti-cyclic citrullinated peptide antibody (CCP) measured using standard clinical laboratory protocols. Note, the universal unit of measure for CCP is Units. |
| Change From Baseline in E-selectin at 3 Months | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) | Leukocyte adhesion molecule E-selectin measured using enzyme linked immunosorbent assay (ELISA) |
| Change From Baseline in Peripheral Arterial Tone (PAT) LnRHI at 3 Months | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) | PAT measured by the EndoPAT 2000 device is a non-invasive method to assess endothelial function. It is a standardized, rapid, and easy to apply method, and has been found to correlate with multiple traditional CV risk factors and to be responsive to interventions. PAT is a validated alternative measure to brachial arterial FMD in assessing endothelial function, and is less operator-dependent than FMD. FMD directly measures the dilation capability of the large-conduit artery, whereas PAT measures flow response hyperemia, which is related to endothelial function of small arteries of microcirculation. PAT measures endothelium-mediated changes in vascular tone using bio-sensors placed on fingertips. The semi-automatically calculated result (Reactive Hyperemia Index) is an index of endothelial function. LnRHI is a Reactive Hyperemia Index after natural log transformation with a matched cutoff: Normal: LnRHI \> 0.51 and Abnormal: LnRHI \<= 0.51 cut-off. |
| Change From Baseline in VCAM-1 at 3 Months | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) | Vascular cell adhesion molecule (VCAM)-1 measured using enzyme linked immunosorbent assay (ELISA) |
| Change From Baseline in CD40L at 3 Months | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) | CD40 ligand (CD40L) measured using enzyme linked immunosorbent assay (ELISA) |
| Change From Baseline in MMP-9 at 3 Months | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) | Matrix metalloproteinase-9 (MMP-9) measured using enzyme linked immunosorbent assay (ELISA) |
| Change From Baseline in MPO at 3 Months | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) | Myeloperoxidase (MPO) measured using enzyme linked immunosorbent assay (ELISA) |
| Serious Adverse Events (SAE) | 6 Months and 2 Weeks from Baseline Visit | SAEs include death, hospitalization or prolonged existing hospitalization, life threatening, persistent or significant disability, birth defect/congenital anomaly, or medically significant event. |
| Adverse Events (AE) Related to Treatment | 6 Months and 2 Weeks from Baseline Visit | AEs related to sildenafil treatment may include headache, flushing, indigestion, or visual disturbance, among others. |
| Change From Baseline in ICAM-1 at 3 Months | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) | Intercellular adhesion molecule (ICAM)-1 measured using enzyme linked immunosorbent assay (ELISA) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Initial Sildenafil Sildenafil 50 mg orally once daily for first 3 months, then after 2-week washout, Placebo orally once daily for 3 months
Sildenafil: Sildenafil 50 mg once daily
Placebo: Placebo once daily with same size, shape, color, and texture as Sildenafil 50 mg pill | 12 |
| Initial Placebo Placebo orally once daily for first 3 months, then after 2-week washout, Sildenafil 50 mg orally once daily for 3 months
Sildenafil: Sildenafil 50 mg once daily
Placebo: Placebo once daily with same size, shape, color, and texture as Sildenafil 50 mg pill | 13 |
| Total | 25 |
Baseline characteristics
| Characteristic | Initial Sildenafil | Initial Placebo | Total |
|---|---|---|---|
| Age, Continuous | 61.1 years STANDARD_DEVIATION 11.2 | 62.9 years STANDARD_DEVIATION 11.1 | 62.0 years STANDARD_DEVIATION 10.9 |
| Cardiovascular Risk Factors Diabetes mellitus | 2 Participants | 2 Participants | 4 Participants |
| Cardiovascular Risk Factors Estrogen replacement use | 1 Participants | 3 Participants | 4 Participants |
| Cardiovascular Risk Factors Family history of CVD | 8 Participants | 6 Participants | 14 Participants |
| Cardiovascular Risk Factors Hyperlipidemia | 6 Participants | 8 Participants | 14 Participants |
| Cardiovascular Risk Factors Hypertension | 7 Participants | 7 Participants | 14 Participants |
| Cardiovascular Risk Factors Obesity | 7 Participants | 6 Participants | 13 Participants |
| Cardiovascular Risk Factors Older age | 10 Participants | 11 Participants | 21 Participants |
| Cardiovascular Risk Factors Postmenopausal | 9 Participants | 8 Participants | 17 Participants |
| Cardiovascular Risk Factors Smoking (ever or current) | 4 Participants | 6 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 13 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 10 Participants | 13 Participants | 23 Participants |
| Region of Enrollment United States | 12 participants | 13 participants | 25 participants |
| Sex: Female, Male Female | 10 Participants | 11 Participants | 21 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 3 / 25 | 3 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 |
Outcome results
Primary
Change From Baseline in Brachial Artery Flow Mediated Dilation (FMD) Without Nitroglycerin at 3 Months
The methods of assessment of endothelial function via FMD will be performed following guidelines. Using Duplex ultrasound with a high-resolution linear array transducer, the difference between the maximum brachial artery diameter (BAD) postocclusion and the baseline diameter will be calculated, expressed as a percentage (%BAD). Generally, %BAD values below 5-7% represent endothelial dysfunction, which is associated with CV risk factors, future CVD and mortality.
Time frame: Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment)
Population: The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil Period | Change From Baseline in Brachial Artery Flow Mediated Dilation (FMD) Without Nitroglycerin at 3 Months | FMD at Baseline | 7.06 percent of BAD | Standard Deviation 4.05 |
| Sildenafil Period | Change From Baseline in Brachial Artery Flow Mediated Dilation (FMD) Without Nitroglycerin at 3 Months | Change in FMD from Baseline at 3 Months | -1.14 percent of BAD | Standard Deviation 4.72 |
| Placebo Period | Change From Baseline in Brachial Artery Flow Mediated Dilation (FMD) Without Nitroglycerin at 3 Months | FMD at Baseline | 6.48 percent of BAD | Standard Deviation 3.23 |
| Placebo Period | Change From Baseline in Brachial Artery Flow Mediated Dilation (FMD) Without Nitroglycerin at 3 Months | Change in FMD from Baseline at 3 Months | 0.814 percent of BAD | Standard Deviation 2.98 |
p-value: 0.18595% CI: [-3.54, 0.68]Mixed Models Analysis
Secondary
Adverse Events (AE) Related to Treatment
AEs related to sildenafil treatment may include headache, flushing, indigestion, or visual disturbance, among others.
Time frame: 6 Months and 2 Weeks from Baseline Visit
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sildenafil Period | Adverse Events (AE) Related to Treatment | 3 Participants |
| Placebo Period | Adverse Events (AE) Related to Treatment | 3 Participants |
Secondary
Change From Baseline in CCP at 3 Months
Anti-cyclic citrullinated peptide antibody (CCP) measured using standard clinical laboratory protocols. Note, the universal unit of measure for CCP is Units.
Time frame: Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment)
Population: Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment.~The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil Period | Change From Baseline in CCP at 3 Months | CCP at Baseline | 60.00 Units | Standard Deviation 107.17 |
| Sildenafil Period | Change From Baseline in CCP at 3 Months | Change in CCP from Baseline at 3 Months | -10.70 Units | Standard Deviation 38.93 |
| Placebo Period | Change From Baseline in CCP at 3 Months | CCP at Baseline | 62.80 Units | Standard Deviation 105.11 |
| Placebo Period | Change From Baseline in CCP at 3 Months | Change in CCP from Baseline at 3 Months | -10.70 Units | Standard Deviation 32.17 |
Secondary
Change From Baseline in CD40L at 3 Months
CD40 ligand (CD40L) measured using enzyme linked immunosorbent assay (ELISA)
Time frame: Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment)
Population: Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment.~The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil Period | Change From Baseline in CD40L at 3 Months | CD40L at Baseline | 7650.22 pg/mL | Standard Deviation 6994.27 |
| Sildenafil Period | Change From Baseline in CD40L at 3 Months | Change in CD40L from Baseline at 3 Months | 2559.09 pg/mL | Standard Deviation 9936.68 |
| Placebo Period | Change From Baseline in CD40L at 3 Months | CD40L at Baseline | 10316.24 pg/mL | Standard Deviation 8513.34 |
| Placebo Period | Change From Baseline in CD40L at 3 Months | Change in CD40L from Baseline at 3 Months | -3857.02 pg/mL | Standard Deviation 6972.17 |
Secondary
Change From Baseline in E-selectin at 3 Months
Leukocyte adhesion molecule E-selectin measured using enzyme linked immunosorbent assay (ELISA)
Time frame: Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment)
Population: The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil Period | Change From Baseline in E-selectin at 3 Months | E-Selectin at Baseline | 37.10 ng/mL | Standard Deviation 14.68 |
| Sildenafil Period | Change From Baseline in E-selectin at 3 Months | Change in E-Selectin from Baseline at 3 Months | 4.91 ng/mL | Standard Deviation 13.37 |
| Placebo Period | Change From Baseline in E-selectin at 3 Months | E-Selectin at Baseline | 42.56 ng/mL | Standard Deviation 14.63 |
| Placebo Period | Change From Baseline in E-selectin at 3 Months | Change in E-Selectin from Baseline at 3 Months | -2.56 ng/mL | Standard Deviation 11.42 |
p-value: 0.06195% CI: [-0.36, 15.63]Mixed Models Analysis
Secondary
Change From Baseline in ESR at 3 Months
Erythrocyte sedimentation rate (ESR) measured using standard clinical laboratory protocols
Time frame: Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment)
Population: Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment.~The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil Period | Change From Baseline in ESR at 3 Months | ESR at Baseline | 19.22 mm/hr | Standard Deviation 15.64 |
| Sildenafil Period | Change From Baseline in ESR at 3 Months | Change in ESR from Baseline at 3 Months | 3.30 mm/hr | Standard Deviation 5.73 |
| Placebo Period | Change From Baseline in ESR at 3 Months | ESR at Baseline | 17.35 mm/hr | Standard Deviation 10.25 |
| Placebo Period | Change From Baseline in ESR at 3 Months | Change in ESR from Baseline at 3 Months | 3.95 mm/hr | Standard Deviation 10.83 |
Secondary
Change From Baseline in hsCRP at 3 Months
High-sensitivity CRP (hsCRP) measured using standard clinical laboratory protocols
Time frame: Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment)
Population: Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment.~The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil Period | Change From Baseline in hsCRP at 3 Months | Change in hsCRP from Baseline at 3 Months | 0.08 mg/dL | Standard Deviation 0.42 |
| Sildenafil Period | Change From Baseline in hsCRP at 3 Months | hsCRP at Baseline | 0.43 mg/dL | Standard Deviation 0.43 |
| Placebo Period | Change From Baseline in hsCRP at 3 Months | hsCRP at Baseline | 0.58 mg/dL | Standard Deviation 0.63 |
| Placebo Period | Change From Baseline in hsCRP at 3 Months | Change in hsCRP from Baseline at 3 Months | 0.43 mg/dL | Standard Deviation 2.55 |
Secondary
Change From Baseline in ICAM-1 at 3 Months
Intercellular adhesion molecule (ICAM)-1 measured using enzyme linked immunosorbent assay (ELISA)
Time frame: Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment)
Population: The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil Period | Change From Baseline in ICAM-1 at 3 Months | ICAM-1 at Baseline | 256.23 ng/mL | Standard Deviation 65.96 |
| Sildenafil Period | Change From Baseline in ICAM-1 at 3 Months | Change in ICAM-1 from Baseline at 3 Months | 26.31 ng/mL | Standard Deviation 77.03 |
| Placebo Period | Change From Baseline in ICAM-1 at 3 Months | ICAM-1 at Baseline | 299.59 ng/mL | Standard Deviation 81.8 |
| Placebo Period | Change From Baseline in ICAM-1 at 3 Months | Change in ICAM-1 from Baseline at 3 Months | -44.33 ng/mL | Standard Deviation 67.97 |
p-value: 0.01195% CI: [12.79, 97.81]Mixed Models Analysis
Secondary
Change From Baseline in MMP-9 at 3 Months
Matrix metalloproteinase-9 (MMP-9) measured using enzyme linked immunosorbent assay (ELISA)
Time frame: Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment)
Population: Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment.~The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil Period | Change From Baseline in MMP-9 at 3 Months | MMP-9 at Baseline | 441.00 ng/mL | Standard Deviation 399.32 |
| Sildenafil Period | Change From Baseline in MMP-9 at 3 Months | Change in MMP-9 from Baseline at 3 Months | -5.61 ng/mL | Standard Deviation 437.21 |
| Placebo Period | Change From Baseline in MMP-9 at 3 Months | MMP-9 at Baseline | 454.85 ng/mL | Standard Deviation 298.36 |
| Placebo Period | Change From Baseline in MMP-9 at 3 Months | Change in MMP-9 from Baseline at 3 Months | -105.65 ng/mL | Standard Deviation 333.04 |
Secondary
Change From Baseline in MPO at 3 Months
Myeloperoxidase (MPO) measured using enzyme linked immunosorbent assay (ELISA)
Time frame: Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment)
Population: Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment.~The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil Period | Change From Baseline in MPO at 3 Months | Change in MPO from Baseline at 3 Months | 17.18 ng/mL | Standard Deviation 242.2 |
| Sildenafil Period | Change From Baseline in MPO at 3 Months | MPO at Baseline | 236.68 ng/mL | Standard Deviation 276.33 |
| Placebo Period | Change From Baseline in MPO at 3 Months | Change in MPO from Baseline at 3 Months | -54.04 ng/mL | Standard Deviation 309.7 |
| Placebo Period | Change From Baseline in MPO at 3 Months | MPO at Baseline | 233.24 ng/mL | Standard Deviation 241.29 |
Secondary
Change From Baseline in Number of Participants With Detectable IL-6 at 3 Months
Interleukin (IL)-6 measured using enzyme linked immunosorbent assay (ELISA) (pg/mL). Since very few subjects had detectable IL-6 levels, the outcome measure reports the number of participants with detectable IL-6 rather than mean levels.
Time frame: Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment)
Population: Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment.~The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sildenafil Period | Change From Baseline in Number of Participants With Detectable IL-6 at 3 Months | Number (%) of Participants with Detectable IL-6 at Baseline | 3 Participants |
| Sildenafil Period | Change From Baseline in Number of Participants With Detectable IL-6 at 3 Months | Change (decrease) in Number (%) of Participants with Detectable IL-6 from Baseline at 3 Months | 1 Participants |
| Placebo Period | Change From Baseline in Number of Participants With Detectable IL-6 at 3 Months | Number (%) of Participants with Detectable IL-6 at Baseline | 8 Participants |
| Placebo Period | Change From Baseline in Number of Participants With Detectable IL-6 at 3 Months | Change (decrease) in Number (%) of Participants with Detectable IL-6 from Baseline at 3 Months | 1 Participants |
Secondary
Change From Baseline in Peripheral Arterial Tone (PAT) LnRHI at 3 Months
PAT measured by the EndoPAT 2000 device is a non-invasive method to assess endothelial function. It is a standardized, rapid, and easy to apply method, and has been found to correlate with multiple traditional CV risk factors and to be responsive to interventions. PAT is a validated alternative measure to brachial arterial FMD in assessing endothelial function, and is less operator-dependent than FMD. FMD directly measures the dilation capability of the large-conduit artery, whereas PAT measures flow response hyperemia, which is related to endothelial function of small arteries of microcirculation. PAT measures endothelium-mediated changes in vascular tone using bio-sensors placed on fingertips. The semi-automatically calculated result (Reactive Hyperemia Index) is an index of endothelial function. LnRHI is a Reactive Hyperemia Index after natural log transformation with a matched cutoff: Normal: LnRHI \> 0.51 and Abnormal: LnRHI \<= 0.51 cut-off.
Time frame: Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment)
Population: The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil Period | Change From Baseline in Peripheral Arterial Tone (PAT) LnRHI at 3 Months | LnRHI at Baseline | 0.77 LnRHI | Standard Deviation 0.29 |
| Sildenafil Period | Change From Baseline in Peripheral Arterial Tone (PAT) LnRHI at 3 Months | Change in LnRHI from Baseline at 3 Months | 0.21 LnRHI | Standard Deviation 0.54 |
| Placebo Period | Change From Baseline in Peripheral Arterial Tone (PAT) LnRHI at 3 Months | LnRHI at Baseline | 0.78 LnRHI | Standard Deviation 0.32 |
| Placebo Period | Change From Baseline in Peripheral Arterial Tone (PAT) LnRHI at 3 Months | Change in LnRHI from Baseline at 3 Months | -0.01 LnRHI | Standard Deviation 0.35 |
p-value: 0.00395% CI: [0.069, 0.331]Mixed Models Analysis
Secondary
Change From Baseline in RF at 3 Months
Rheumatoid factor (RF) measured using standard clinical laboratory protocols
Time frame: Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment)
Population: Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment.~The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil Period | Change From Baseline in RF at 3 Months | RF at Baseline | 128.17 IU/ml | Standard Deviation 337.02 |
| Sildenafil Period | Change From Baseline in RF at 3 Months | Change in RF from Baseline at 3 Months | 20.00 IU/ml | Standard Deviation 81.29 |
| Placebo Period | Change From Baseline in RF at 3 Months | RF at Baseline | 138.96 IU/ml | Standard Deviation 296.77 |
| Placebo Period | Change From Baseline in RF at 3 Months | Change in RF from Baseline at 3 Months | -16.20 IU/ml | Standard Deviation 59.47 |
Secondary
Change From Baseline in VCAM-1 at 3 Months
Vascular cell adhesion molecule (VCAM)-1 measured using enzyme linked immunosorbent assay (ELISA)
Time frame: Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment)
Population: The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil Period | Change From Baseline in VCAM-1 at 3 Months | VCAM-1 at Baseline | 751.30 ng/mL | Standard Deviation 294.35 |
| Sildenafil Period | Change From Baseline in VCAM-1 at 3 Months | Change in VCAM-1 from Baseline at 3 Months | 46.12 ng/mL | Standard Deviation 117.2 |
| Placebo Period | Change From Baseline in VCAM-1 at 3 Months | VCAM-1 at Baseline | 771.86 ng/mL | Standard Deviation 231.11 |
| Placebo Period | Change From Baseline in VCAM-1 at 3 Months | Change in VCAM-1 from Baseline at 3 Months | -33.23 ng/mL | Standard Deviation 123.4 |
p-value: 0.07795% CI: [-7.98, 157.84]Mixed Models Analysis
Secondary
Serious Adverse Events (SAE)
SAEs include death, hospitalization or prolonged existing hospitalization, life threatening, persistent or significant disability, birth defect/congenital anomaly, or medically significant event.
Time frame: 6 Months and 2 Weeks from Baseline Visit
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sildenafil Period | Serious Adverse Events (SAE) | 0 Participants |
| Placebo Period | Serious Adverse Events (SAE) | 0 Participants |