Does Sildenafil Improve Endothelial Dysfunction in Rheumatoid Arthritis?

• Sponsor: Kimberly Liang (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02908490
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Arms: 2
• Actual Duration (Months): 45
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Arthritis, Rheumatoid; Atherosclerosis	Drug: Sildenafil; Other: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Does Sildenafil Improve Endothelial Dysfunction in Rheumatoid Arthritis?
• Actual Study Start Date: Apr 1, 2017
• Actual Primary Completion Date: Jun 4, 2020
• Actual Study Completion Date: Dec 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Initial Sildenafil Sildenafil 50 mg orally once daily for first 3 months, then after 2-week washout, Placebo orally once daily for 3 months	Drug: Sildenafil; Sildenafil 50 mg once daily; Other Names: Viagra Revatio ; Other: Placebo; Placebo once daily with same size, shape, color, and texture as Sildenafil 50 mg pill
Placebo Comparator: Initial Placebo Placebo orally once daily for first 3 months, then after 2-week washout, Sildenafil 50 mg orally once daily for 3 months	Drug: Sildenafil; Sildenafil 50 mg once daily; Other Names: Viagra Revatio ; Other: Placebo; Placebo once daily with same size, shape, color, and texture as Sildenafil 50 mg pill

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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

3. 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

4. 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.

5. 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

6. 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."

7. 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)

8. 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)

9. 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)

10. 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)

11. 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)

12. 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)

13. 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.

14. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Exclusion Criteria:

• Aged <18 years

• Pregnant women

• Known personal history of CVD (clinical diagnoses of stroke, transient ischemic attack, myocardial infarction, acute coronary syndrome, peripheral arterial disease, percutaneous coronary intervention or coronary bypass graft surgery)

• Use of high-dose statins (e.g., atorvastatin 40-80 mg/day or rosuvastatin 20-40 mg/day) currently or within past 3 months, or any dose changes of statins or of blood pressure medications that may affect endothelial function (i.e., angiotensin-converting-enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]) within past 3 months. If on statin or an ACE-I or ARB, there should be no anticipated dose changes over the next 6 months.

• Persons with intra-cardiac and intra-pulmonary shunts, unstable cardiopulmonary conditions, or anyone on chronic oxygen therapy

• Persons taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl trinitrate (nitroglycerin), sodium nitroprusside, amyl nitrite ("poppers")

• Severe hepatic impairment (liver function tests >1.5 times upper limit of normal) within past 4 weeks

• Severe impairment in renal function (serum creatinine ≥1.5 mg/dL) within past 4 weeks

• Hypotension (defined as blood pressure [BP] <90/60)

• Hereditary degenerative retinal disorders (including genetic disorders of retinal phosphodiesterases)

• Persons already taking (or taken within 3 months) sildenafil or other PDE inhibitors (i.e., tadalafil, vardenafil)

• Persons unable to provide voluntary written informed consent

• Severe hypertension (BP >170/110)

• Persons with HIV/AIDS

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213

Sponsors and Collaborators

• Kimberly Liang

Investigators

• Principal Investigator: Kimberly P Liang, MD, University of Pittsburgh

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 10, 2019

More Information

Publications

None provided.

• Responsible Party: Kimberly Liang, MD, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT02908490
• Other Study ID Numbers: PRO14120209
• First Posted: Sep 21, 2016
• Last Update Posted: Aug 13, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Kimberly Liang, MD, University of Pittsburgh: Arthritis, Rheumatoid; Atherosclerosis
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Atherosclerosis; Sildenafil Citrate

Study Results

Participant Flow

Arm/Group Title	Initial Sildenafil	Initial Placebo
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	12	13
COMPLETED	10	11
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Initial Sildenafil	Initial Placebo	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	12	13	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.1 (11.2)	62.9 (11.1)	62.0 (10.9)
Sex: Female, Male (Count of Participants)
Female	10 83.3%	11 84.6%	21 84%
Male	2 16.7%	2 15.4%	4 16%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	12 100%	13 100%	25 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 16.7%	0 0%	2 8%
White	10 83.3%	13 100%	23 92%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%	13 100%	25 100%
Cardiovascular Risk Factors (Count of Participants)
Older age	10 83.3%	11 84.6%	21 84%
Obesity	7 58.3%	6 46.2%	13 52%
Smoking (ever or current)	4 33.3%	6 46.2%	10 40%
Hypertension	7 58.3%	7 53.8%	14 56%
Hyperlipidemia	6 50%	8 61.5%	14 56%
Diabetes mellitus	2 16.7%	2 15.4%	4 16%
Family history of CVD	8 66.7%	6 46.2%	14 56%
Postmenopausal	9 75%	8 61.5%	17 68%
Estrogen replacement use	1 8.3%	3 23.1%	4 16%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Brachial Artery Flow Mediated Dilation (FMD) Without Nitroglycerin at 3 Months
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	20	19
FMD at Baseline	7.06 (4.05)	6.48 (3.23)
Change in FMD from Baseline at 3 Months	-1.14 (4.72)	0.814 (2.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil Period
	Comments
	Type of Statistical Test	Superiority
	Comments	Given the cross-over design, analyses included a random effects model for within-subject comparisons of sildenafil versus placebo periods, adjusting for the baseline FMD within that period and a term for treatment order.
Statistical Test of Hypothesis	p-Value	0.185
	Comments	The a priori threshold for statistical significance was <0.05.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-1.42
	Confidence Interval	(2-Sided) 95%; -3.54 to 0.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Peripheral Arterial Tone (PAT) LnRHI at 3 Months
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	19	20
LnRHI at Baseline	0.77 (0.29)	0.78 (0.32)
Change in LnRHI from Baseline at 3 Months	0.21 (0.54)	-0.01 (0.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil Period
	Comments
	Type of Statistical Test	Superiority
	Comments	Given the cross-over design, analyses included a random effects model for within-subject comparisons of sildenafil versus placebo periods, adjusting for the baseline EndoPAT within that period and a term for treatment order.
Statistical Test of Hypothesis	p-Value	0.003
	Comments	The a priori threshold for statistical significance was <0.05.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.200
	Confidence Interval	(2-Sided) 95%; 0.069 to 0.331
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in hsCRP at 3 Months
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	20	20
hsCRP at Baseline	0.43 (0.43)	0.58 (0.63)
Change in hsCRP from Baseline at 3 Months	0.08 (0.42)	0.43 (2.55)

4. Secondary Outcome

Title	Change From Baseline in ESR at 3 Months
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	20	20
ESR at Baseline	19.22 (15.64)	17.35 (10.25)
Change in ESR from Baseline at 3 Months	3.30 (5.73)	3.95 (10.83)

5. Secondary Outcome

Title	Change From Baseline in Number of Participants With Detectable IL-6 at 3 Months
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	16	19
Number (%) of Participants with Detectable IL-6 at Baseline	3 25%	8 61.5%
Change (decrease) in Number (%) of Participants with Detectable IL-6 from Baseline at 3 Months	1 8.3%	1 7.7%

6. Secondary Outcome

Title	Change From Baseline in RF at 3 Months
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	20	20
RF at Baseline	128.17 (337.02)	138.96 (296.77)
Change in RF from Baseline at 3 Months	20.00 (81.29)	-16.20 (59.47)

7. Secondary Outcome

Title	Change From Baseline in CCP at 3 Months
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	20	20
CCP at Baseline	60.00 (107.17)	62.80 (105.11)
Change in CCP from Baseline at 3 Months	-10.70 (38.93)	-10.70 (32.17)

8. Secondary Outcome

Title	Change From Baseline in E-selectin at 3 Months
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	16	19
E-Selectin at Baseline	37.10 (14.68)	42.56 (14.63)
Change in E-Selectin from Baseline at 3 Months	4.91 (13.37)	-2.56 (11.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil Period
	Comments
	Type of Statistical Test	Superiority
	Comments	Given the cross-over design, analyses included a random effects model for within-subject comparisons of sildenafil versus placebo periods, adjusting for the baseline biomarker within that period and a term for treatment order.
Statistical Test of Hypothesis	p-Value	0.061
	Comments	The a prior threshold for statistical significance was <0.05.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	7.63
	Confidence Interval	(2-Sided) 95%; -0.36 to 15.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in ICAM-1 at 3 Months
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	16	19
ICAM-1 at Baseline	256.23 (65.96)	299.59 (81.80)
Change in ICAM-1 from Baseline at 3 Months	26.31 (77.03)	-44.33 (67.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil Period
	Comments
	Type of Statistical Test	Superiority
	Comments	Given the cross-over design, analyses included a random effects model for within-subject comparisons of sildenafil versus placebo periods, adjusting for the baseline biomarker within that period and a term for treatment order.
Statistical Test of Hypothesis	p-Value	0.011
	Comments	The a prior threshold for statistical significance was <0.05.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	55.30
	Confidence Interval	(2-Sided) 95%; 12.79 to 97.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in VCAM-1 at 3 Months
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	16	19
VCAM-1 at Baseline	751.30 (294.35)	771.86 (231.11)
Change in VCAM-1 from Baseline at 3 Months	46.12 (117.2)	-33.23 (123.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sildenafil Period
	Comments
	Type of Statistical Test	Superiority
	Comments	Given the cross-over design, analyses included a random effects model for within-subject comparisons of sildenafil versus placebo periods, adjusting for the baseline biomarker within that period and a term for treatment order.
Statistical Test of Hypothesis	p-Value	0.077
	Comments	The a priori threshold for statistical significance was <0.05.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	74.93
	Confidence Interval	(2-Sided) 95%; -7.98 to 157.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline in CD40L at 3 Months
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	15	19
CD40L at Baseline	7650.22 (6994.27)	10316.24 (8513.34)
Change in CD40L from Baseline at 3 Months	2559.09 (9936.68)	-3857.02 (6972.17)

12. Secondary Outcome

Title	Change From Baseline in MMP-9 at 3 Months
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	16	19
MMP-9 at Baseline	441.00 (399.32)	454.85 (298.36)
Change in MMP-9 from Baseline at 3 Months	-5.61 (437.21)	-105.65 (333.04)

13. Secondary Outcome

Title	Change From Baseline in MPO at 3 Months
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	16	19
MPO at Baseline	236.68 (276.33)	233.24 (241.29)
Change in MPO from Baseline at 3 Months	17.18 (242.20)	-54.04 (309.70)

14. Secondary Outcome

Title	Serious Adverse Events (SAE)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	25	25
Count of Participants [Participants]	0 0%	0 0%

15. Secondary Outcome

Title	Adverse Events (AE) Related to Treatment
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sildenafil Period	Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study	Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
Measure Participants	25	25
Count of Participants [Participants]	3 25%	3 23.1%

Adverse Events

Time Frame	Adverse event data were collected over the entire study duration for each participant (i.e., 6 months and 2 weeks).
Adverse Event Reporting Description	The definition of adverse event and/or serious adverse event did not differ from the clinicaltrials.gov definitions.
Arm/Group Title	Sildenafil Period		Placebo Period
Arm/Group Description	Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study		Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study
All Cause Mortality
	Sildenafil Period		Placebo Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)
Serious Adverse Events
	Sildenafil Period		Placebo Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Sildenafil Period		Placebo Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/25 (12%)		3/25 (12%)
Musculoskeletal and connective tissue disorders
Back pain	1/25 (4%)	1	0/25 (0%)	0
Joint Pain	0/25 (0%)	0	1/25 (4%)	1
Nervous system disorders
Headache	1/25 (4%)	1	0/25 (0%)	0
Insomnia	1/25 (4%)	1	0/25 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/25 (0%)	0	1/25 (4%)	1
Bronchospasm	0/25 (0%)	0	1/25 (4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.