Does Sildenafil Improve Endothelial Dysfunction in Rheumatoid Arthritis?

Phase 2

Terminated

Conditions: Arthritis, Rheumatoid
Atherosclerosis

Interventions: Drug: Sildenafil
Other: Placebo

Registration Number: NCT02908490

Lead Sponsor: Kimberly Liang

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 25

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Initial Placebo	Sildenafil	Placebo orally once daily for first 3 months, then after 2-week washout, Sildenafil 50 mg orally once daily for 3 months
Initial Placebo	Placebo	Placebo orally once daily for first 3 months, then after 2-week washout, Sildenafil 50 mg orally once daily for 3 months
Initial Sildenafil	Placebo	Sildenafil 50 mg orally once daily for first 3 months, then after 2-week washout, Placebo orally once daily for 3 months
Initial Sildenafil	Sildenafil	Sildenafil 50 mg orally once daily for first 3 months, then after 2-week washout, Placebo orally once daily for 3 months

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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)
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 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 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)
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 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 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)
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.
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.