西地那非治疗皮肤硬化症

ARTHRITIS & RHEUMATISM Vol. 63, No. 3, March 2011, pp 775–782 DOI 10.1002/art.30195 © 2011, American College of Rheumatology Modified-Release Sildenafil Reduces Raynaud’s Phenomenon Attack Frequency in Limited Cutaneous Systemic Sclerosis Ariane L. Herrick,1 Frank van den Hoogen,2 Armando Gabrielli,3 Nihad Tamimi,4 Carol Reid,4 Damian O’Connell,4 Maria-Dolores Va´zquez-Abad,5 and Christopher P. Denton6 Objective. To examine the effect of sildenafil in patients with Raynaud’s phenomenon (RP) secondary to limited cutaneous systemic sclerosis (lcSSc). Methods. In this double-blind, placebo-controlled study, 57 patients with RP secondary to lcSSc were ran- domized to receive modified-release sildenafil 100 mg once daily for 3 days followed by modified-release sildenafil 200 mg once daily for 25 days or placebo. The primary assessment was the percentage change in the number of RP attacks per week in the per-protocol population. Secondary end points included Raynaud’s Condition Score, duration of attacks, RP pain score, endothelial dysfunction assessed by a peripheral arte- rial tonometric (PAT) device, and serum biomarker levels. Results. The mean percentage reduction from baseline to day 28 in attacks per week was greater for modified-release sildenafil than for placebo (�44.0% versus �18.1%, P � 0.034); the mean number of attacks per week improved from 25.0 at baseline to 19.3 after placebo treatment and from 30.5 to 18.7 after modified- release sildenafil treatment (P� 0.244). Decreases from baseline in Raynaud’s Condition Score, duration of attacks, and RP pain score were not significantly differ- ent between groups. Mean values and changes from baseline in PAT responses and serum biomarker levels were similar between groups. The most frequent adverse events were headache and dyspepsia; the majority of adverse events were mild or moderate. Conclusion. Our findings indicate that modified- release sildenafil reduced attack frequency in patients with RP secondary to lcSSc and was well tolerated. Modified-release sildenafil may be a treatment option in this patient population. Raynaud’s phenomenon (RP) is a cardinal fea- ture of systemic sclerosis (SSc) and occurs in almost all cases (1). Associated structural vasculopathy makes this a particularly troublesome symptom (2,3) and, com- bined with intermittent vasospasm, is responsible for the serious digital vascular complications of SSc, includ- ing digital ulceration, soft tissue or bone infection, and critical ischemia or gangrene (3,4). In addition, symp- toms of RP attacks themselves are an important mor- bidity in SSc. The pathologic process in SSc is not fully under- stood. Reduction in the production and release of nitric oxide and up-regulated endothelin production by dys- functional endothelium may result in a tendency toward vasoconstriction and reduced vasodilatory capacity (2). Endothelial cell dysfunction and altered vascular tone may directly contribute to the SSc disease process (4). The hyperemic response, thought to be an indicator of endothelial cell (dys)function (5), can be measured noninvasively by a peripheral arterial tonometric (PAT) device and has been used to identify patients with early coronary atherosclerosis (6) and to predict late cardio- vascular events (7). Elevated levels of adhesion mole- cules, including soluble vascular cell adhesion molecule Supported by Pfizer Inc. 1Ariane L. Herrick, MD, FRCP: University of Manchester, Manchester Academic Health Science Centre, Salford Royal Hospital, Salford, UK; 2Frank van den Hoogen, MD, PhD: St. Maartenskliniek, Nijmegen, The Netherlands; 3Armando Gabrielli, MD: Universita` Politecnica delle Marche and Ospedali Riuniti, Ancona, Italy; 4Nihad Tamimi, FRCP, Carol Reid, PhD, Damian O’Connell, MD, PhD: Pfizer Ltd., Sandwich, UK; 5Maria-Dolores Va´zquez-Abad, MD: Pfizer Inc., New London, Connecticut; 6Christopher P. Denton, PhD, FRCP: Royal Free and University College, London, UK. Dr. Herrick has received speaking fees from Actelion and consulting fees from Actelion and Pfizer (less than $10,000 each); she has served as a study investigator for Actelion, Mediquest, and United Therapeutics. Dr. Gabrielli has received speaking fees from Actelion (less than $10,000), has served as a study investigator for Roche, and has received grant support from Roche and Wyeth. Drs. Reid and Va´zquez-Abad own stock or stock options in Pfizer. Dr. Denton has received consulting fees and/or honoraria from Pfizer, Encysive, Actelion, GlaxoSmithKline, and Novartis. Address correspondence to Ariane L. Herrick, MD, FRCP, University of Manchester, Rheumatic Diseases Centre, Salford Royal Hospital, Salford M6 8HD, UK. E-mail: ariane.herrick@manchester. ac.uk. Submitted for publication March 6, 2010; accepted in revised form December 7, 2010. 775 (VCAM), intercellular adhesion molecule (ICAM), and N-terminal type I procollagen propeptide (PINP), are found in patients with SSc relative to healthy controls and, although not validated biomarkers, may be useful for tracking disease progress (8–13), and so may be included for exploratory analysis in studies of treatment response. Secondary RP, such as that occurring with SSc, is typically more severe and thus more difficult to treat than primary idiopathic RP (14). Prostacyclin and pros- tacyclin analogs are effective when given intravenously but require hospitalization (15,16). Vasodilator drugs have proved variably effective in clinical trials but many have significant adverse effects (17). Sildenafil and other phosphodiesterase type V (PDE V) inhibitors are attractive candidates for therapy in patients with RP secondary to SSc. Vascular smooth muscle relaxation and vasodilation occur when nitric oxide diffuses through the endothelial cell layer and activates guanylate cyclase to produce cyclic guanosine monophosphate (cGMP), which provides the signal leading to smooth muscle relaxation. Because PDE V breaks down cGMP in endothelial cells, its inhibition by sildenafil increases the level of cGMP available to promote vascular smooth muscle relaxation and conse- quently improves local blood flow. Some encouraging results have emerged from case studies and limited clinical trials of PDE V inhibitors in RP (14,18); how- ever, the inclusion of patients with idiopathic primary disease and those with disease secondary to non-SSc connective tissue diseases restricts applicability to pa- tients with limited cutaneous SSc (lcSSc). Therefore, in this randomized, double-blind, placebo-controlled study, we examined the effect of sildenafil specifically in pa- tients with RP secondary to lcSSc. A modified-release formulation was used to permit once-daily dosing. PATIENTS AND METHODS Study design. This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study that took place between January and June 2003. Patients with RP secondary to lcSSc were randomized in a 1:1 ratio to receive either modified-release sildenafil 100 mg once daily for 3 days followed by modified-release sildenafil 200 mg once daily for 25 days or placebo for 28 days. The 2-step dosing was used to enhance tolerability. Modified-release sildenafil uses a swellable core technology, with expected overall exposure for 200 mg of modified-release sildenafil once daily similar to that of 50 mg of immediate-release sildenafil 3 times daily (19). Each patient had 5 visits: a screening visit (days�14 to �7), a baseline visit (day 1), 2 visits while receiving treatment (days 14 and 28), and a followup visit (7–14 days following day 28). Patients completed a daily diary during the 7–14 days before baseline and during the 28-day treatment phase. Clin- ical and other outcome measures and pharmacokinetic and laboratory safety samples were obtained at screening, baseline, on days 14 and 28, and at the followup visit. The protocol was approved by an independent ethics committee or institutional review board at each study center, and the study was conducted in compliance with the ethics principles of the Declaration of Helsinki. All patients provided written informed consent before initiating study procedures. Patients. The study included men and women ages 18–75 years with a diagnosis of RP secondary to lcSSc con- firmed by the investigator. Patients had at least 7 RP attacks per week with attacks on 5 or more days per week as de- termined from the daily diaries. RP was defined as episodic digital pallor followed by cyanosis and/or erythema in response to cold or emotion; lcSSc was defined using the criteria of LeRoy et al (1), with skin involvement limited to hands, forearms, feet, and face. Patients with diffuse cutaneous SSc (dcSSc) were excluded. Other key exclusion criteria included hemodynamic instability or systolic arterial pressure �95 mm Hg; a history of stroke, myocardial infarction, severe cardiac failure, unstable angina, or life-threatening arrhythmia within the previous 6 months; creatinine clearance �30 ml/minute; impaired hepatic function (Child-Pugh class C); untreated proliferative retinopathy; diabetes mellitus; vibration-induced RP; therapy with nitrates or nitric oxide donors, alpha block- ers, iloprost, bosentan, calcium-channel blockers, nonsteroidal antiinflammatory drugs, angiotensin-converting enzyme inhib- itors, corticosteroids (except stable doses), aspirin �325 mg/ day, dipyridamole, or antiplatelet agents 14 days before begin- ning the study; current smoking or use of smoking cessation treatments. Efficacy assessments. The primary assessment was the number of RP attacks per week. Secondary assessments were Raynaud’s Condition Score, RP pain score, mean duration of RP attacks, PAT-reactive hyperemic response, serum levels of biomarkers (VCAM, ICAM, and PINP), and plasma sildenafil concentration. Clinical evaluation. The number and duration of RP attacks were recorded in patient diaries throughout the study. The Raynaud’s Condition Score was a number selected by the patient to best indicate the difficulty the patient had that day with RP on an 11-point scale, where 0� no difficulty and 10� extreme difficulty, and is a validated outcome measure (20). The RP pain score was a number selected by the patient to best describe the pain caused by their RP during the past 24 hours on an 11-point scale, where 0 � no pain and 10 � worst possible pain. Serum samples for biomarker tests were collected at baseline and 4–6 hours after dosing on days 1, 14, and 28. Blood samples (5 ml) for pharmacokinetic sampling of sil- denafil were collected before administration of the first dose of study drug (baseline only) and 4–6 hours after the study drug doses taken at baseline and on days 14 and 28. The PAT test was performed at 4 of the 11 study sites. PAT, as stated above, is thought to indicate endothelial dys- function; the device measured the magnitude and time course of changes in arterial pulsatile blood flow in the fingertip. Patients were in a temperature-controlled environment (22– 24°C � 0.5°C) for at least 30 minutes before and during the test. A PAT finger probe was applied to each hand and recordings began. A cuff was inflated on the nondependent arm to 60 mm Hg greater than the systolic pressure for 5 776 HERRICK ET AL minutes. The cuff was deflated; recordings continued for an additional 5 minutes. The ratio between the preocclusion PAT and the postocclusion PAT constituted the hyperemic response. All reported adverse events were recorded at every visit during treatment (including up to 7 days after drug dis- continuation); investigators assessed seriousness and relation to treatment (deemed treatment related if no causality was noted or if the event was described as having probable, possible, or uncertain relationship to study treatment). Exac- erbations of illnesses recorded at baseline or abnormal test findings that resulted in a change in study drug dosage or study discontinuation were recorded as adverse events. Additional safety measures included sitting blood pres- sure and heart rate and clinical laboratory tests (hematology, clinical chemistry, and electrocardiogram [EKG]). Sitting blood pressure and heart rate were recorded at screening, baseline (before and after first dose), on days 14 and 28, and at followup. A 12-lead EKG recording was obtained at screening, on day 28, and at followup. Statistical analysis. The sample size was calculated using the primary end point and assuming a mean � SD difference from baseline of 9 � 12 attacks per week between patients receiving modified-release sildenafil and patients re- ceiving placebo. Thirty patients per group were required to detect a difference with 80% power at a 2-sided significance level of 5%. The intent-to-treat (ITT) population included all ran- domized patients who received �1 dose of study drug and had a baseline and a postbaseline efficacy assessment. The per- protocol population included all randomized patients who received all planned treatments, were compliant with diary completion, and completed the study without a serious proto- col violation. Primary analysis. For the primary efficacy assessment, the number of RP attacks per week, the percentage change from baseline (day �6 to day 0) to week 4 (day 21 to day 27) was analyzed in the per-protocol population. An analysis of covariance (ANCOVA) with treatment as a factor and baseline as a covariate was used in the per-protocol population. Secondary analyses. The change from baseline to week 4 in the number of RP attacks per week was analyzed with an ANCOVA with treatment as a factor, baseline and random- ization date as continuous covariates, and center as a discrete covariate. It was thought that center and randomization date might reflect changes in temperature that might affect the results; randomization date was coded as a whole number describing the day from a fixed baseline. Additionally, the change from baseline to week 4 in the square root transformed number of RP attacks per week and the change from baseline to week 4 in the number of RP attacks per week with or without influential observations were analyzed with an ANCOVA with treatment as a factor and baseline as a covariate. To examine robustness, these analyses were also performed on the ITT population. Model assump- tions underlying these analyses were examined in a series of diagnostic plots. Mean Raynaud’s Condition Score, mean RP pain score, and mean duration of RP attacks were analyzed as changes from baseline to week 4. End points were analyzed for the per-protocol population with an ANCOVA using treat- ment as a factor and baseline as a covariate. PAT-reactive hyperemic response and serum levels of biomarkers for VCAM, ICAM, and PINP were summarized as absolute values and changes from baseline by treatment at each study visit with no statistical analysis. Plasma sildenafil concentrations were plotted against other efficacy end points to assess pharmacokinetic and pharmacodynamic relation- ships. All volunteered or observed adverse events were re- corded, and the findings were summarized. Figure 1. Disposition of the patients (A) and patient populations (B). Patients treated with placebo were excluded from the per-protocol (PP) population for unstable steroid dosing (n � 1) and Raynaud’s phenomenon (RP) attacks �5 days per week at baseline (n � 1). Patients treated with modified-release (MR) sildenafil were excluded for RP attacks �5 days per week at baseline (n� 4), insufficient diary entries (n� 2), concomitant nonsteroidal antiinflammatory drug use (n� 1), unstable steroid dosing (n� 1), and insufficient diary entry combined with �7 RP attacks per week at baseline (n � 1). AEs � adverse events; ITT � intent to treat. SILDENAFIL IN RAYNAUD’S PHENOMENON 777 RESULTS Patient characteristics. Patient progress through the study is shown in Figure 1A. Demographic char- acteristics were similar for both treatment groups (Table 1). The median duration of treatment in both groups was 29 days. The ITT and per-protocol popula- tions are shown in Figure 1B. Primary end point. The percentage change from baseline to week 4 in the number of RP attacks per week was significantly greater for modified-release sildenafil than for placebo in the per-protocol population (P � 0.034) (Figure 2). The number of RP attacks per week improved from baseline in both the placebo group (from 25.0 to 19.3) and the modified-release sildenafil group (30.5 to 18.7) (P � 0.244 for modified-release sildenafil versus placebo). Adjusting for center and randomization date (as surrogates for outdoor temperature) appeared to have no significant effect on the number of attacks. The results of sensitivity analyses supported the primary end point: the change from baseline to week 4 in the square root transformed number of RP attacks per week and the number of attacks excluding influential observations (n � 3) favored modified-release sildenafil over placebo (P � 0.047 and P � 0.050, respectively). For robustness, the same primary and secondary analy- ses were conducted on the ITT population; results were consistent with those for the per-protocol population. Secondary end points. Decreases relative to base- line in Raynaud’s Condition Score and the mean dura- tion of attacks were greater for the modified-release sildenafil group than for the placebo group, but did not reach statistical significance (Table 2). Changes in the RP pain score were similar in the 2 groups. Mean values and changes from baseline in PAT hyperemic re- sponses and serum levels of biomarkers (soluble VCAM, soluble ICAM, and PINP) showed similar results for the modified-release sildenafil and placebo groups (Table 3). No apparent pharmacokinetic or pharmaco- dynamic relationships with sildenafil were observed for any end points (data not shown). Safety. The number of patients with all-cause and treatment-related adverse events and the total number of adverse events were greater in the modified-release sildenafil group than in the placebo group. In the modified-release sildenafil group, 28 patients reported 76 adverse events of all causes and 21 patients reported Table 1. Demographic characteristics of the patients with RP secondary to SSc* Placebo Modified-release sildenafil 200 mg Men (n � 3) Women (n � 24) Men (n � 3) Women (n � 27) Age, years 53.7 (38–64) 50.3 (34–73) 49.3 (34–62) 51.4 (31–72) Weight, kg 79.0 (61–102) 64.9 (49–99) 77.4 (71–82) 64.4 (45–111) Height, cm 174.7 (172–176) 161.9 (149–181) 174.7 (173–176) 163.6 (153–172) * Values are the mean (range). The mean (range) duration since Raynaud’s phenomenon (RP) diagnosis was 16.3 (3.0–57.0) years in the placebo group and 14.3 (2.6–40.2) years in the modified-release sildenafil 200 mg group. The mean (range) duration since systemic sclerosis (SSc) diagnosis was 8.8 (0.3–22.0) years in the placebo group and 7.6 (0.3–23.0) years in the modified-release sildenafil 200 mg group. Figure 2. A, Mean change from baseline to week 4 in the number of Raynaud’s phenomenon (RP) attacks per week in the per-protocol population. Error bars show 95% confidence intervals. B, Mean percentage change from baseline to week 4 in the number of RP attacks per week in the per-protocol population. � � P � 0.034 versus adjusted mean in the placebo group. MR � modified release. 778 HERRICK ET AL 43 treatment-related adverse events. In the placebo group, 16 patients reported 33 adverse events of all causes and 8 patients reported 17 treatment-related adverse events. The most frequent adverse events were headache and dyspepsia (Table 4); the majority of adverse events were mild or moderate. At baseline, 5 patients in each group had dyspepsia, a frequent symptom in patients with RP secondary to SSc; more patients in the modified-release sildenafil group (n � 9) than the placebo group (n � 5) had dyspepsia on day 28. Treatment-related adverse events leading to dis- continuati