A Pilot Study to Evaluate the Safety and Efficacy of Oral Treprostinil in the Treatment of Calcinosis in Patients With Systemic Sclerosis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Median Rate of Change of Calcinosis in Radiograph Following Treatment With Oral Treprostinil as Assessed by a Novel Radiographic Scoring System
研究概览
简要总结
This is a prospective open-label trial that will enroll 12 patients with systemic sclerosis (SSc) and at least one calcinotic lesion of the hands that is palpable on physical examination and also measureable on hand radiographs, at one single center. Each subject will receive treprostinil orally for 12 months, and follow-up evaluations will be performed every 3 months. Our main objective is to determine whether oral treprostinil is safe, and effective in reducing calcinosis in patients with SSc. We hypothesize that calcinosis is a result of microvascular injury and ischemic damage, and that therefore treprostinil may be beneficial in the treatment of calcinosis in patients with SSc.
详细描述
- Background:
Calcinosis cutis is the deposition of calcium in the skin and subcutaneous tissues. It is a common and potentially debilitating manifestation of systemic sclerosis (SSc), affecting almost one quarter of these patients. Several studies have found an association between calcinosis and vascular manifestations of SSc including digital ulcers (DU), and acro-osteolysis. The investigators confirmed this in a retrospective multi-center international cohort study of 5280 patients with SSc where DUs were the strongest predictor of calcinosis in multivariate analysis (OR 3.7, 95%CI 2.6-5.3, p<0.0001).
Treprostinil delivered by continuous subcutaneous infusion was effective in both the healing and prevention of DU in patients with SSc in an open-label, single-center clinical trial of 5 (of 12) patients who were able to tolerate the medication. A study of 148 subjects with DU showed that the administration of oral treprostinil up to 16 mg twice daily for 20 weeks was associated with a small but statistically insignificant reduction in net ulcer burden in comparison to placebo. Additionally, preliminary observations in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) registry have found that two patients with SSc-PAH and calcinosis treated with subcutaneous treprostinil for PAH experienced approximately 50% radiographic improvement in their calcinosis lesions after 6 months of therapy.
The investigators developed and validated a novel radiographic scoring system to assess the severity of calcinosis affecting the hands of patients with SSc that accounts for area coverage, density, and anatomic location. This scoring system is feasible and was found to have excellent intra- and inter-rater reliability with intra-class correlation coefficients (ICC) of .93 (.89-.97) and .89 (.86-.92), respectively.
Given that calcinosis is a frequent, debilitating complication of SSc associated with digital vascular ischemia with no effective therapies, a clinical trial, using novel outcome measures, testing the safety and efficacy of a powerful vasodilator for the treatment of calcinosis is warranted. 2. Primary/Secondary objectives:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed written informed consent
- •Age > 18 years of age
- •Diagnosis of limited or diffuse cutaneous systemic sclerosis (SSc) according to the revised 2013 ACR/EULAR classification criteria for SSc
- •Radiological and physical examination evidence of at least one subcutaneous calcium deposition in the hands that is clinically apparent as part of routine clinical care.
- •If female of childbearing potential, the patient must have a negative pregnancy test at screening and baseline visits
- •Oral corticosteroids (≤ 10 mg/day of prednisone or equivalent) and NSAIDs are permitted if the patient is on a stable dose regimen for ≥ 2 weeks prior to screening and throughout the study
- •Calcium channel blockers, alpha-1-antagonists, ACE-inhibitors, angiotensin receptor blockers, and protein-pump inhibitors are permitted as long as the doses are stable for 4 weeks prior to screening and throughout the study
- •Women of childbearing potential must agree to use adequate contraception when sexually active with any combination of at least 2 effective methods of birth control (except for women who have a partner who is sterile, i.e. due to vasectomy)
排除标准
- •Rheumatic disease other than SSc
- •Patients with pulmonary arterial hypertension (PAH), NYHA Class III or IV, as determined by right heart catheterization or on PAH approved medications for PAH
- •Patients with moderate or severe hepatic impairment (Child Pugh Class C), or transaminase elevation (ALT or AST) > 3 x the upper limit of normal at screening visit
- •Patients with diverticulosis
- •Hemoglobin < 75% of the lower limit of the normal range
- •Systolic blood pressure < 95 mmHg or diastolic blood pressure < 50 mmHg
- •Patients who are hemodynamically unstable, or have acute renal, cardiac or pulmonary failure, or any life-threatening condition.
- •Concurrent malignancy except non-melanoma skin cancers
- •Patients receiving specific (sildenafil, tadalafil) or unspecific phosphodiesterase-5 inhibitors (dipyridamole, theophylline), endothelin receptor antagonists, prostanoids, riociguat, or NO donors (nitrates) within 4 weeks of screening
- •Patients receiving bisphosphonates, warfarin, colchicine, minocycline, intravenous immunoglobulins, or biological agents including abatacept or rituximab within 4 weeks of screening
- •Patients receiving local treatments for calcinosis including surgical removal or intralesional steroid injections within 12 weeks of screening or throughout the study.
- •Patients who have participated in another clinical trial of an investigative agent within 30 days of screening (or 5 half-lives of the investigational drug, whichever is longer)
- •Pregnant or nursing women
- •Patients with a history of drug or alcohol abuse within 6 months of screening
- •Any medical condition that, in the opinion of the investigator, might interfere with the subject's participation in the study or poses an added risk for the subject
- •Inability to comply with study and follow-up procedures
研究组 & 干预措施
Oral treprostinil
Treprostinil 0.125 mg TID orally, which will be increased by 0.125 mg TID every 3 to 4 days as tolerated for 12 months
干预措施: Oral treprostinil (Drug)
结局指标
主要结局
Median Rate of Change of Calcinosis in Radiograph Following Treatment With Oral Treprostinil as Assessed by a Novel Radiographic Scoring System
时间窗: Baseline, month 12
Median rate of change of calcinosis in radiograph following treatment with oral treprostinil as assessed by the Scleroderma Clinical Trial Consortium (SCTC) radiographic scoring system. Historical average SCTC scores in this patient population have ranged from 4.08 to 472.88, with higher scores indicating more severe symptoms. The SCTC radiographic score for calcinosis is a validated radiographic scoring system to assess the severity of calcinosis affecting the hands of patients with SSc that accounts for area coverage, density, and anatomic location, higher scores mean worse calcinosis. Physician rates density and percentage of area for 22 regions of each hand, each deferentially weighted in the overall score; individual region values are multiplied my their weight then summed to create an overall score.
Number of Participants With Treatment-related Adverse Events Following Treatment With Oral Treprostinil
时间窗: 12 months
Number of participants with treatment-related adverse events following treatment with oral treprostinil at 12 months. We defined adverse event as any untoward medical experience occurring to a subject during a clinical trial whether or not it is related to the study drug.
次要结局
- Change in Scleroderma Health Assessment Questionnaire (SHAQ)(Baseline, 12 months)
- Change in Cochin Hand Functional Scale(Baseline, 12 months)
- Change in Mawdsley Calcinosis Questionnaire(Baseline, 12 months)
- Baseline Cortical Area Measured by HR-pQCT in SSc Patients With Calcinosis.(Baseline visit (average approximately 3 hours for the scan))
- Change in Patient Global Assessment of Calcinosis Severity(Baseline, 12 months)
- Change in Physician Global Assessment of Calcinosis Severity(Baseline, 12 months)
- Baseline Cortical Porosity Measured by HR-pQCT in SSc Patients With Calcinosis.(Baseline visit (average approximately 3 hours for the scan))
- Number of Patients With Changes in Vascular and SSc-Pulmonary Arterial Hypertension (PAH) Associated Biomarkers Following Treatment With Treprostinil at 1 Year Compared to Baseline(12 months)
- Change in Short Form (SF)-36(Baseline, 12 months)
- Change in Raynaud Condition Score(Baseline, 12 months)
研究者
Lorinda S Chung
Associate professor of medicine (Immunology & Rheumatology)
Stanford University