REstoration With Calcifediol of VItamin D Deficiency in Pulmonary Arterial Hypertension Patients
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 102
- 主要终点
- Clinical improvement without clinical worsening
研究概览
简要总结
Background. Pulmonary arterial hypertension (PAH) is a heterogeneous pathophysiological condition characterized by progressive pulmonary vascular narrowing that ultimately results in right-sided heart failure and eventually death or lung transplantation. The effectiveness of current pharmacological treatments is suboptimal and a large proportion of patients still had events or died despite receiving combination therapy. Vitamin D deficiency has been found to be much more frequent in PAH patients than in the general population or even compared to patients with other severe cardiovascular diseases. Moreover, vitamin D deficiency has a negative prognostic impact in PAH. Animal studies support that vitamin D deficiency worsens PAH.
Hypothesis. In patients with PAH and vitamin D deficiency, restoration of vitamin D status with calcifediol improves their symptomatology and prognosis.
Design: Multicenter clinical trial with the participation of 9 hospitals, placebo-controlled, randomized (1:1 ratio), in two parallel groups (without crossover), triple blind, and add-on on existing treatments (add-on). It will include at least 102 subjects (51 in the calcifediol group and 51 in the placebo group) followed for 24 weeks of treatment.
Inclusion criteria: Patients of both sexes (18-75 years) with hemodynamic diagnosis of PAH and severe vitamin D deficiency (25-OHvitD <= 12 ng/ml) and without previous diagnosis of osteoporosis or osteomalacia.
Treatments: 1) Calcifediol Hydroferol® 0.266 mg once every 10 days for the first 12 weeks and once every two weeks for the following 12 weeks. 2) Placebo.
Main objective: A composite endpoint of clinical improvement without clinical worsening at week 24.
Expected outcome: Restoration of vitamin D status is an unexpensive measure, very easily implantable and that could improve the evolution of the disease as well as other aspects such as bone or immune health and that has few side effects.
详细描述
RESEARCH TEAM PI: Diego A. Rodríguez Chiaradía, Co-PI: Francisco Perez-Vizcaino. Investigators: Joan A. Barberá, Isabel Blanco Vich, Manuel Lopez Meseguer, Amaya Martinez Menaca, Gregorio M Perez Peñate, Raquel López Reyes, Alberto García Ortega, Jose Andres Tenes, Remedios Otero.
RATIONALE: There is no evidence to support that there is a causal link, at least in humans, between vitamin D deficiency and PAH. Moreover, if present, the causal relationship might be in either direction: vitamin D causing/aggravating PAH or PAH inducing vitamin D deficiency. Only data from preclinical or small uncontrolled trials are available that suggest that low vitamin D aggravates PH. Thus, the key clinical question for PAH patients that we are addressing herein is: Does restoration of vitamin D levels lead to clinical improvement and better prognosis in PAH patients?
Thus, our HYPOTHESIS is that in patients with stable PAH and vitamin D deficiency, restoration of the vitamin D status with calcifediol supplements improves symptoms and prognosis.
MAIN OBJECTIVE. To analyze whether a vitamin D supplement (0,266 mg calcifediol, once every 10 days for the first 12 weeks and once every second week in the following 12 weeks) induces clinical improvement without clinical worsening at week 24 compared with placebo.
DISEASE. The study will be performed in patients with PAH and severe deficit of vitamin D. Patients will be at intermediate risk of 1-year mortality according to 2022 European Respiratory Society /European Society of Cardiology guidelines despite receiving standard treatment for PAH for at least 6 weeks before randomisation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Placebo capsules will be identical to those of the active treatment. The batch of capsules for each patient will be codified and codes will be provided by the producing company to the SCReN platform who will keep them so that patients and investigators and the local pharmacy will be blind.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female patients aged 18 -75 years.
- •Patients with diagnosis of PAH of the following types according to 2022 ERS/ESC guidelines: idiopathic, hereditary, drug and toxin-induced PAH or associated to connective tissues disease.
- •Patients who are stable and treated with standard medications for PAH on monotherapy or with combinations of drugs, including calcium channel blockers, phosphodiesterase type 5 inhibitors (PDE5i), endothelin receptor antagonists (ERA), prostacyclin analogues or selexipag or with stable dose of diuretics who had no treatment modification for at least 6 weeks before randomization.
- •Patients with an intermediate-low and intermediate-high risk score according to 2022 ERS/ESC guidelines.
- •Patients with severe deficiency of vitamin D, defined herein as plasma or serum 25(OH)vitamin D levels equal to or lower than 12 ng/ml
- •Patients who can understand and follow instructions, and who are able to participate in the study for the entire study.
- •Patients must have given their written informed consent to participate in the study after having received adequate previous information and before any study-specific procedures.
排除标准
- •Participation in another interventional clinical study within 30 days before screening.
- •Previous randomisation to treatment during this study (no re-randomisation).
- •Pregnant women or breastfeeding women, or women with childbearing potential not using a effective contraception method throughout the study.
- •Patients with a medical disorder, condition, or history of such that would impair the patient's ability to participate in or complete this study, in the opinion of the investigator.
- •Patients with substance abuse (eg, alcohol or drug abuse) within the previous 3 months before and at randomisation.
- •Patients with underlying medical disorders with an anticipated life expectancy <2 years.
- •Patients with a history of severe allergies or multiple drug allergies or with hypersensitivity to the investigational drug or any of the excipients.
- •Patients unable to perform a valid 6MWD test (eg, orthopaedic disease or peripheral artery occlusive disease that affects the patient's ability to walk).
- •Excluded medication/treatment: active treatment with digoxin.
研究组 & 干预措施
Calcifediol
Calcifediol (25-OH vitamin D3) in oral soft capsules (Hidroferol® 0,266 mg, equivalent to 15960 IU vitamin D).
干预措施: Calcifediol Oral Capsule (Drug)
Placebo
Placebo in oral soft capsules (externally indistinguishable from Hidroferol®).
干预措施: Placebo (Drug)
结局指标
主要结局
Clinical improvement without clinical worsening
时间窗: 24 weeks
Clinical improvement is defined as a change in at least two of the following variables: 1) increase in 6 minutes walking distance (6MWD) \>= 10% or more than 30 m, 2) change from intermediate-low or intermediate-high risk to low risk score or change from intermediate-high to intermediate-low risk according to 2022 ERS/ESC guidelines), 3) reduction in BNP or NT-proBNP \>= 30%, 4) increase in the TAPSE/SPAP ratio \>= 25%. Clinical worsening is defined as any of the following events: a) hospitalization related to PAH, b) therapeutic escalation, c) progression of symptoms, d) lung or cardiopulmonary transplantation, e) atrial septostomy and f) mortality related to PAH.
次要结局
- 6 minute walking distance(24 weeks)
- Quality of life will be compared using the emPHasis-10 questionnaire.(24 weeks)
- Serum noggin levels(24 weeks)
- serum BNP or nt-pro-BNP(24 weeks)
- functional class (WHO/NYAS)(24 weeks)
- noninvasive risk score (NIRS) based on the three previous variables(24 weeks)
- ventricular function analyzed echocardiographically by TAPSE(24 weeks)
研究者
Diego Agustín Rodríguez
MD, PhD. Head of Pneumology Department
Parc de Salut Mar