Phase II Clinical Trial Evaluating the Effect of Loratadine Associated to Rapamicyn in Patients With Lymphangioleiomyomatosis
试验速览
- 阶段
- 2 期
- 入组人数
- 62
- 试验地点
- 6
- 主要终点
- Incidence of Treatment-Emergent Adverse Events (safety) of loratadine in combination with sirolimus after 52 weeks of treatment
研究概览
简要总结
INTRODUCTION: LAM is a rare and lethal disease characterized by progressive cystic lung destruction. Inhibition of mTOR with rapamycin is the current standard of care (SOC), which can slow-down disease. Plasma major histamine metabolite (Methylimidazoleacetic acid [MIAA]) is increased in LAM. Loratadine is a histamine receptor antagonist (HR1), which inhibits LAM cell proliferation. Therefore, a novel phase-II clinical trial for assessing safety and potential benefits of loratadine in LAM has been initiated.
METHODS: LORALAM clinical trial, phase-II, double-blind, randomized, placebo controlled, parallel-group, multicentre study initiates recruitment in July 2020. Enrollment plan includes 62 subjects with LAM on treatment with rapamycin ≥3 months, randomized 1:1 to add oral loratadine 10mg/day or placebo, once daily, for 52 weeks. Recruitment will end in June 2021. The primary endpoints are 1) to assess the safety profile of loratadine associated with rapamycin, 2) lung function decline after 52 weeks of treatment. The secondary endpoints are a) quality of life and progression free-survival time, b) changes in the established LAM serum biomarker VEGFD, c) the utility of MIAA for monitoring disease progression and biological treatment effect.
ETHICS AND DISSEMINATION: The study will be carried out in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and each ethical committee. This clinical trial contemplates the possibility of increasing the number of centers and including patients from patient support groups (LAM foundation, AELAM)
详细描述
Lymphangioleiomyomatosis (LAM) is a rare and lethal lung disease affecting almost exclusively women of childbearing age and characterized by progressive cystic lung destruction. LAM results from germline and somatic loss-of-function mutations in the tuberous sclerosis complex 1 and 2 genes (TSC1/2), and therefore diseased cells show abnormal activation of the mechanistic target of rapamycin (mTOR). Inhibition of mTOR with rapamycin (also known as sirolimus) is the current standard of care. However, this therapy does not fully kill LAM cells, shows variable tolerability and treatment answer. Therefore, sirolimus has slowed-down disease progression but young patients still need lung transplantation despite treatment. In addition, LAM diagnosis and clinical monitoring is also challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, guided by comprehensive preclinical data obtained in the context of a Spanish research network for LAM, and with the support of the national Association of LAM patients (AELAM), the investigators propose a phase-II clinical trial for assessing if the tricyclic antihistamine loratadine is effective in slowing the progression of lung disease in LAM. Loratadine is an histamine receptor 1 (HR1) antagonist, widely used for allergic process, that also acts through different intracellular signaling, including Akt/MITF and PKCBII-tyrosine kinase. Recent studies have demonstrated that co-treatment with loratadine sensitize KBV20C resistant cells to vincristine, which improve the onco-therapeutical effect. The primary study objective is to assess the safety profile of loratadine 10 mg/day associated with the current standard treatment (sirolimus) and its potential benefit abrogating the lung function decline after 52 weeks of treatment. The secondary objectives include; a) an assessment of quality of life and progression free-survival time, and, b) to determine the clinical usefulness of the major histamine-derived metabolite methylimidazoleacetic acid (MIAA) for monitoring of disease progression and biological treatment effect.
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
- Triple (Participant, Care Provider, Investigator)
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
- •Written informed consent consistent with GCP and local laws signed prior to entry into the study.
- •Patients with LAM and > 18 years-old with:
- •FEV1 > 35% and DLCO > 20%
- •Oxygen saturation (SpO2) > 85% by pulse oximetry while breathing ambient air at rest
- •Patients with a definite diagnosis consistent with LAM prior to screening based on International consensus criteria within 10 years prior to randomization
- •HRCT within 12 months prior to randomization with central reading demonstrating a radiological pattern suggesting LAM and some other criteria for initiating sirolimus (symptoms, FEV1 decline or the presence of abdominal lynphangioleiomiomas).
排除标准
- •Concomitant use of other HR1 antagonist
- •Hypersensitivity to HR1 antagonists
- •Current smoker or ex-smoker having quit smoking < 4 months prior to firs screening visit - Use of systemic immunosuppressants or chemotherapy within 30 days of screening.
- •Receiving oral corticosteroids>15mg/day, vasodilator therapies for pulmonary hypertension (e.g., bosentan), unapproved and/or investigational therapies for LAM or administration of such therapies within 4 weeks of initial screening.
- •At baseline/screening visit, values of liver transaminases above 3 times upper limit, alkaline phosphatase above 2.5 times upper limit, or bilirubin above 1.5 times upper limit
- •Creatinine clearance (CrCl)<60ml/min (determined by Cockcroft-Gault Equation) at baseline/ screening visit.
- •Patients treated with strong inhibitors and inducers of CYP either during the study or 14 days prior to enrolment in the study: antifungals (e.g., ketoconazole, itraconazole), clarithromycin, telithromycin, cobicistat, protease inhibitors (e.g., atazanavir, ritonavir, and saquinavir) and grapefruit juice, phenytoin, carbamazepine, barbiturates, rifampin.
- •Current allergic asthma or other major allergic diseases that requires different daily anti- histaminic treatment.
- •History of coexistent and clinically significant (in the opinion of the Investigator) chronic obstructive pulmonary disease (COPD), bronchiectasis, asthma, inadequately treated sleep- disordered breathing, or any clinically significant pulmonary diseases other than LAM.
研究组 & 干预措施
Loratadine treatment on rapamycin
Loratadine (oral administration, daily dose 10mg) in LAM patients that are treated with rapamycin
干预措施: Loratadine (Drug)
Placebo treatment on rapamycin
Placebo (oral administration, daily dose 10 mg) in LAM patients that are treated with rapamycin
干预措施: Placebo 10mg/day added to rapamycin for 12 months (Drug)
结局指标
主要结局
Incidence of Treatment-Emergent Adverse Events (safety) of loratadine in combination with sirolimus after 52 weeks of treatment
时间窗: 52 weeks
To compare the incidence of adverse events in LAM patients treated with sirolimus and loratadine versus sirolimus alone. Any adverse event related to both drugs, including nausea, diarrhea, stomach discomfort, vomiting, headache and liver hipertransaminasemia, will be evaluated.
次要结局
- To evaluate the effect of loratadine associated with sirolimus on hospitalization rate(52 weeks)
- To evaluate the effect of loratadine associated with sirolimus on quality of life measured by the Saint George's Questionnaire(52 weeks)
- Study-drug discontinuation(52 weeks)
- Serum levels of sirolimus(52 weeks)
- To evaluate the effect of loratadine associated with sirolimus on progression-free survival time(52 weeks)
- To evaluate the effect of loratadine associated with sirolimus on serum biomarkers(52 weeks)
研究者
Maria Molina
Chief of Interstitial Lung Diseases Unit, Respiratory Department. Associated Professor (University of Barcelona)
Institut d'Investigació Biomèdica de Bellvitge