A Phase 2 interventional study of Loratadine and Placebo 10mg/day added to rapamycin for 12 months in Lymphangioleiomyomatosis, sponsored by Institut d'Investigació Biomèdica de Bellvitge. Status unknown at 6 sites in Spain. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-01-27.
Sponsored by Institut d'Investigació Biomèdica de Bellvitge · Phase 2, Interventional, and Treatment
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)
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.
46 studies on the registry are indexed under Lymphangioleiomyomatosis; 11 are open to participants now.
This study's planned enrollment of 62 is above the median of 24 across 29 interventional studies indexed under Lymphangioleiomyomatosis.
Browse Lymphangioleiomyomatosis studies →Institut d'Investigació Biomèdica de Bellvitge is the lead sponsor of 19 studies on the registry; 9 are open to participants now.
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Written informed consent consistent with GCP and local laws signed prior to entry into the study.
Exclusion Criteria:
Loratadine (oral administration, daily dose 10mg) in LAM patients that are treated with rapamycin
Drug: Loratadine
Placebo (oral administration, daily dose 10 mg) in LAM patients that are treated with rapamycin
Drug: Placebo 10mg/day added to rapamycin for 12 months
Loratadine 10mg/day added to rapamycin for 12 months
Also known as: Clarytine
Placebo in the same type of capsule than the experimental drug
Incidence of Treatment-Emergent Adverse Events (safety) of loratadine in combination with sirolimus after 52 weeks of treatment
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.
Time frame: 52 weeks
To evaluate the effect of loratadine associated with sirolimus on quality of life measured by the Saint George's Questionnaire
The Saint George's Questionnaire is one of the most validated questionnaires in respiratory diseases that evaluates three dimensions; symptoms, activity and disease impact, and the total score ranges from 0 (worse situation) to 100 (best situation).
Time frame: 52 weeks
Study-drug discontinuation
To compare the rate of study-drug discontinuation during the study in both arms
Time frame: 52 weeks
Serum levels of sirolimus
Analyzing the number of patients that maintain the serum levels of sirolimus on window range that is considered therapeutic and safe (5-15 pg).
Time frame: 52 weeks
To evaluate the effect of loratadine associated with sirolimus on progression-free survival time
Progression-free survival time, which will be considered when some of these events are present: FEV1 decrease \> 10%, DLCO decrease \> 15%, lung transplant, death.
Time frame: 52 weeks
To evaluate the effect of loratadine associated with sirolimus on hospitalization rate
Hospitalization. Registration of any cause of hospitalization.
Time frame: 52 weeks
To evaluate the effect of loratadine associated with sirolimus on serum biomarkers
Serum biomarkers: measuring changes on the single established biomarker to date (VEGF-D)
Time frame: 52 weeks
Plan to share: No
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Institut d'Investigació Biomèdica de Bellvitge