Effect of Loratadine in Lymphangioleiomyomatosis

NCT ID: NCT05190627

Last Updated: 2022-01-27

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-11-01
• Study Completion Date: 2023-12-30

Brief Summary

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)

Detailed Description

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.

Conditions

Lymphangioleiomyomatosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Loratadine treatment on rapamycin

Loratadine (oral administration, daily dose 10mg) in LAM patients that are treated with rapamycin

Group Type: EXPERIMENTAL

Loratadine

Intervention Type: DRUG

Loratadine 10mg/day added to rapamycin for 12 months

Placebo treatment on rapamycin

Placebo (oral administration, daily dose 10 mg) in LAM patients that are treated with rapamycin

Group Type: PLACEBO_COMPARATOR

Placebo 10mg/day added to rapamycin for 12 months

Intervention Type: DRUG

Placebo in the same type of capsule than the experimental drug

Interventions

Loratadine

Loratadine 10mg/day added to rapamycin for 12 months

Intervention Type: DRUG

Placebo 10mg/day added to rapamycin for 12 months

Placebo in the same type of capsule than the experimental drug

Intervention Type: DRUG

Other Intervention Names

Clarytine

Eligibility Criteria

Inclusion Criteria

• 1. Written informed consent consistent with GCP and local laws signed prior to entry into the study.

2. 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).

Exclusion Criteria

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Institut d'Investigació Biomèdica de Bellvitge

OTHER

Sponsor Role: lead

Responsible Party

Maria Molina

Chief of Interstitial Lung Diseases Unit, Respiratory Department. Associated Professor (University of Barcelona)

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Maria Molina-Molina, MD, PhD

Role: STUDY_DIRECTOR

Institut d'Investigació Biomèdica de Bellvitge

Locations

University Hospital of Bellvitge

L'Hospitalet de Llobregat, Barcelona, Spain

Site Status: RECRUITING

Hospital Vall d'Hebron

Barcelona, , Spain

Site Status: NOT_YET_RECRUITING

Hospital La Princes

Madrid, , Spain

Site Status: ACTIVE_NOT_RECRUITING

Hospital Puerta de Hierro

Madrid, , Spain

Site Status: ACTIVE_NOT_RECRUITING

Hospital Marqués de Valdecillas

Santander, , Spain

Site Status: NOT_YET_RECRUITING

Hospital Virgen del Rocío

Seville, , Spain

Site Status: NOT_YET_RECRUITING

Countries

Spain

Central Contacts

Mar Chicote, PM

Role: CONTACT

ufip@bellvitgehospital.cat

0034932607689

Facility Contacts

Vanesa Vicens-Zygmunt, PI

Role: primary

ufip@bellvitgehospital.cat

0034 932607689

Bea Saez, MD

Role: primary

David Iturbe, MD, PhD

Role: primary

Jose Antonio Rodriguez Portal, MD, PhD

Role: primary

Related Links

http://idibell.cat

IDIBELL webpage

Other Identifiers

LORALAM

Identifier Type: -

Identifier Source: org_study_id