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Effect of Loratadine in Lymphangioleiomyomatosis (LORALAM)

Primary Purpose

Lymphangioleiomyomatosis

Status

Recruiting

Phase

Phase 2

Locations

Spain

Study Type

Interventional

Intervention

Loratadine

Placebo 10mg/day added to rapamycin for 12 months

About this trial

This is an interventional treatment trial for Lymphangioleiomyomatosis focused on measuring LAM, Rapamycin, Loratadine

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University Hospital of BellvitgeRecruiting
Hospital Vall d'Hebron
Hospital La Princes
Hospital Puerta de Hierro
Hospital Marqués de Valdecillas
Hospital Virgen del Rocío

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Loratadine treatment on rapamycin

Placebo treatment on rapamycin

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).

Study-drug discontinuation

To compare the rate of study-drug discontinuation during the study in both arms

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).

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.

To evaluate the effect of loratadine associated with sirolimus on hospitalization rate

Hospitalization. Registration of any cause of hospitalization.

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)

Full Information

NCT ID

NCT05190627

First Posted

December 11, 2021

Last Updated

January 12, 2022

Sponsor

Institut d'Investigació Biomèdica de Bellvitge

1. Study Identification

Unique Protocol Identification Number

NCT05190627

Brief Title

Effect of Loratadine in Lymphangioleiomyomatosis

Acronym

LORALAM

Official Title

Phase II Clinical Trial Evaluating the Effect of Loratadine Associated to Rapamicyn in Patients With Lymphangioleiomyomatosis

Study Type

Interventional

2. Study Status

Record Verification Date

January 2022

Overall Recruitment Status

Recruiting

Study Start Date

November 1, 2021 (Actual)

Primary Completion Date

December 30, 2022 (Anticipated)

Study Completion Date

December 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Institut d'Investigació Biomèdica de Bellvitge

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Lymphangioleiomyomatosis

Keywords

LAM, Rapamycin, Loratadine

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

62 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Loratadine treatment on rapamycin

Arm Type

Experimental

Arm Description

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

Arm Title

Placebo treatment on rapamycin

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Loratadine

Other Intervention Name(s)

Clarytine

Intervention Description

Loratadine 10mg/day added to rapamycin for 12 months

Intervention Type

Drug

Intervention Name(s)

Placebo 10mg/day added to rapamycin for 12 months

Intervention Description

Placebo in the same type of capsule than the experimental drug

Primary Outcome Measure Information:

Title

Incidence of Treatment-Emergent Adverse Events (safety) of loratadine in combination with sirolimus after 52 weeks of treatment

Description

Time Frame

52 weeks

Secondary Outcome Measure Information:

Title

To evaluate the effect of loratadine associated with sirolimus on quality of life measured by the Saint George's Questionnaire

Description

Time Frame

52 weeks

Title

Study-drug discontinuation

Description

To compare the rate of study-drug discontinuation during the study in both arms

Time Frame

52 weeks

Title

Serum levels of sirolimus

Description

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

Title

To evaluate the effect of loratadine associated with sirolimus on progression-free survival time

Description

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

Title

To evaluate the effect of loratadine associated with sirolimus on hospitalization rate

Description

Hospitalization. Registration of any cause of hospitalization.

Time Frame

52 weeks

Title

To evaluate the effect of loratadine associated with sirolimus on serum biomarkers

Description

Serum biomarkers: measuring changes on the single established biomarker to date (VEGF-D)

Time Frame

52 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Mar Chicote, PM

Phone

0034932607689

ufip@bellvitgehospital.cat

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Maria Molina-Molina, MD, PhD

Organizational Affiliation

Institut d'Investigació Biomèdica de Bellvitge

Official's Role

Study Director

Facility Information:

Facility Name

University Hospital of Bellvitge

City

Hospitalet de Llobregat

State/Province

Barcelona

ZIP/Postal Code

08907

Country

Spain

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Vanesa Vicens-Zygmunt, PI

Phone

0034 932607689

ufip@bellvitgehospital.cat

Facility Name

Hospital Vall d'Hebron

City

Barcelona

Country

Spain

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Bea Saez, MD

Facility Name

Hospital La Princes

City

Madrid

Country

Spain

Individual Site Status

Active, not recruiting

Facility Name

Hospital Puerta de Hierro

City

Madrid

Country

Spain

Individual Site Status

Active, not recruiting

Facility Name

Hospital Marqués de Valdecillas

City

Santander

Country

Spain

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

David Iturbe, MD, PhD

Facility Name

Hospital Virgen del Rocío

City

Sevilla

Country

Spain

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jose Antonio Rodriguez Portal, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD

Links:

URL

http://idibell.cat

Description

IDIBELL webpage

Learn more about this trial

Effect of Loratadine in Lymphangioleiomyomatosis

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