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)
Recruitment Criteria
Accepts Healthy Volunteers
Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms
No
Study Type
An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.
An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.
Searching Both is inclusive of interventional and observational studies.
Interventional
Eligible Ages
18 Years and Over
Gender
All
More Inclusion & Exclusion 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.
Trial Details
Trial ID:
This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.
Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.
Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.
Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.
Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
Phase 2
Lead Sponsor
The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.
Institut d'Investigació Biomèdica de Bellvitge
Principal Investigator
The person who is responsible for the scientific and technical direction of the entire clinical study.
Maria Molina-Molina, MD, PhD
Principal Investigator Affiliation
Institut d'Investigació Biomèdica de Bellvitge
Agency Class
Category of organization(s) involved as sponsor (and collaborator) supporting the trial.
Other
Overall Status
Recruiting
Countries
Spain
Conditions
The disease, disorder, syndrome, illness, or injury that is being studied.
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.
Arms & Interventions
Arms
Experimental: Loratadine treatment on rapamycin
Loratadine (oral administration, daily dose 10mg) in LAM patients that are treated with rapamycin
Placebo Comparator: Placebo treatment on rapamycin
Placebo (oral administration, daily dose 10 mg) in LAM patients that are treated with rapamycin
Interventions
Drug: - Loratadine
Loratadine 10mg/day added to rapamycin for 12 months
Drug: - Placebo 10mg/day added to rapamycin for 12 months
Placebo in the same type of capsule than the experimental drug
Contact a Trial Team
If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.
International Sites
University Hospital of Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
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