E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
EFFECT OF LORATADINE ON LYMPHANGIOLEIOMYOMATOSIS |
EFECTO DE LORATADINA EN LINFANGIOLEIOMIOMATOSIS |
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E.1.1.1 | Medical condition in easily understood language |
EFFECT OF LORATADINE ON LYMPHANGIOLEIOMYOMATOSIS |
EFECTO DE LORATADINA EN LINFANGIOLEIOMIOMATOSIS |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10049459 |
E.1.2 | Term | Lymphangioleiomyomatosis |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Evaluate the safety profile of loratadine in combination with rapamycin after 52 weeks Assess security (incidence of adverse events according to their intensity, severity, relation to treatment) of the combination of loratadine and rapamycin compared with rapamycin in monotherapy in patients with LAM. |
Evaluar el perfil de seguridad de loratadina en combinación con rapamicina tras 52 semanas. Evaluar la seguridad (incidencia de acontecimientos adversos según su intensidad, gravedad, relación con el tratamiento) de la combinación de loratadina y rapamicina comparada con rapamicina en monoterapia en pacientes con LAM. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives evaluate: a) quality of life and progression free-survival time, b) changes in the established LAM serum biomarker VEGFD, c) the utility of the major histamine-derived metabolite methylimidazoleacetic acid (MIAA) for monitoring disease progression and biological treatment effect. |
Los objetivos secundarios evalúan: a) calidad de vida y tiempo de supervivencia libre de progresión, b) cambios en el biomarcador de suero LAM establecido VEGFD, c) la utilidad del principal metabolito ácido metilimidazolacético (MIAA) derivado de la histamina para controlar la progresión de la enfermedad y el efecto del tratamiento biológico. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
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). - Taking stable doses of rapamycin for at least the last 3 months. |
Pacientes afectas de LAM, mayores de 18 años, que presenten: - Diagnóstico definitivo de LAM basado en el consenso internacional y guías clínicas, máximo 10 años antes de la randomización. El diagnóstico deberá ser de certeza (tras evaluación por Comité Multidisciplinar de Intersticio de cada centro participante). - FEV1 > 35% y DLCO > 20% - Saturación de oxígeno (SatO2) > 85% en reposo y sin oxígeno suplementario - TAC de torax 12 meses antes de la randomización sugestivo de LAM - Toma de dosis estables de rapamicina como mínimo en los últimos 3 meses |
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E.4 | Principal 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 antihistaminic treatment. - History of coexistent and clinically significant (in the opinion of the Investigator) chronic obstructive pulmonary disease (COPD), bronchiectasis, asthma, inadequately treated sleepdisordered breathing, or any clinically significant pulmonary diseases other than LAM. |
- Uso concomitante habitual (mínimo 3 días/semana) de cualquier antagonista de la histamina (incluido además de loratadina, ebastina, y similares). - Hipersensibilidad a los antagonistas de la histamina o anti-histamínicos, especialmente del receptor HR1. - Embarazo. - Lactancia y voluntad de procreación en el año siguiente a la inclusión. - Tratamiento contraceptivo inadecuado. - Tabaquismo activo (en momento estudio o toma de último cigarro hace menos de 3 meses). - Uso de inmunosupresores o inmunomoduladores sistémicos o quimioterapia dentro de los 30 días del screening. - Toma corticoides orales a dosis > 15 mg/día, terapias vasodilatadoras para la hipertensión arterial pulmonar (ejemplo; bosentan), fármacos no aprobados o en investigación para LAM en el periodo de 4 semanas antes de la visita de screening. - Insuficiencia hepática grave. - Insuficiencia renal: Clearance de creatinina (CrCl) < 60 ml/min - Pacientes que reciban como tratamiento algún potente inhibidor o inductorde la enzima hepática CYP durante el screening o 14 días previos a la randomización: antifúngicos (ej. Ketoconazol, itraconazol), claritromicina, telitromicina, cobicistato, fenitoina, carbamacepina, barbitúricos, rifampicina, inhibidores de proteasas como atazanavir, ritonavir y saquinavir, o bien toma de pomelo. - Asma alérgica u otro trastorno alérgico mayor que requiera la toma diaria o habitual de anti-histamínicos. - Otra enfermedad pulmonar grave coexistente (en opinión del investigador) como enfisema severo, bronquiectasieas, asma, SAHS severo no controlado. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of adverse effects associated with taking loratadine associated with rapamycin, including nausea, diarrhea, abdominal pain, vomiting, headache, hypertransaminasemia. |
Incidencia de efectos adversos asociados a la toma de loratadina asociada a rapamicina, incluyendo nausea, diarrea, dolor abdominal, vómito, cefalea, hipertransaminasemia. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The assessment of the primary point is at 52 weeks |
La valoración de la variable primaria es a las 52 semanas |
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E.5.2 | Secondary end point(s) |
-Progression-free survival time, which will be considered when some of these events are present: FEV1 decrease > 10%, DLCO decrease > 15%, lung transplant, death. -Hospitalization. Registration of any cause of hospitalization |
- Mantenimiento de la estabilidad clínica (caída FEV1 < 10% o de la DLCO < 15%). - Decrease in the number of hospitalizations for any cause and respiratory cause. - Lung transplant. - Death. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The assessment of the primary point is at 52 weeks |
La valoración de la variable primaria es a las 52 semanas |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |