| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 14.1 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10038738 |
| E.1.2 | Term | Respiratory, thoracic and mediastinal disorders |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| 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 |
To evaluate the efficacy of QGE031 240 mg s.c. every two weeks compared to matched placebo when
added to existing asthma therapy by comparing the responder rates* following 16 weeks treatment in
patients inadequately controlled** on high dose inhaled corticosteroids plus long-acting β2agonists
(GINA treatment step 4). |
| Valutare, rispetto al placebo corrispondente, l’efficacia di QGE031 240 mg s.c. ogni due settimane, in aggiunta alla terapia esistente per l’asma, confrontando i tassi di risposta* dopo 16 settimane di trattamento in pazienti non adeguatamente controllati** con corticosteroidi ad alte dosi per inalazione in associazione a β2-agonisti ad azione prolungata (trattamento GINA step 4). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the superiority of QGE031 240 mg s.c. every two weeks compared to omalizumab (administered as per locally approved dosing tables) when added to existing asthma therapy by
comparing the responder rates* following 16 weeks treatment in patients inadequately controlled** on
high dose inhaled corticosteroids plus long-acting β2agonists (GINA treatment step 4).
* Response is defined as a decrease of 0.5 or more of the ACQ7 score from baseline)
**Inadequate control is defined as an ACQ7 score of ≥1.5 at the end of the run-in epoch (Juniper et al,
2006). |
| Valutare la superiorità rispetto ad omalizumab di QGE031 240 mg s.c. ogni due settimane (somministrato secondo le tabelle di dosaggio approvate a livello locale), in aggiunta alla terapia esistente per l’asma, confrontando i tassi di risposta* dopo 16 settimane di trattamento in pazienti non adeguatamente controllati** con corticosteroidi ad alte dosi per inalazione in associazione a β2-agonisti ad azione prolungata (trattamento GINA step 4). * La risposta è definita come una diminuzione di 0.5 o più rispetto al basale del punteggio ACQ7. **Il controllo inadeguato è definito come un punteggio ACQ7 ≥1.5 al termine del periodo di run-in (Juniper et al, 2006). |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PHARMACOGENETIC:
Vers:v01
Date:2012/08/02
Title:A Multi-Center, Randomized, Double Blind, Placebo and Active-Controlled study with exploratory dose-ranging, to investigate the efficacy and safety of 16 weeks treatment with subcutaneous QGE031 in asthma patients not adequately controlled with high-dose inhaled corticosteroids and long acting β2-agonists
Objectives:N.A.
|
FARMACOGENETICA:
Vers:v01
Data:2012/08/02
Titolo:Studio multicentrico, randomizzato, in doppio cieco, controllato verso placebo e verso controllo attivo, con variazione esploratoria della dose, per valutare l’efficacia e la sicurezza del trattamento con QGE031 per via sottocutanea per 16 settimane in pazienti affetti da asma non adeguatamente controllato con corticosteroidi ad alte dosi per inalazione e β2-agonisti ad azione prolungata
Obiettivi:Vi informiamo che, anche se il protocollo non prevede uno sottostudio formalmente definito (ovvero strutturato con un protocollo specifico) ma una indagine complementare opzionale, la stessa viene classificata come sottostudio e quindi formalizzata nell’apposita sezione del CTA Form. Di seguito il dettaglio: • Indagine di farmacogenetica, a cui parteciperanno tutti i centri italiani coinvolti nello studio. L’eventuale non accettazione di tale sottostudio da parte del Comitato Etico e/o da parte del paziente non comprometterà in alcun modo la partecipazione allo studio principale.
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| E.3 | Principal inclusion criteria |
| Patients eligible for inclusion in this study have to fulfill all of the following criteria: For all patients (treatment arms A to G): 1. Signed written informed consent before any assessment is performed, including any adjustments to asthma medication at Visit 1. 2. Male and female adult patients aged ≥ 18 -≤75 years. 3. Patients with a diagnosis of asthma (according to GINA 2011 guidelines) for a period of at least 24 months prior to Visit 1. 4. A documented history of two asthma exacerbation(s) in the previous 24 months (with one episode occurring within the last 12 months). Both episodes of asthma exacerbation must have documented treatment with systemic corticosteroids for at least 3 days. 5. FEV1 of ≥ 40% and ≤ 80% of the predicted normal value for the patient, after withholding bronchodilators1. 6. Patients must demonstrate an increase in FEV1 of ≥12% and 200 mLs within 30 minutes after administration of 400 μg salbutamol/albuterol (or equivalent dose) prior to randomization2. • All patients must perform a reversibility test at Visit 101 If reversibility is not demonstrated at Visit 101: • Patients may be permitted to enter the study with historical evidence of reversibility that was performed according to ATS/ERS guidelines within the 12 months prior to Visit 12. If reversibility is not demonstrated at Visit 101 and historical evidence of reversibility is not available (or was not performed according to ATS/ERS guidelines): • The reversibility test may be repeated on one occasion at an unscheduled visit prior to randomization. 7. Body mass index (BMI) must be within the range of 18 to 35 kg/m2 inclusive. 8. Daily treatment with: • At Visit 1: Medium or high dose3 ICS plus a LABA (b.i.d.) for ≥ 3 months prior to Visit 1*, and • At Visit 201: High dose ICS3 plus a LABA (b.i.d.) that has been stable for at least 4 weeks prior to Visit 201. See Appendix 3 for definitions of “Medium” and “High” dose ICS (per GINA 2011) *Patients receiving medium dose ICS at Visit 1 should be up-titrated to high dose ICS at Visit 101; this dose should then remain stable during the 4 week run-in epoch prior to Visit 201. 9. Asthma which is not adequately controlled on current treatment, as demonstrated by an Asthma Control Questionnaire (ACQ) score of ≥ 1.5 (Juniper et al, 2006) and prior to randomization. 10. Patients should be allergic or atopic to a perennial aeroallergen (house dust mite [dermatophagoides pteronyssinus, dermatophagoides farina], cockroach, mold, cat/dog/animal dander), as diagnosed at Visit 101, prior to entry into the study, by either a skin prick test (≥ 3mm diameter above background) or a positive in-vitro specific IgE (e.g. RAST/CAP) test. 11. Compliance with Electronic Peak Flow/ ediary device4 during the screening epoch (at the investigators judgment the run-in epoch can be extended to collect 14 days of acceptable ePEF/ediary data). 1 Withholding of bronchodilators prior to spirometry: short-acting β2-agonist for ≥ 6 hrs and long-acting beta2-agonist (or fixed dose combinations of LABA and ICS) for ≥ 24 hours. 2 Where a patient is assessed as eligible based on historical evidence of reversibility, a copy of the original printed spirometry report with relevant spirometry tracings must be available as source documentation. 3 See Appendix 3 for GINA 2011 definition of medium and high dose ICS. 4 Compliance is defined as ≥ 85% of the ePEF assessments or and ≥ 85% of the morning or evening ediary entries completed correctly in the 14 days prior to the randomization. Thresholds will be automatically calculated by the ePEF/ediary device. |
| Consenso informato scritto firmato prima dell’effettuazione di qualsiasi valutazione, compreso qualsiasi aggiustamento del trattamento per l’asma alla Visita 1. Pazienti adulti di sesso maschile e femminile, di età ≥ 18 anni e ≤ 75 anni, con diagnosi di asma (secondo le linee guida GINA 2011) per un periodo di almeno 24 mesi prima della Visita 1. Anamnesi documentata positiva per due esacerbazioni asmatiche nei 24 mesi precedenti (con un episodio verificatosi nei 12 mesi precedenti). Per entrambi gli episodi devono avere documentato il trattamento con corticosteroidi sistemici per almeno 3 giorni. FEV1 ≥ 40% e ≤ 80% del valore normale predetto per il paziente, dopo la sospensione dei broncodilatatori. Pazienti che mostrano un aumento del FEV1 12% e 200 mLs nei 30 minuti successivi alla somministrazione di una dose di salbutamolo/albuterolo fino a 400 μg (o dose equivalente) prima della randomizzazione. Tutti i pazienti devono effettuare un test di reversibilità alla Visita 101 Se la reversibilità non è dimostrata alla Visita 101: Ai pazienti potrà essere consentito l’ingresso in studio con evidenza storica di reversibilità, verificata secondo le linee guida ATS/ERS nei 24 mesi precedenti la Visita 1. Se la reversibilità non è dimostrata alla Visita 101 e non è disponibile l’evidenza storica di reversibilità (o non è stata verificata secondo le linee guida ATS/ERS): Il test di reversibilità può essere ripetuto in una occasione ad una visita non programmata prima della randomizzazione. Indice di massa corporea (Body Mass Index – BMI) compreso nel range 18-35 kg/m2, estremi inclusi. Trattamento quotidiano con: Alla Visita 1: ICS a medie o alte dosi4 in associazione a LABA (b.i.d.) per ≥ 3 mesi prima della Visita 1* e Alla Visita 201: ICS ad alte dosi4 in associazione a LABA (b.i.d.) stabile da almeno 4 settimane prima della Visita 201 Asma non adeguatamente controllato dal trattamento in corso, come dimostrato da un punteggio ≥ 1.5 del questionario Asthma Control Questionnaire (ACQ) (Juniper et al, 2006) alla Visita 101 e prima della randomizzazione. Pazienti allergici o atopici ad un aeroallergene perenne (acari della polvere domestica, scarafaggi, muffa, squame di pelle di gatto/cane), come diagnosticato alla Visita 101, prima dell’ingresso nello studio, tramite prick test cutaneo o con test in vitro, specifico per IgE, positivo |
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| E.4 | Principal exclusion criteria |
| Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients. For all patients (treatment arms A to G): 1. Patients whose baseline serum IgE levels1 or body weight are outside the limits of the locally approved omalizumab dosing table. 1See Section 6.6.1.2 for definition of baseline serum IgE and refer to relevant locally approved omalizumab dosing table in the QGE031B2201 study manual. 2. Who have smoked or inhaled tobacco products within the 6 month period prior to Visit 1, or who have a smoking history of greater than 10 pack years (e.g.10 pack years = 1 pack /day x 10 yrs., or ½ pack/day x 20 yrs.). 3. Who have had an asthma attack/exacerbation requiring a short burst of systemic corticosteroids for at least 3 days within 6 weeks prior to Visit 1. 4. If patients experience an asthma attack/exacerbation requiring a short burst of systemic corticosteroids during screening and run-in they may be re screened 6 weeks after recovery from the exacerbation. 5. Who have had a respiratory tract infection or asthma worsening within 4 weeks prior to Visit 1. 6. If patients experience a respiratory tract infection or asthma worsening during screening and run-in they may be re screened 4 weeks after recovery from their respiratory tract infection. 7. Patients with a history of life-threatening asthma, including a history of significant hypercarbia (pCO2>45mmHg), prior intubation (endotracheal and NIPPV), respiratory arrest, or seizures as a result of asthma. 8. Patients with evidence upon visual inspection (laboratory culture is not required) of clinically significant oropharyngeal candidiasis during screening and run-in, with or without treatment. Patients may be re screened once their candidiasis has been treated and has resolved. 9. Patients with any chronic conditions affecting the upper respiratory tract (eg. chronic sinusitis) which in the opinion of the investigator may interfere with the study evaluation or optimal participation in the study. 10. Patients with a history of chronic lung diseases other than asthma, including (but not limited to) chronic obstructive pulmonary disease, bronchiectasis, sarcoidosis, interstitial lung disease, cystic fibrosis, and tuberculosis. 11. Patients with aspirin or other nonsteroidal anti-inflammatory drug related asthma. 12. Patients with elevated serum IgE levels for reasons other than atopic conditions (e.g., parasitic infections, hyperimmunoglobulin E syndrome, allergic bronchopulmonary aspergillosis). 13. Patients with uncontrolled diabetes Type I or uncontrolled diabetes Type II. 14. Patients who have a clinically significant laboratory abnormality at run-in, in the judgment of the investigator. 15. Patients who, either in the judgment of the investigator have a clinically significant condition such as (but not limited to) unstable ischemic heart disease, NYHA Class III/IV left ventricular failure arrhythmia, uncontrolled hypertension, cerebrovascular disease, neurodegenerative diseases, or other neurological disease, uncontrolled hypo- and hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic state, or ophthalmologic disorder or patients with a medical condition that might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study. 16. Patients with a history of myocardial infarction within the previous 12 months. 17. With a history or current treatment for hepatic disease including but not limited to acute or chronic hepatitis, cirrhosis or hepatic failure or an AST/ALT or INR of more than 1.5x ULN at run-in. 18. PLS SEE PROTOCOL |
| Livelli di IgE sieriche o peso corporeo al di fuori dei limiti riportati nelle tabelle di dosaggio di omalizumab approvate a livello locale. Pazienti che hanno fumato o inalato prodotti del tabacco nei 6 mesi precedenti la Visita 1, o che hanno un’anamnesi positiva per abitudine al fumo superiore a 10 pacchetti-anno. Crisi/esacerbazione asmatica che abbia richiesto un breve corso di corticosteroidi sistemici per almeno 3 giorni nelle 6 settimane precedenti la Visita 1; nel caso in cui essa si verifichi durante il periodo di screening o di run-in, i pazienti possono essere sottoposti nuovamente a screening 6 settimane dopo la risoluzione dell’esacerbazione Infezione dell’apparato respiratorio o peggioramento dell’asma nelle 4 settimane precedenti la Visita 1; nel caso in cui essa si verifichi durante il periodo di screening o di run-in i pazienti possono essere sottoposti nuovamente a screening 4 settimane dopo la risoluzione dell’infezione. Anamnesi positiva per asma che abbia messo in pericolo di vita, compresa ipercapnia significativa (pCO2>45mmHg), precedente intubazione (endotracheale e NIPPV), arresto respiratorio o convulsioni come esito dell’asma. Anamnesi positiva per schistosomiasi, o esame delle feci positivo per uova o parassiti (al run-in), o viaggi in un’area endemica per schistosomiasi o infezione da elminti (nei 6 mesi precedenti la Visita 1). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Responder rate compared to placebo |
| Tassi di risposta (Responder rate) confrontato al placebo |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline, Week 16 |
| Basale, Settimana 16 |
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| E.5.2 | Secondary end point(s) |
| 1) Responder rate compared to omalizumab 2) ACQ score 3) Change from baseline in ACQ score less than -1.1 4) AQLQ score |
| 1) Tasso di risposta (Responder rate confrontato all omalizumab 2) ACQ punteggio 3) Cambiamenti rispetto al basale nel punteggio dell ACQ -1.1 4) AQLQ punteggio |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 1) Baseline, Week 16 2) Baseline, Week 4, Week 8, Week 12, Week 16 and Week 28 3) Baseline, Week 16 |
| 1) Basale, Settimana 16 2) Basale, Settimana 4, Settimana 8, Settimana 12, Settimana 16 e Settimana 28 3) Basale, Settimana 16 |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| - Stesso farmaco ad altro dosaggio |
| - same IMP used at different dosage |
|
| E.8.2.4 | Number of treatment arms in the trial | 14 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Canada |
| Israel |
| Russian Federation |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| LVLS 12/MAY/2014 |
| LVLS 12/05/2014 |
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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 | 0 |
| E.8.9.1 | In the Member State concerned months | 16 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 19 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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