| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe uncontrolled asthma with an eosinophilic phenotype |
| Severe uncontrolled asthma with an eosinophilic phenotype |
|
| E.1.1.1 | Medical condition in easily understood language |
| Severe asthma |
| Severe asthma |
|
| 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 | 20.0 |
| 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 |
|
| 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 GSK3511294 100 mg (SC) every 26 weeks
versus placebo in participants with severe uncontrolled asthma with an
eosinophilic phenotype on top of existing asthma therapy |
| Valutare l’efficacia di GSK3511294 100 mg (SC) somministrato ogni 26 settimane rispetto al placebo in partecipanti affetti da asma grave non controllata con un fenotipo eosinofilo in aggiunta alla terapia per l’asma esistente |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate GSK3511294 100 mg (SC) every 26 weeks versus placebo on
health-related quality of life (HRQoL) and additional efficacy
assessments on top of existing asthma therapy |
| Valutare GSK3511294 100 mg (SC) somministrato ogni 26 settimane rispetto al placebo sulla qualità della vita legata alla salute (HRQoL) e ulteriori valutazioni di efficacia in aggiunta alla terapia per l’asma esistente |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age: Adults and adolescents =12 years of age, at the time of signing
the informed consent/assent. [For countries where local regulations or
the regulatory status of study medication permit enrolment of adults
only, participants recruited will be =18 years of age]
2. Asthma: Participants must have a documented physician diagnosis of
asthma for =2 years that meets the National Heart, Lung, and Blood
Institute guidelines [NHLBI, 2007] or GINA guidelines [GINA, 2020]
AND
a) Eosinophilic phenotype: Have, or with high likelihood of having,
asthma with an eosinophilic phenotype as per Randomisation Criteria 1
and 2 (see Section 5.3 of the protocol)
AND
b) Exacerbation history: Have previously confirmed history of =2
exacerbations requiring treatment with systemic corticosteroids ( CS)
(IM, IV, or oral), in the 12 months prior to Visit 1, despite the use of
medium to high-dose inhaled corticosteroids (ICS) (see criterion 4). For
participants receiving maintenance CS, the CS treatment for the
exacerbations must have been a two-fold dose increase or greater.
3. Airflow obstruction: Persistent airflow obstruction as indicated by:
a) For participants =18 years of age at Visit 1, a pre-bronchodilator FEV1
<80% predicted (NHANES III) recorded at Visit 1
b) For participants 12-17 years of age at Visit 1:
• A pre-bronchodilator FEV1 <90% predicted (NHANES III) recorded at
Visit 1 OR
• FEV1:Forced Vital Capacity (FVC) ratio <0.8 recorded at Visit 1
4. Inhaled Corticosteroid: A well-documented requirement for regular
treatment with medium to high dose ICS (in the 12 months prior to Visit
1 with or without maintenance OCS). The maintenance ICS dose must be
=440 mcg FP HFA daily, or clinically comparable [GINA, 2020; see
Appendix 10 of the protocol]. Participants who are treated with medium
dose ICS will also need to be treated with Long-acting beta-agonist
(LABA) to qualify for inclusion.
5. Additional Controller Medication: Current treatment with at least one
additional controller medication, besides ICS, for at least 3 months [e.g.,
LABA, long-acting muscarinic antagonist (LAMA), leukotriene receptor
antagonist (LTRA), or theophylline].
6. Male or eligible female.
• A female participant is eligible to participate if she is not pregnant or
breastfeeding, and one of the following conditions applies:
o Is a woman of non-childbearing potential (WONCBP) as defined in
Section 10.4.1 of the protocol
OR
Is a woman of childbearing potential (WOCBP) and using a contraceptive
method that is highly effective, with a failure rate of <1%, as described
in Section 10.4.2 of the protocol from at least 14 days prior to the first
dose of study intervention until at least 30 weeks after the last
administered dose of study intervention.
•A WOCBP must have a negative highly sensitive serum pregnancy test
at screening Visit 1 and a negative highly sensitive urine pregnancy test
within 24 hours before the first dose of study intervention. Additional
requirements for pregnancy testing during and after study intervention
are located in Section 8.3.5. of the protocol
•Contraceptive use by women should be consistent with local
regulations regarding the methods of contraception for those
participating in clinical studies.
• The investigator should evaluate the potential for contraceptive
method failure (e.g., noncompliance, recently initiated in relationship to
the first dose of study intervention).
• The investigator is responsible for review of medical history, menstrual
history, and recent sexual activity to decrease the risk for inclusion of a
woman with an early undetected pregnancy. |
1. Età: adulti e adolescenti di età =12 anni al momento della firma del consenso/assenso informato. [Per i paesi in cui le normative locali o lo stato regolatorio del farmaco dello studio consentono/consente l’arruolamento solo di adulti, i partecipanti reclutati saranno di età =18 anni]
2. Asma: i partecipanti devono presentare una diagnosi di asma documentata da un medico per =2 anni che soddisfi le linee guida del National Heart, Lung, and Blood Institute [NHLBI, 2007] o le linee guida GINA [GINA, 2020] E
a) Fenotipo eosinofilo: avere, o presentare un’elevata probabilità di avere, asma con un fenotipo eosinofilo come da criteri di randomizzazione 1 e 2 (vedere sezione 5.3 del protocollo)
E
b) Anamnesi di riacutizzazioni: avere un’anamnesi precedentemente confermata di =2 riacutizzazioni che richiedono un trattamento con corticosteroidi sistemici (CS) (IM, EV o orali), nei 12 mesi precedenti la Visita 1, nonostante l’uso di corticosteroidi inalatori (ICS) da medio ad alto dosaggio (vedere criterio 4). Per i partecipanti che ricevono CS di mantenimento, il trattamento con CS delle riacutizzazioni deve essere costituito da una dose raddoppiata o più alta.
3. Ostruzione del flusso d’aria: ostruzione persistente del flusso d’aria, come indicato da:
a) un volume espiratorio forzato in un secondo (FEV1) pre-broncodilatatore previsto <80% (NHANES III) registrato alla Visita 1, per i partecipanti di età =18 anni alla Visita 1
b) per i partecipanti di età compresa tra i 12 e i 17 anni alla Visita 1:
• un FEV1 pre-broncodilatatore previsto <90% (NHANES III) registrato alla
Visita 1 OPPURE
• un rapporto FEV1:capacità vitale forzata (FVC) <0,8 registrato alla Visita 1
4. Corticosteroidi inalatori: un requisito ben documentato per il trattamento regolare con ICS da medio ad alto dosaggio (nei 12 mesi precedenti la Visita 1 con o senza OCS di mantenimento). La dose di ICS di mantenimento deve essere =440 mcg FP HFA al giorno o prodotto clinicamente comparabile [GINA, 2020; vedere appendice 10 del protocollo]. I partecipanti trattati con ICS a dosaggio medio dovranno essere trattati con un beta-agonista a lunga durata d’azione (LABA) per essere idonei all’inclusione.
5. Farmaco di controllo aggiuntivo: trattamento attuale con almeno un farmaco di controllo aggiuntivo, oltre a ICS, per almeno 3 mesi [ad es., LABA, antagonista muscarinico a lunga durata d’azione (LAMA), antagonista dei recettori dei leucotrienici (LTRA) o teofillina]. |
|
| E.4 | Principal exclusion criteria |
1. Concurrent Respiratory Disease: Presence of a known pre-existing,
clinically important lung condition other than asthma. This includes (but
is not limited to) current infection, bronchiectasis, pulmonary fibrosis,
bronchopulmonary aspergillosis, or diagnoses of emphysema or chronic
bronchitis (chronic obstructive pulmonary disease other than asthma) or
a history of lung cancer.
2. Eosinophilic Diseases: Participants with other conditions that could
lead to elevated eosinophils such as hyper-eosinophilic syndromes
including (but not limited to) Eosinophilic Granulomatosis with
Eosinophilic Esophagitis.
3. Parasitic infection: Participants with a known, pre-existing parasitic
infestation within 6 months prior to Visit 1.
4. Immunodeficiency: A known immunodeficiency (e.g. human
immunodeficiency virus – HIV), other than that explained by the use of
CSs taken as therapy for asthma.
5. Malignancy: A current malignancy or previous history of cancer in
remission for less than 12 months prior to screening (Participants that
had localised carcinoma of the skin which was resected for cure will not
be excluded).
6. Liver Disease: Cirrhosis or current unstable liver or biliary disease per
investigator assessment defined by the presence of ascites,
encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or
gastric varices, persistent jaundice.
NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert's
syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C)
are acceptable if participant otherwise meets entry criteria.
7. Other Concurrent Medical Conditions: Participants who have known,
preexisting, clinically significant cardiac, endocrine, autoimmune,
metabolic, neurological, renal, gastrointestinal, hepatic, haematological
or any other system abnormalities that are uncontrolled with standard
treatment.
8. Vasculitis: Participants with current diagnosis of vasculitis.
Participants with high clinical suspicion of vasculitis at screening will be
evaluated and current vasculitis must be excluded prior to enrolment.
9. COVID-19: Participants that, according to the investigator's medical
judgment, are likely to have active COVID-19 infection should be
excluded. Participants with known COVID-19 positive contacts within the
past 14 days should be excluded for at least 14 days following the
exposure during which the participant should remain symptom-free.
10. Monoclonal antibodies targeting IL-5/5R: Participants who have
received mepolizumab (Nucala), reslizumab (Cinqair/Cinqaero), or
benralizumab (Fasenra) within 12 months prior to Visit 1 or who have a
previous documented failure with anti-IL-5/5R therapy.
11. Other mAbs in the treatment of asthma: Participants who have
received omalizumab (Xolair) or dupilumab (Dupixent) within 130 days
prior to Visit 1.
12. Other mAbs not used for the treatment of asthma: Participants who
have received any mAb within 5 half-lives of Visit 1.
13. Investigational Medications: Participants who have received
treatment with an investigational drug within the past 30 days or five
terminal phase half-lives of the drug whichever is longer, prior to Visit 1
(this also includes investigational formulations of marketed products).
14. Previous participation: Previously participated in any study with
mepolizumab, reslizumab, or benralizumab and received study
intervention (including placebo) within 12 months prior to Visit 1.
15. ECG Assessment: QTcF =450 msec or QTcF =480 msec for
participants with Bundle Branch Block at screening Visit 1.
16. Smoking history: Current smokers or former smokers with a smoking
history of =10 pack years (number of pack years = (number of cigarettes
per day / 20) x number of years smoked). A former smoker is defined as
a participant who quit smoking at least 6 months prior to Visit 1. |
1. Malattia respiratoria concomitante: presenza di una condizione polmonare clinicamente importante preesistente e nota diversa dall’asma. Ciò include (ma non è limitato a) infezione in corso, bronchiectasia, fibrosi polmonare, aspergillosi broncopolmonare o diagnosi di enfisema o bronchite cronica (malattia polmonare ostruttiva cronica diversa dall’asma) o anamnesi di carcinoma polmonare.
2. Malattie eosinofili: partecipanti con altre condizioni che potrebbero portare ad elevati eosinofili, come le sindromi ipereosinofiliche incluse (ma non solo) granulomatosi eosinofila con poliangioite (EGPA, precedentemente nota come sindrome di Churg-Strauss) o esofagite eosinofila.
3. Infezione parassitaria: partecipanti con infestazione parassitaria nota e preesistente nei 6 mesi precedenti la Visita 1.
4. Immunodeficienza: immunodeficienza nota (ad es. virus dell’immunodeficienza umana - HIV) diversa da quella dovuta all’uso di CS assunti come terapia per l’asma.
5. Tumore maligno: partecipanti con neoplasia maligna attuale o precedente anamnesi di tumore in remissione da meno di 12 mesi prima dello screening (non saranno esclusi i partecipanti con carcinoma cutaneo localizzato che è stato resecato come cura).
6. Malattia epatica: cirrosi o attuale malattia epatica o biliare instabile secondo la valutazione dello sperimentatore, definita dalla presenza di ascite, encefalopatia, coagulopatia, ipoalbuminemia, varici esofagee o gastriche, ittero persistente.
NOTA: una malattia epatica cronica stabile non cirrotica (inclusa la sindrome di Gilbert, calcoli biliari asintomatici ed epatite B o C cronica stabile) è accettabile se il partecipante soddisfa i criteri di arruolamento.
7. Altre condizioni mediche concomitanti: partecipanti che presentano anomalie cardiache, endocrine, autoimmuni, metaboliche, neurologiche, renali, gastrointestinali, epatiche, ematologiche o di qualsiasi altro tipo, note, preesistenti, clinicamente significative e non controllate da un trattamento
standard.
8. Vasculite: partecipanti con diagnosi attuale di vasculite. I partecipanti con elevato sospetto clinico di vasculite allo screening saranno valutati e la presenza di vasculite dovrà essere esclusa prima dell’arruolamento.
9. COVID-19: i partecipanti che, secondo il giudizio medico dello sperimentatore, potrebbero presentare un’infezione attiva da COVID-19 dovranno essere esclusi. I partecipanti che hanno avuto contatti con persone positive alla COVID-19 negli ultimi 14 giorni devono essere esclusi per almeno 14 giorni dopo l’esposizione, durante questo periodo i partecipanti non devono manifestare sintomi.
10. Anticorpi monoclonali contro IL-5/5R: partecipanti che hanno ricevuto mepolizumab (Nucala), reslizumab (Cinqair/Cinqaero) o benralizumab (Fasenra) nei 12 mesi precedenti la Visita 1 o che hanno un precedente fallimento documentato con la terapia anti-IL-5/5R.
11. Altri mAb utilizzati nel trattamento dell’asma: partecipanti che hanno ricevuto omalizumab (Xolair) o dupilumab (Dupixent) nei 130 giorni precedenti la Visita 1.
12. Altri mAb non utilizzati per il trattamento dell’asma: partecipanti che hanno ricevuto un mAb nelle 5 emivite dalla Visita 1.
13. Farmaci sperimentali: partecipanti che hanno ricevuto un trattamento con farmaco sperimentale negli ultimi 30 giorni o cinque emivite della fase terminale del farmaco, a seconda di quale sia il periodo più lungo, prima della Visita 1
(si includono anche formulazioni sperimentali di prodotti commercializzati).
14. Partecipazione precedente: precedente partecipazione a qualsiasi studio con mepolizumab, reslizumab o benralizumab, con somministrazione dell’intervento dello studio (compreso il placebo) nei 12 mesi precedenti la Visita 1.
15. Valutazione ECG: QTcF =450 msec o QTcF =480 msec per i partecipanti con blocco di branca alla Visita 1 di screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Annualised rate of clinically significant exacerbations over 52 weeks |
| Tasso annualizzato di riacutizzazioni clinicamente significative nell’arco di 52 settimane |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 0 through Week 52 |
| Dalla Settimana 0 alla Settimana 52 |
|
| E.5.2 | Secondary end point(s) |
1.Change from baseline in St. George's Respiratory Questionnaire
(SGRQ) total score at Week 52
2.Change from baseline in Asthma Control Questionnaire-5 (ACQ-5)
score at Week 52
3.Change from baseline in pre-bronchodilator forced expiratory volume
in one second (FEV1) at Week 52
4.Annualised rate of exacerbations requiring hospitalisation and/or
Emergency Department (ED) visit over 52 weeks |
1. Variazione rispetto al basale nel punteggio totale del questionario del St. George’s Hospital sui disturbi respiratori (SGRQ) alla Settimana 52
2. Variazione rispetto al basale nel punteggio del questionario sul controllo dell’asma a 5 voci (ACQ-5) alla Settimana 52
3. Variazione rispetto al basale nel FEV1 pre-broncodilatatore alla Settimana 52
4. Tasso annualizzato di riacutizzazioni che richiedono un ricovero e/o visite in pronto soccorso nell’arco di 52 settimane |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Basale (Settimana 0) e Settimana 52
2. Basale (Settimana 0) e Settimana 52
3. Basale (Settimana 0) e Settimana 52
4. Dalla Settimana 0 alla Settimana 52 |
1.Baseline ( Week 0) and Week 52
2.Baseline ( Week 0) and Week 52
3.Baseline ( Week 0) and Week 52
4.Week 0 through Week 52 |
|
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| 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 | Information not present in EudraCT |
| 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 |
| Canada |
| Japan |
| United States |
| France |
| Italy |
| Poland |
| Spain |
| Czechia |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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