E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
asthma with allergic fungal airway disease (AFAD). |
|
E.1.1.1 | Medical condition in easily understood language |
asthma with allergic fungal airway disease (AFAD). |
|
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 | LLT |
E.1.2 | Classification code | 10001705 |
E.1.2 | Term | Allergic asthma |
E.1.2 | System Organ Class | 100000004855 |
|
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 3 doses of GSK3772847 (administered every 4 weeks)
compared with placebo in moderate to severe asthma participants with allergic fungal airway disease (AFAD) who are currently on Standard of Care (SoC) |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the serum pharmacokinetics (PK) of 3 doses of GSK3772847 (administered every 4 weeks) in moderate to severe asthma participants with AFAD
To evaluate the pharmacodynamics (PD) of GSK3772847 in moderate to severe asthma participants with AFAD
To evaluate the levels and specificity of any anti-drug antibodies formed following dosing with GSK3772847
To evaluate the health status of moderate to severe asthma participants with AFAD currently on SoC, and who are treated with GSK3772847 compared with placebo-treated participants
To evaluate the effect on lung function of moderate to severe asthma participants with AFAD currently on SoC, treated with GSK3772847
compared with placebo
To evaluate the safety and tolerability of GSK3772847 compared with placebo in
moderate to severe asthma participants with AFAD |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be at least 18 years of age inclusive, at the time of signing the
informed consent.
Type of Participant and Disease Characteristics
2. Documented history of physician diagnosed moderate or severe asthma for ≥12 months based on [GINA, 2017] Guidelines and treated with inhaled corticosteroid (ICS) and long-acting beta-2-agonist (LABA) for at least 4 months (≥500 µg/day fluticasone propionate or equivalent as defined in the [GINA, 2017] guidelines.
Additional therapy: with a leukotriene receptor antagonist (LTRA), with
anticholinergics, with anti-fungal medication is permissible.
3. Pre-bronchodilator FEV1 35-79% of predicted value for participant inclusive
4. FeNO ≥ 25ppb at Screening (Visit 1)
5. ACQ-5 score ≥1.5 at Screening (Visit 1)
6. Blood eosinophils ≥ 300 cells/microliter at Screening (Visit 1)
7. Evidence of allergic fungal airway disease:
Fungal sensitisation to at least one of the following fungi: Aspergillus fumigatus,
Penicillium chrysogenum (notatum) at screening measured by serum-specific IgE
test. Documented fungal sensitisation either by serum-specific IgE or skin prick test is also acceptable.
A history of exacerbations (at least 1 severe exacerbation (defined as requiring a
minimum of 3 days of high-dose oral corticosteroids for asthma symptoms) in the
previous 12 months.
Weight
8. Body weight within 50-150 kg (inclusive).
Sex
9. Male and female
a. Female participants:
A female participant is eligible to participate if she is not pregnant (as defined in the protocol), not breastfeeding, and at least one of the following conditions applies:
i. Not a woman of childbearing potential (WOCBP) as defined in the protocol
OR
ii. A WOCBP who agrees to follow the contraceptive guidance in the protocol
during the treatment period and for at least 16 weeks after the last dose of
study treatment.
Informed Consent
10. Capable of giving signed informed consent as described in the protocol which
includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. |
|
E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Historical diagnosis of cystic fibrosis
2. Concurrent respiratory diseases: Presence of a known pre-existing, clinically
important respiratory conditions (e.g. pneumonia, pneumothorax, atelectasis
segmental or larger, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, or other respiratory abnormalities) other than asthma or AFAD
3. Has a history of chronic or recurrent non-pulmonary infectious disease or ongoing non-pulmonary infection including, but not limited to, chronic renal infection, chronic chest infection, recurrent urinary tract infection (eg, recurrent pyelonephritis, chronic non-remitting cystitis), or open, draining skin wound or an ulcer
4. Serious infection within 8 weeks of enrolment, including, but not limited to hepatitis, pneumonia, sepsis, or pyelonephritis; or has been hospitalised for an infection; or has been treated with IV antibiotics for an infection, within 8 weeks prior to the first administration of study drug
5. Evidence of poorly controlled chronic medical conditions other than asthma, e.g., patients with known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, cardiovascular, gastrointestinal, hepatic, and haematological or any other system abnormalities that are uncontrolled with standard treatment.
6. Cardiovascular disease: Clinically significant organic heart disease (e.g. CAD,
NYHA Class III/IV heart failure).
7. Participants with a diagnosis of malignancy or in the process of investigation for a malignancy. Participants with carcinoma that have not been in complete remission for at least 5 years. Participants who have had carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded based on the 5 year waiting period if the patient has been considered cured by treatment..
8. Eosinophilic diseases: Other conditions that could lead to elevated eosinophils such as hypereosinophilic syndromes. Participants with a known, pre-existing parasitic infestation within 6 months prior to Screening (Visit 1).
Prior/Concomitant Therapy
9. Use of the medications listed in Table 2 of the protocol in exclusion criteria section, is not permitted within the defined time intervals prior to Screening (Visit 1) and throughout the study. Potential participants should not be washed out of their medication solely for the purpose on enrolling in the trial.
Diagnostic assessments
10. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
11. A known immunodeficiency such as human immunodeficiency virus infection.
12. Hypersensitivity: significant allergies to humanised monoclonal antibodies or
biologic or to any components of the formulation used in this study.
13. Clinically significant multiple or severe drug allergies, intolerance to topical
corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin a dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).
14. Clinically significant abnormality on 12-lead ECG assessment at screening (Visit 1).
Site investigators will be provided with ECG over-read conducted by a centralised
independent cardiologist, to assist in evaluation of participant eligibility. For this
study, an abnormal and clinically significant ECG that would preclude a participant from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the findings in Table 3 of the protocol in exclusion criteria section).
Other Exclusions
15. Smoking history: current smokers or former smokers with a smoking history ≥10 pack years (pack years = number of cigarettes smoked per day / 20 * number of years smoked).
16. History of alcohol or illegal substance abuse within 2 years prior to Screening
(Visit1).
17. Participants at risk of non-compliance, or unable to comply with the study
procedures. Participants who are unable to follow study instructions such as visit
schedule and paper diary completion. Participants who have known evidence of lack of adherence to controller medication and/or ability to follow physician’s
recommendations. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
•Change from baseline (Week 0) in blood eosinophils over time
•Change from baseline (Week 0) in fractional exhaled nitric oxide (FeNO) over time
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
•Serum concentrations of GSK3772847
•Serum levels of free and total soluble ST2
•Incidence and titres of serum anti-GSK3772847 antibodies post dosing
•Change from baseline (Week 0) in Asthma Control Questionnaire -5 (ACQ-5) absolute score
•Change from baseline (Week 0) in Asthma Quality of Life Questionnaire (AQLQ) total and domain scores
•Proportion of responders to ACQ-5. A responder to ACQ-5 will be defined as a subject who has a decrease from baseline in ACQ-5 score of 0.5 or more.
•Proportion of responders to AQLQ. A responder to AQLQ will be defined as a subject who has an increase from baseline in AQLQ score of 0.5 or more.
•Change from baseline (Week 0) in spirometry parameters
•Safety and tolerability [Treatment emergent adverse events (AE); Clinical Laboratory safety data; Vital signs (blood pressure, heart rate, body temperature); 12–Lead Electrocardiogram (ECG) monitoring; 24-hour Holter monitoring]
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Serum concentrations of GSK3772847 at weeks 0 to 24. •Serum levels of free and total soluble ST2 at weeks 0-24. •Incidence and titres of serum anti-GSK3772847 antibodies post dosing at weeks 0-24. •Change from baseline (Week 0) in Asthma Control Questionnaire -5 (ACQ-5) absolute score at Weeks 2, 4, 8 and 12 •Change from baseline (Week 0) in Asthma Quality of Life Questionnaire (AQLQ) total and domain scores at Weeks 2, 4, 8 and 12 •Proportion of responders to ACQ-5. A responder to ACQ-5 will be defined as a subject who has a decrease from baseline in ACQ-5 score of 0.5 or more at Weeks 2, 4, 8 and 12 •Proportion of responders to AQLQ. A responder to AQLQ will be defined as a subject who has an increase from baseline in AQLQ score of 0.5 or more at Weeks 2, 4, 8 and 12.Refer protocol. |
|
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
sponsor open to selected study team members for interim analysis |
|
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |