| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| T2-High and T2-Low severe asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Sub-types of severe asthma |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10005503 |
| E.1.2 | Term | Blood eosinophils |
| E.1.2 | System Organ Class | 100000004848 |
|
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049868 |
| E.1.2 | Term | Asthma exacerbation prophylaxis |
| E.1.2 | System Organ Class | 100000004865 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068462 |
| E.1.2 | Term | Eosinophilic 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 |
(i) Identify patients with severe, exacerbation prone asthma in UK specialist severe asthma centres.
(ii) Stratify patients using blood eosinophil levels into T2-HIGH/T2-LOW phenotypes.
(iii) Conduct two 58 week, phase II, randomised double blind placebo controlled exacerbation trials (RDBPCT) of oral dexpramipexole (T2-HIGH) and oral doxycycline (T2-LOW).
|
|
| E.2.2 | Secondary objectives of the trial |
Patients in both T2 HIGH/LOW treatment cohort randomised controlled trials will be assessed for change from baseline at 3, 6, 9 and 12 months for:
• Juniper six-point Asthma Control Score (ACQ-6, a questionnaire to determine how well controlled asthma symptoms are through current medication)
• Asthma Quality of Life Questionnaire (AQLQ S, a quality of life questionnaire specifically focused on asthma symptoms)
• Asthma follow up and lung function tests
• Blood eosinophil levels (blood results which determines which asthma sub-type the participant has and whether this is affected by treatment)
• Blood neutrophil levels (blood cells which help fight off infection and can be an indication of infection)
• Percentage sputum eosinophils (see blood eosinophil levels)
• Percentage and total sputum neutrophils (see blood neutrophil levels)
• Sino-nasal Outcome Test (SNOT-22, a questionnaire to determine nasal issues in participants)
• EuroQOL-5D-5L Questionnaire (baseline and penultimate vi |
|
| 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 |
CompEx Sub-Study. Date and version are the same as the master protocol.
The CompEx sub-study uses a statistical algorithm to evaluate daily trends in peak flow, broncho-dilator reliever use and symptoms (PRS) so that 'sub clinical' exacerbation events can be identified. The impact of trial interventions upon CompEx defined exacerbations will be evaluated as a mechanistic sub-study analysis. |
|
| E.3 | Principal inclusion criteria |
Screening Eligibility Criteria:
1. Exacerbation prone (≥2 record confirmed severe exacerbations).
AND
2. Severe asthma (defined by a hospital specialist or severe asthma Multi-Disciplinary Team (MDT) (or non-English equivalent), according to the ATS/ERS consensus criterion.
3. Male and female patients aged ≥18 years and <80 years of age.
4. Capable of giving written informed consent.
5. Willing and able to comply with study protocol requirements.
Overarching T2-High and T2-Low criteria:
1. Male and female patients aged ≥18 years and <80 years of age.
2. Capable of giving written informed consent.
3. Diagnosis of severe asthma defined by a specialist Multi Disciplinary Team (MDT; or non-English equivalent) as per the ATS/ERS severe asthma guidelines (participants may be included with a lower dose of current ICS than endorsed by the ATS/ERS criteria at the discretion of the Investigator if previous high ICS dose had led to side effects.
4. Stable asthma therapy for at least 1 month before screening.
5. History of ‘exacerbation prone asthma’ defined as ≥ two record confirmed severe exacerbations within 12 months of MDT initial pre-screening review. Defined as worsening asthma symptoms necessitating one or more of the following:
(i) Use of systemic steroids (tablets, suspension or injection) or an increase in systemic steroids (for those on stable maintenance steroids) for ≥3 days.
(ii) A new prescription of antibiotics because of worsening asthma/airways disease for ≥3 days.
(iii) Both (i) and (ii)
(iv) An admission to hospital because of asthma, or an emergency department requiring systemic steroids (tablets, suspension or injection) or antibiotics.
[If any of the above are identified >7 days apart, these would be defined as separate/new exacerbation events].
7. Willing and able to comply with study protocol requirements. |
|
| E.4 | Principal exclusion criteria |
1.Current or within the last 6 months (or maximum relevant wash out period, whichever is longer) participation in an investigational drug or device trial at the time of screening.
2.Patients who are planning to take more than a 21 day consecutive holiday during the trial period.
3.Have received treatment with biologics such as omalizumab, mepolizumab, reslizumab, benralizumab or dupilumab within four months or five half-lives (whichever is longer) prior to screening.
4.Recent treatment with bronchial thermoplasty, defined as completion of all thermoplasty treatment sessions within 6 months of screening.
5.Patients who have been hospitalised or required a new prescription of high-dose (≥10mg prednisolone/day) oral corticosteroid (OCS) therapy within 4 weeks of the screening visit.
6.Recent (within 4 weeks of screening) or current lower respiratory tract infection requiring antibiotics (this excludes antibiotics taken for other purposes other than asthma exacerbations).
7.Acute illness other than asthma which, in the investigator’s opinion, may compromise the well-being of the patient or study endpoint assessments at the start of the study.
8.History of unstable or severe cardiac, hepatic, or renal disease, or other medically significant illness which the investigator believes would be a contraindication to study participation.
9.Current smoking within the past year or a prior smoking history of ≥15 pack-years (including e cigarettes).
10.Patients with a body mass index (BMI) ≤ 17 or ≥ 45 kg/m2.
11.History of human immunodeficiency virus (HIV) or hepatitis B or C.
12.History of malignancy of any organ system (other than localised basal cell carcinoma of the skin), treated or untreated, currently or within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
13.History (or suspected history) of alcohol or substance abuse as defined by the Diagnostic and Statistical manual of mental Disorders (5th edition) substance use disorders guidelines within two years of screening.
14.If female, is pregnant or lactating or intends to become pregnant during the study period where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
15.Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using 2 highly effective forms of contraception during dosing of study treatment and for a minimum of 1 month after their last treatment.
16.Males unwilling to use effective methods of contraception during dosing of trial treatment and for at least 3 months after their last dose.
17.Patients with clinically significant laboratory abnormalities (not associated with the study indication) at screening including (but not limited to):
• AST or ALT>2.0 x upper limit of normal (ULN) or total bilirubin >1.3 X ULN at screening (with the exception of patients with Gilberts syndrome where suitability for inclusion will be left to the discretion of the local investigator).
• Estimated Glomerular Filtration Rate (eGFR) by the MDRD equation <60 mL/minute/1.73 m2 at screening.
Additional Exclusion criteria for T2-LOW only:
1.Patients who are unwilling to stay out of the sun or wear sun block.
2.History of myasthenia gravis or systemic lupus erythematosus.
3.Prior history of ‘severe’ (as defined by the patient), gastrointestinal intolerance to tetracyclines.
4.Documented drug allergy to/ or concurrent use of tetracyclines such as doxycycline and methoxyflurane or prior anaphylaxis due to tetracyclines.
5.Current treatment with anticoagulants such as warfarin.
6.Current treatment with long term (defined as ≥3 months) macrolides for asthma.
7.Current use of any prophylactic (defined as ≥3 months) antibiotic for asthma or any other condition.
8.Recent use of any prophylactic antibiotic (defined as ≥3 months), within 3 months of study entry.
9.Current or active exfoliative dermatitis.
10.Concurrent use of retinoids due to the increased risk of benign intra-cranial hypertension.
11.Participant is unwilling to take the trial medication as it contains beef and pork gelatine is not Halal or Kosher certified or vegetarian/vegan.
Additional Exclusion Criteria for T2-HIGH only:
1.Treatment with pramipexole (Mirapex®) within 4 weeks of baseline.
2.Patients where untreated infection with helminthic parasites is suspected by the clinician.
3.Concomitant use of drugs known to be associated with significant neutropenia.
4.Absolute neutrophil count < 2.0 x 10^9/L at screening, or any documented history of absolute neutrophil count < 2.0 x 10^9/L on an NHS electronic pathology system available to the local investigator within two years of screening.
5.Prior history of neutropenic illness, such as neutropenic sepsis.
6.History of long QT syndrome or whose QTcF interval (Fridericia's) is prolonged >450 msec at screening or baseline. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Annual rate of severe exacerbations defined as one or more of:
(i) Use of systemic steroids (tablets, suspension or injection) or an increase in systemic steroids (if stable maintenance) for ≥3 days
(ii) A new prescription of antibiotics for worsening asthma/airways disease for ≥3 days
(iii) Both (i) and (ii)
(iv) An admission to hospital because of asthma, or an emergency department requiring systemic steroids or antibiotics |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The end point of this primary outcome measure is 13.5 months after the patient has been registered to the T2-High or T2-Low cohort randomised controlled trial. |
|
| E.5.2 | Secondary end point(s) |
1. Juniper six-point Asthma Control Score (ACQ-6 questionnaire)
2. Asthma Quality of Life Questionnaire (AQLQ S)
3. Pre and Post bronchodilator FEV1 and FEV1/FVC
4. Absolute blood eosinophil levels (x10^9/L) and neutrophil levels (x10^9/L)
5. Percentage sputum eosinophils
6. Fractional exhaled nitric oxide levels (FeNO)
7. Percentage and total sputum neutrophils
8. Sino-nasal Outcome Test (SNOT-22)
9. EuroQOL-5D-5L Questionnaire
10. Work productivity and Activity Impairment (WPAI) Questionnaire
11. Adverse events
12. Patient treatment adherence and compliance
13. Time to first severe exacerbation and annual rate of severe exacerbation events defined by the use of systemic steroids, antibiotics or both. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The end point of the secondary outcome measures is 13.5 months after the participant has been registered to the T2-High or T2-Low cohort randomised controlled trial. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 15 |
| 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 | 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
|
| The BEAT-SA platform trial, which this Master protocol describes, will be regarded as closed once the last patient has undertaken their final visit and data collection is complete for the last intervention (treatment cohort) being tested in the platform. However, final BEAT-SA platform trial closure will be when all final sample analysis has been completed. |
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | 29 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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