Primary

The main research objective is to determine, in 6–14 year old children with asthma, uncontrolled on low-dose ICS, whether their control can be improved by adding in a long-acting beta-2 agonist (salmeterol) or a leukotriene receptor antagonist (montelukast) as measured by a reduced number of exacerbations requiring treatment with oral corticosteroids over the 48 week study period.

Primary Objective

To determine, in 6–14 year old children with asthma uncontrolled on low-dose ICS, whether their control can be improved by adding in a long-acting beta2 agonist (salmeterol) or a leukotriene receptor antagonist (montelukast) as measured by a reduced number of exacerbations requiring treatment with oral corticosteroids over the 48 week study period.

Potential Risks

The potential risks of the three products (fluticasone propionate, salmeterol and montelukast) used in MASCOT are summarised individually in the tables below. For more detailed information on the potential risks, special warning and precautions for use of these medications please refer to the Summary of Product Characteristics.

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000) and very rare (< 1/10,000) including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. Rare and very rare events were generally determined from spontaneous data.

Known Potential Benefits

All of the medications have Marketing Authorisations and have been shown to be efficacious for children with chronic asthma when used appropriately as preventative therapy. The ultimate aims of preventative asthma treatment are the prevention of chronic symptoms, maintenance of near normal lung function and normal activity levels and prevention of recurrent acute episodes in order to maximise quality of life. The potential benefit for participants of taking these medications as part of the trial is that they will improve control of their asthma, reducing symptoms and exacerbations and meeting the goals above.

5.1.1. Inclusion Criteria

1. Children with physician diagnosed asthma aged 6 years–14 years, 11months
2. Those requiring frequent short-acting beta2 agonist relief therapy ≥ 7 puffs in the past seven days
3. Those with symptoms of asthma (i.e. wheeze, shortness of breath but not cough alone) resulting in:
   1. Nocturnal wakening in the last week because of asthma symptoms and/or
   2. Asthma has interfered with usual activities in the last week and/or
   3. Those who have had exacerbations, defined as a short course of oral corticosteroids, an unscheduled GP or A&E Department visit or a hospital admission within the previous 6 months
4. Fully informed written (proxy) consent and assent, where appropriate

5.1.2. Exclusion Criteria

1. Children receiving long acting beta2-agonists, leukotriene receptor antagonists, regular theophylline therapy or high dose ICS > 1000 micrograms and unlicensed beclometasone dipropionate or equivalent (at the discretion of the investigator)
2. Children with other respiratory diseases, cystic fibrosis, cardiac disease or immunological disorders
3. Non-English speaking

5.2.1. Inclusion Criteria

1. Children with asthma aged 6 years–14 years
2. Those requiring frequent short-acting beta2 agonist relief therapy ≥ 7 puffs in the past seven days
3. Those with symptoms of asthma (i.e. wheeze, shortness of breath but not cough alone) resulting in
   1. Nocturnal wakening in the last week because of asthma symptoms and/or
   2. Asthma has interfered with usual activities in the last week
4. Continuing consent/assent (where appropriate)

5.2.2. Exclusion Criteria

1. Children whose asthma is controlled after the 4 week run-in, where control is defined as the absence of any symptoms of asthma (except cough alone) or where the symptoms of asthma have not interfered with usual activities in the last week
2. Children receiving long acting beta2-agonists, leukotriene receptor antagonists, regular theophylline therapy or high dose ICS > 1000 micrograms and unlicensed beclometasone dipropionate or equivalent (at the discretion of the investigator)
3. Children with other respiratory diseases, cystic fibrosis, cardiac disease or immunological disorders.
4. Non-English speaking

5.3.1. Patient Transfers

For patients moving from the area, every effort should be made for the patient to be followed up at another participating trial centre and for this trial centre to take over responsibility for the patient or for follow-up via GP.

A copy of the patient's Case Report Forms (CRFs) should be provided to the new site. The patient and their parent/legal representative will have to sign a new consent form at the new site and, until this occurs, the patient remains the responsibility of the original centre. The CTU should be notified in writing of patient transfers.

5.3.2. Withdrawal from Trial Intervention

Patients may be withdrawn from treatment for any of the following reasons:

1. Parent/legal representative (or, where applicable, the patient) withdraws consent for treatment.
2. Unacceptable adverse effects.
3. Intercurrent illness preventing further treatment.
4. Development of serious disease preventing further treatment or any change in the patient's condition that justifies the discontinuation of treatment in the clinician's opinion.
5. Lack of efficacy.

The patient should be asked if they are willing to still have data collected as per trial schedule or, failing this, to allow routine follow-up data to be used for trial purposes. Patients who withdraw from trial treatment but are willing to allow further data collection must have a discussion with the investigator as to whether to they will be unblinded at this point or remain blind to their randomised treatment allocation until the end of their 48 week follow-up period. The decision should be based on the patient and their carers' own preferences and whether the investigator feels they need to be aware of the patient's randomised treatment allocation in order to enable appropriate follow on care.

5.3.3. Withdrawal from Trial Completely

Patients are free to withdraw consent at any time without providing a reason. Patients who wish to withdraw consent for the trial will have anonymised data collected up to the point of that withdrawal of consent included in the analyses. The patient will not contribute further data to the study and the MCRN CTU should be informed in writing by the responsible physician and a withdrawal CRF should be completed. MCRN CTU will endeavour to unblind the patient and inform their GP of their randomised treatment allocation within seven days. Data up to the time of withdrawal will be included in the analyses unless the patient explicitly states that this is not their wish.

Recruitment Strategy #1

This strategy covers all primary care centres including (but not limited to) general practices and health centres, NHS walk-in centres, GP and nurse-led out of hours services and minor injury centres. Participants will be identified via General Practitioners, community-based specialist paediatric/respiratory nurses and other appropriate clinicians working within primary care. The primary care practitioners will be asked for an estimate on the number of their patients who meet the MASCOT eligibility criteria and, if they do see this patient population, they will be asked if they are willing to take part in helping to identify participants for the trial. This identification will be done by the primary care staff who will search their own patient database/s (either electronically – see Appendix C for search guidance – or manually) to find potentially eligible participants and then write to them (a standard letter will be provided), enclosing a Patient Information Sheet and instructions on how to proceed if they are interested in taking part or finding out more about the study. They will be asked either to send a reply slip back directly to the RN who would then contact them by telephone to ascertain potential eligibility and invite them to a T–4 visit OR to contact the RN by telephone/e-mail for further information. Following this initial mailout, the primary care practitioners may also follow up the letter with a telephone call or one subsequent letter.

Recruitment Strategy #2

In addition to the database searches outlined above, primary care practitioners will also conduct opportunistic recruitment and will ask any patients they identify if they are willing for their contact details to be passed to the research team. If they agree, the RN will then contact them directly to ascertain potential eligibility and invite them to a T–4 visit. Alternatively the practitioner can provide the family with a Patient Information Sheet, which gives the contact details of the research team, with advice to contact them directly if they want to find out more about the trial OR provide them with the approved MASCOT lay person poster (produced as a A5 sized handout) which also gives the contact details of the research team.

Recruitment Strategy #3

Participants will be identified via General Practitioners in primary care. The GPs will be asked for an estimate on the number of their patients who meet the MASCOT eligibility criteria. If they do see this patient population, they will be asked if they are willing to take part in the trial and to take on the role of PI. The practice staff will identify potentially eligible patients and write to them (a standard letter will be provided and printed on practice headed paper), enclosing a Patient Information Sheet and instructions on how to proceed if they are interested in taking part or finding out more about the study. They will be asked to either send a reply slip back directly to the GP who would contact them by telephone to ascertain potential eligibility and then invite them to the T–4 visit OR to contact the GP by telephone/e-mail for further information. Following this initial search, GPs will subsequently conduct opportunistic recruitment and will ask any patients they identify if they are willing for their contact details to be passed to the research team. If they agree, the RN will then contact them directly to ascertain potential eligibility and invite them to a T–4 visit.

Recruitment Strategy #4

Participants will be identified by community pharmacists. During the course of a patient's regular medication review, or whilst providing education on the use of asthma medications, pharmacists may identify patients they believe are potentially eligible for the trial. They will ask any patients who they think may be eligible if they are willing for their contact details to be passed to the research team. If they agree, the RN will then contact them to discuss the trial, ascertain potential eligibility and invite them to a T–4 visit (if appropriate). Alternatively the pharmacist can provide the family with a Patient Information Sheet, which gives the contact details of the research team, with advice to contact them directly if they want to find out more about the trial OR provide them with the approved MASCOT lay person poster (produced as a A5 sized handout) which also gives the contact details of the research team. All pharmacies agreeing to participate in this way will be fully briefed on the trial beforehand. Where it is more appropriate, pharmacists may flag a patient's potential eligibility for the trial to their GP instead of directly to the research team. The GP may then follow any of the methods listed in recruitment strategies #1 & #2 at their own discretion.

Recruitment Strategy #5

Participants will be identified via health professionals with a remit to work within schools (e.g. school nurses, health visitors). They may search their registers and databases to find potentially eligible patients. These patients will then be written to (a standard letter will be provided) enclosing a Patient Information Sheet and instructions on how to proceed if they are interested in taking part or in finding out more about the trial. Following this initial mailout, the school health team may also follow up the letter with a telephone call or one subsequent letter. Alternatively, they may identify patients who are potentially eligible during the course of their normal role. After gaining permission from the patient's parent/legal guardian, the health professional will pass their contact details to the research team. The RN will then contact the family directly to discuss the trial, ascertain potential eligibility and invite them to a T–4 visit (if appropriate).

Recruitment Strategy #6

Participants will be identified via secondary care (A&E admissions, routine OPD appointments, specialist nurse-led clinic appointments). Secondary care professionals will be approached by the MASCOT RN/LRN nurses and the PI and informed about the trial. If a patient presents who may be eligible for the trial, the medical staff treating them initially can follow one of two routes: 1) contact the local PI/RN and ask them to come and speak to the patient there and then about the trial, inviting them to attend a T–4 visit if they are potentially eligible and interested in participating OR 2) give the patient a PISC and ask for their permission to pass their contact details on to the RN who will call the patient later to discuss the trial and invite them for a T–4 visit if they are eligible.

Recruitment Strategy #7

Participants will be identified via secondary care by their usual NHS clinical team who will search the Trust databases to find potentially eligible participants. These patients will then be written to (a standard letter will be provided and printed on Trust headed paper), enclosing a PISC and instructions on how to proceed if they are interested in taking part or finding out more about the trial. They could either be asked to send a reply slip back directly to the RN who would contact them by telephone to ascertain the patient's eligibility and then invite them to the T–4 visit OR to contact the RN by telephone/e-mail for further information. Following this initial mailout, the secondary care team may also follow up the letter with a telephone call or one subsequent letter.

Recruitment Strategy #8

The trial may also be promoted via appropriate websites, magazines and newspapers to be accessed by both health professionals and the general public. Approval will be sought from the REC for any specific features or advertisements designed to promote the trial directly to the public, prior to submitting them for publication.

Screening at T–4 (See Section 8 for T–4 assessments)

1. Confirm aged 6–14 years, 11 months
2. Explanation of the two different phases of the trial and understanding that eligibility for trial treatment will be reassessed at T0 visit
3. Fully informed written proxy consent (and assent, where appropriate) to participate in the trial
4. Assessments to determine eligibility (inc. review of medical history, symptoms, concomitant medications)
5. Fluticasone propionate dispensed (open label)
6. Submission of T–4 CRF to MCRN CTU within seven days of registration
7. Forward copy of consent/assent forms to MCRN CTU within seven days of registration

Screening at T0

1. A check of compliance with hand held asthma record completion
2. Review of symptoms and exacerbations
3. A check of concomitant medications prescribed/administered since T–4 visit
4. Complete physical examination performed
5. Verification that the eligibility criteria for randomisation is fulfilled
6. See Section 8 for T0 assessments

Randomisation Process

1. Continuing consent and assent (where appropriate) obtained verbally
2. Completion of randomisation CRF and trial prescription
3. Attend local pharmacy (see Table 1 for pharmacy contact details)
4. Participant's treatment allocation ascertained by pharmacy using the site randomisation list
5. Issue of treatment pack by pharmacy department (ensuring the patient and researcher are blinded to the allocation)
6. Submission of T0 CRF to MCRN CTU within seven days of randomisation

Table 1

Pharmacy Contact Details

A: Fluticasone propionate

B: Salmetrol + Fluticasone propionate

C: Montelukast

Placebo

Dispensing

For each randomised patient, treatment will continue for a maximum period of 48 weeks. Patients will be randomised by pharmacy using a randomisation list provided to the site by the coordinating centre. Pharmacy will ensure that the participant and the researcher are blinded to the treatment allocation. After randomisation patients will be dispensed their first treatment pack. Each treatment pack contains three months of trial medication, consisting of:

• Three inhalers (each inhaler containing 60 inhalations or 30 days treatment)
• Three blister packs (each blister pack containing 35 days treatment)

All treatments will be dispensed at the standard dose throughout the trial, unless interruption or discontinuation is warranted and agreed by the PI (see Section 7.4). The dose regimens are:

1. inhaled fluticasone propionate 100 micrograms twice daily + placebo tablet once daily
2. inhaled fluticasone propionate 100 micrograms and salmeterol 50 micrograms twice daily (combination inhaler) + placebo tablet once daily
3. inhaled fluticasone propionate 100 micrograms twice daily + montelukast 5 mg tablet once daily.

When pharmacy dispense the trial treatments they will add their own dispensing label, which will include information such as the name and address of the hospital, the patient's name or initials, date of dispensing and instructions for use. They will also complete the information specified on the medication trial labels (i.e. patient trial number, visit number etc.).

The medications will be dispensed upon production of a valid, signed trial prescription to either the RN or directly to the patient and their carer/s as detailed below^*:

Administration

The patient and their carer/s will be instructed in the correct use of the medications dispensed. Patients will be instructed in the proper use and care of their inhaler by the RN at T–4 and will have their technique assessed. Further guidance will be provided throughout the remainder of the trial where necessary.

The trial treatments have two different routes of administration:

1. inhalation (fluticasone/salmeterol). One inhalation to be taken twice daily at regular intervals (e.g. once in the morning and once in the evening).
2. oral (montelukast/placebo). One tablet is to be administered daily, to be taken in the evening. If taken in conjunction with food, montelukast should be taken one hour before or two hours after eating.

T0 study visit

All registered participants will be asked to bring the fluticasone inhaler they were issued at T–4 to the T0 study visit. The research doctor/nurse will ask the participant and their carer/s about compliance with the treatment regime and whether any doses have been missed. At the end of the study visit, after the patient has left, the researcher will use the dose counter on the inhaler to verify the information provided by the family. The number of inhalations reported by both the participant and the dose counter will be recorded on the CRF along with the reason given for any doses missed (if applicable).

T+8 study visit

The research nurse will collect all used medications and packaging from the participant. The participant will have been issued with 12 weeks of treatment at T0 so will retain one inhaler and one monthly blister pack for use over the next four weeks.

The research nurse will ask the participant and their carer/s about compliance with the treatment regime since their last visit and whether any inhalations or tablets have been missed. At the end of the study visit, after the patient has left, the researcher will use the dose counter on the inhaler and conduct a full pill count to verify the information provided by the family. The number of doses reported by the participant and from the medication counts will be recorded on the CRF along with the reason given for any doses missed (if applicable).

T+24 study visit

The research nurse will collect all used and unused medications and packaging from the participant. They will ask the participant and their carer/s about compliance with the treatment regime since their last visit and whether any inhalations or tablets have been missed. At the end of the study visit, after the patient has left, the researcher will use the dose counter on the inhaler and conduct a full pill count to verify the information provided by the family. The number of doses reported by the participant and from the medication counts will be recorded on the CRF along with the reason given for any doses missed (if applicable).

T+36 telephone call

The research nurse will ask the participant and/or their carer/s about compliance with the treatment regime since their last visit and whether any inhalations or tablets have been missed. The number of doses reported by the participant will be recorded on the CRF along with the reason given for any doses missed (if applicable). The RN will remind the participant to bring all used and unused medications and packaging to their next study visit.

T+48 study visit

The research nurse will collect all used and unused medications and packaging from the participant. They will ask the participant and their carer/s about compliance with the treatment regime since their last visit and whether any inhalations or tablets have been missed. At the end of the study visit, after the patient has left, the researcher will use the dose counter on the inhaler and conduct a full pill count to verify the information provided by the family. The number of doses reported by the participant and from the medication counts will be recorded on the CRF along with the reason given for any doses missed (if applicable).

Early withdrawal

If a patient wishes to prematurely withdraw from trial treatment, the research nurse will collect all used and unused medications and packaging from the participant. They will ask the participant and their carer/s about compliance with the treatment regime since their last visit and whether any inhalations or tablets have been missed. The researcher will use the dose counter on the inhaler and conduct a full pill count to verify the information provided by the family. The number of doses reported by the participant and from the medication counts will be recorded on the CRF along with the reason given for any doses missed (if applicable).

7.7.1. Medications Permitted

Details of concomitant medications will be collected at the T–4 visit and recorded on the CRF. They will be reviewed at all subsequent study visits (clinic visits, telephone call) until T+48. The trial treatments have very few adverse interactions with other medicinal products so concomitant medications, with the exception of those listed in Section 7.7.2, are permissible at the discretion of the investigator.

7.7.2. Medications Not Permitted/Precautions Required

The following are not permitted for the duration of the trial period:

• Inhaled corticosteroids (other than the trial treatment)
• Long-acting beta2 agonists (other than trial treatment)
• Leukotriene receptor antagonists (other than trial treatment)
• All beta-blockers
• Theophylline

Caution should be exercised when prescribing CYP3A inhibitors as they may affect the efficacy of montelukast (see Singulair SPC Section 4.5 ‘Interactions with other medicinal products and other forms of interaction’). CYP3A inhibitors (e.g. ketaconazole, itraconazole) are not permitted for regular or frequent use during the trial treatment period. All prescribed CYP3A inhibitors should be documented on the Concomitant Medications CRF.

7.7.3. Data on Concomitant Medication

The dose and name of all concomitant medications should be documented on the CRF at T–4. This will be reassessed at each trial visit by the PI/RN. Any new medications introduced or any changes to current medications should be documented on the CRF.

7.8.1. Procedure

Four Week Run-in Period (Study visit)

Patients will be screened in GP surgeries in primary care and in paediatric clinics in secondary care. Following full informed written (proxy) consent, those eligible will be registered into the study, have their inhaler technique checked and be provided with information about asthma and its management. All research centres taking part will be centrally trained and instructed in the approach to the patients and their families in an attempt to obtain uniformity. They will all be dispensed the same low-dose inhaled corticosteroid, fluticasone propionate, in the dose of 100 micrograms twice daily. They will participate in an open four week ‘run-in’ period and will complete a hand-held patient record that will provide information to aid assessment of ongoing control (see 8.2.1).

The same criteria will be used in all centres to determine whether the patient is effectively controlled or not. Poorly controlled, as defined in sections 5.1 and 5.2, will be those requiring frequent short-acting beta2 agonist relief therapy ≥ 7 puffs per week and with asthma symptoms affecting sleeping and/or usual activities in the last week and/or who have had exacerbations (defined as a short course of oral corticosteroids, an unscheduled GP or A&E Department visit or a hospital admission within the previous six months).

The purpose of this run-in period is to ensure that we are only recruiting those patients for whom control of their asthma presents a problem, rather than those for whom inhaler technique and management advice will be sufficient to provide symptomatic relief. Most run-ins lose approximately 25% patients but we anticipate that improved education and attention to compliance in this study may well make up to 50% ineligible for entry into the randomised part of the study. All patients registered will have GP data follow-up one year after registration, regardless of continuation into the main trial, which is detailed in the patient information sheet and consent form (PISC). We will collect data on things such as symptoms, exacerbations, hospital appointments, medication changes and use.

At the T–4 review, families will also be issued with a copy of the PISC requesting the collection of a DNA sample for storage and investigation at a later date (section 8.4.1). They will be invited to consent and provide a DNA sample (saliva) at their T0 clinic visit. Consent to provide a DNA sample is documented separately to that of consent for the main trial.

The next study visit (T0) will be organised with the participant and their carer/s to be in no less than 24 days time and no longer than 30 days time from T–4.

Time 0: Entry into full study (Study visit)

Following the run-in period patients will be re-assessed for study entry based upon inclusion and exclusion criteria (section 5.2). Those patients achieving the threshold criteria for T0 will be entered into the randomised part of the study.

Symptoms, exacerbations and beta2 agonist use will be ascertained by reviewing the hand held record with the patient and their carer/s. Baseline Paediatric Asthma Quality of Life Questionnaire (interviewer administered if child is 10 years of age or younger, patient administered if aged 11 years or more) and Paediatric Asthma Caregivers Quality of Life Questionnaire (carer administered) assessments will be conducted and a complete physical examination will be performed, including height and weight measurements. Spirometry will be carried out to measure the patient's FEV₁, FVC and FEV₁/FVC ratio (best of three before and after bronchodilator).

Each patient is then randomised by pharmacy using a randomisation list supplied centrally and dispensed their first three month treatment pack according to their treatment allocation. Treatment is to continue for eight weeks and the allocated treatment will be double-blinded, achieved by using identical inhalers and placebo tablets, with patients allocated to receive either:

1. Inhaled fluticasone propionate 100 micrograms twice daily plus placebo tablet once daily
2. Inhaled fluticasone propionate 100 micrograms and salmeterol 50 micrograms twice daily (combination inhaler) plus placebo tablet once daily
3. Inhaled fluticasone propionate 100 micrograms twice daily plus montelukast 5 mg tablet once daily.

Following a separate consent process, a DNA specimen will be obtained (see Section 8.4.1). Individuals declining to provide DNA will not be precluded from entry into main trial.

Randomisation + 8 weeks (Study visit)

Symptoms, exacerbations and beta2 agonist use will be ascertained by reviewing the hand held record with the patient and their carer/s. The Health Economics questionnaire completed throughout the time period since the last clinic visit will be checked for completeness and removed. A new, blank questionnaire will be inserted into the hand held record to be used until the next appointment. Repeat Quality of Life Assessments will be administered (interviewer [if child is 10 years of age or younger], patient [if aged 11 years or more] and carer administered) and a symptom-directed physical examination will be performed as appropriate. Adverse events will be reported and recorded.

Those who have achieved control of their asthma symptoms will continue on the same treatment for the next 16 weeks. For those whose symptoms have not improved but are no worse, the PI/RN will discuss their willingness to continue with randomised treatment.

Those who are clinically worse may be withdrawn from randomised treatment and given alternative treatment according to clinician's advice as in routine practice. The decision to withdraw the patient from trial treatment is based on the patient's current clinical presentation and the review of information on symptoms/exacerbations etc collected in the hand held record over the preceding weeks. The decision is made at the discretion of the investigator using their informed clinical opinion. The reason for discontinuation of trial treatment must be documented on the CRF. Follow-up should be continued until the end of the trial as per the study visit schedule.

In certain circumstances, the PI/RN may conduct the T+8 study visit at the family home where it is appropriate and necessary to do so. The PI/RN must only conduct a study visit in the family home if this has been authorised for their site by the coordinating centre and appropriate lone working procedures are in place.

Randomisation + 24 weeks (Study visit)

Symptoms, exacerbations and beta2 agonist use will be ascertained by reviewing the hand held record with the patient and their carer/s. The Health Economics questionnaire completed throughout the time period since the last clinic visit will be checked for completeness and removed. Two new, blank questionnaires will be inserted into the hand held record to be used until the next study visit. Repeat Quality of Life Assessments will be administered (interviewer [if child is 10 years of age or younger], patient [if aged 11 years or more] and carer administered) and a symptom-directed physical examination will be performed as appropriate. Adverse events will be reported and recorded.

Those who have achieved control of their asthma symptoms will continue on the treatment. For those whose symptoms have not improved but are no worse, the PI/RN will discuss their willingness to continue with randomised treatment.

Those who are clinically worse may be withdrawn from randomised treatment and given alternative treatment according to clinician's advice as in routine practice. The decision to withdraw the patient from trial treatment is based on the patient's current clinical presentation and the review of information on symptoms/exacerbations etc collected in the hand held record over the preceding weeks. The decision is made at the discretion of the investigator using their informed clinical opinion. The reason for discontinuation of trial treatment must be documented on the CRF. Follow-up should be continued until the end of the trial as per the study visit schedule.

In certain circumstances, the PI/RN may conduct the T+24 study visit at the family home where it is appropriate and necessary to do so. The PI/RN must only conduct a study visit in the family home if this has been authorised for their site by the coordinating centre and appropriate lone working procedures are in place.

Randomisation + 36 weeks (Telephone call)

Symptoms, exacerbations and beta2 agonist use will be ascertained from the patient and/or their carer/s. The RN will check that they are continuing to complete the hand held record and that they have completed the inserted Health Economics questionnaire for the time period since their last clinic visit. They will be asked to remove the completed questionnaire and place it to the back of the record to avoid any confusion. The RN will remind them to begin a new Health Economics questionnaire to be used until their next appointment.

Adverse events will be reported and recorded. Those who have achieved control of their asthma symptoms will continue on the trial treatment. For those whose symptoms have not improved but are no worse, the RN will discuss their willingness to continue with randomised treatment. Those whose asthma symptoms appear to be worse will either be offered an unscheduled study appointment with a member of the research team (if possible) or advised to visit their General Practitioner to seek further medical advice. If the practitioner believes they are clinically worse the patient may be withdrawn from randomised treatment and given alternative treatment according to clinician's advice as in routine practice. The reason for discontinuation of trial treatment must be documented on the CRF. Follow-up should be continued until the end of the trial as per the study visit schedule.

Randomisation + 48 weeks (Clinic visit)

Symptoms, exacerbations and beta2 agonist use will be ascertained by reviewing the hand held record with the patient and their carer/s. The two Health Economics questionnaires completed throughout the time period since the last clinic visit will be checked for completeness and removed. Final Quality of Life assessments will be administered (interviewer [if child is 10 years of age or younger], patient [if aged 11 years or more] and carer administered) and a basic physical examination will be performed, including height and weight measurements. Further examination will be symptom led. Spirometry will be carried out to measure the patient's FEV₁, FVC and FEV₁/FVC ratio (best of three before and after bronchodilator). Adverse events will be reported and recorded.

Patients will be asked to provide current details for their General Practitioner (GP). They will be informed that their GP will be provided with details of which treatment they have been taking within seven days. If the patient was under the care of a different clinician for their asthma management prior to entering the study, that clinician will also be provided with details of the treatment wherever possible. The PI/RN will discuss future management with patients and their carer/s.

8.2.1. Hand Held Records

Hand held records will be used throughout by participants, from T–4 through to T0, and continuing until study completion (T+48) for those patients who proceed with randomisation at T0. The records are A6 sized folders, which are divided into sections relating to different aspects of a child's asthma and their management of it. They were developed by The Guy Hilton Asthma Trust and have been modified for the purposes of the MASCOT trial to collect data relevant to the trial outcomes.

There are sections in the records to capture information on daily symptoms, exacerbations, use of beta2 agonist relief therapy, management/treatment schedule and emergency contact numbers. The records can be completed by patients and/or their carer/s on a continuous basis so the information recorded will be current and accurate.

The records will be brought along to every study visit and reviewed by the PI/RN in conjunction with the patient and their carer/s. The information collected in the records will be used to assess how well participants' asthma is being controlled on the trial treatments and will be important in determining whether they should progress to the next stage of the trial. The information collected in the hand held records will be regarded as source data so at each clinic visit the completed pages will be removed from the record.

The original sheets will be sent to CTU, a copy retained in the Site File and the family will be provided with a copy for their own records (if requested).

The review of hand held records at each study visit, detailing patients' symptoms and exacerbations, will indicate how effectively their asthma is being controlled and so can be used to assess efficacy of the trial treatments.

8.2.2. Spirometry

Spirometry will be carried out at baseline (T0) and study completion (T+48) and will provide an objective measure of efficacy. Spirometry will be undertaken pre and post bronchodilator and will only be accepted if meeting American Thoracic Society (ATS)/European Respiratory Society (ERS) standards for acceptability and reproducibility. The following values will be recorded in the CRF:

• Date and time of spirometry
• Whether readings meet ATS standards for acceptability and reproducibility
• Whether bronchodilators withheld for appropriate length of time – short-acting 4 hours and long-acting 24 hours
• FEV₁ pre and post 400 micrograms of salbutamol
• FVC pre and post 400 micrograms of salbutamol

8.2.3. Paediatric Asthma Quality of Life Questionnaire (PAQLQ)

The Quality of Life (QoL) scores obtained at different timepoints (T0, T + 8, T + 24 and T + 48) throughout the trial can be used as a subjective measure of efficacy. The PAQLQ, devised by Elizabeth Juniper, will measure the physical, emotional, occupational and social effects of asthma in children. There are two versions of the PAQLQ, interviewer administered for children 10 years & younger and patient administered for children 11 years & older. The RN will select the version appropriate for the individual child's age and stage of development. Children will be asked to recall information from the previous seven days and to use this when selecting their responses. The child's asthma may also affect the parents' quality of life and so an additional scale, the Paediatric Asthma Caregivers Quality of Life Questionnaire (PACQLQ), will also be used. The PACQLQ has been designed by Elizabeth Juniper to complement the PAQLQ.

The PAQLQ has been selected for use in MASCOT due to its short recall requirement and ability to detect small but clinically important changes that children experience as a result of treatment or fluctuation in their asthma. (See Section 8.5 for procedure).

8.4.1. Genetic Study

The study will include the collection of DNA (from saliva) which will be securely stored at the University of Liverpool for pharmacogenetic analysis at a later date.

A separate consent process will be undertaken for this purpose at the T0 visit. All participants registered in the trial will be asked to provide a sample, regardless of whether they are eligible for the randomised phase. If consent and assent (where applicable) is provided at T0, the genetic sample will be collected by asking the child to spit directly into a collection kit. The kit is specifically designed for the preservation, transportation and purification of DNA from saliva and is a non-invasive, highly reliable method of DNA collection. The amount of saliva required from the participant is 2 ml so the child may have to spit more than once in order to obtain a sufficient amount of material for DNA extraction. Once the saliva has been deposited, the RN will then seal and label the container with the child's unique trial identifier number. When the kit has been sealed the sample will remain stable at room temperature. It will be sent directly to a central facility at the University of Liverpool where it will be stored for future study.

The genetic samples collected will be used in the future to help determine whether specific polymorphisms affect severity or long term prognosis of asthma and its symptoms. For the patients who enter the randomised part of the trial, the samples will also be used to explore the possibility that a difference may be seen in those children responding to long acting beta2 agonists (LABAs) or leukotriene receptor antagonists (LTRAs) dependent on specific single nucleotide polymorphisms (SNPs) within the beta2 agonist receptor or the leukotriene receptor genes. However, no specific study is planned at this time. Approval from a Research Ethics Committee will be sought before any pharmacogenetic analyses are conducted.

8.4.2. RECRUIT

It is proposed that MASCOT will involve a qualitative substudy ‘Processes in recruitment to randomised controlled trials (RCTs) of medicines for children (RECRUIT)’. RECRUIT was approved in its own right by the North West REC on 2nd March 2007 (ref 07/MRE08/6).

RECRUIT will be examining communication processes in the recruitment of participants to MASCOT with the aim of identifying strategies for subsequent trials of medicines for children to improve trial recruitment and conduct. RECRUIT will involve:

1. Routine audio-recording of MASCOT discussions (consultations) between families and practitioners (trial recruiters)
2. Follow-up interviews with up to eight families (parents and children, where aged seven or over) who agree to participate in MASCOT
3. Follow-up interviews with up to eight families (parents and children, where aged seven or over) who decline to participate in MASCOT
4. Follow-up interviews with up to eight trial recruiters involved in approaching families to take part in MASCOT

Collection of data for 1 will be facilitated by MASCOT staff who will routinely seek permission to audio-record recruitment consultations from the families whom they approach for MASCOT. Data for 2, 3 and 4 will be collected by the Research Associates (RAs) employed on RECRUIT, who will be entirely independent of MASCOT.

If permission for audio-recording is declined by a family the recruitment consultation will not be recorded. If permission is given the recruiter will activate an audio-recorder. At the end of the MASCOT recruitment consultation the recruiter will discuss RECRUIT with the family and seek their permission to pass their details to one of the RAs employed on RECRUIT, who will then make contact with families and obtain written informed consent for participation in the RECRUIT study. Recordings from families who decline RECRUIT will be erased as soon as practicable. All families who express an interest in RECRUIT but are not selected for follow-up interview will be contacted by letter to thank them and inform them that their recordings have been erased. Audio-recordings of the recruitment consultations will only be released to the RECRUIT RAs after the consent of the participants has been obtained.

All interviews for RECRUIT will be conducted by experienced RAs with proven skills in the conduct of research in sensitive settings. Any distress during the interviews will be managed with care and compassion by the RAs and participants will be free to decline to answer any questions that they do not wish to answer or to stop the interview at any point. The RAs will receive appropriate training and follow a clear protocol for managing participants whose level of distress gives cause for concern. Any such families will be supported in obtaining appropriate help. If necessary, and after discussion with the participant, the lead clinician responsible for the child's care will be informed.

To allow MASCOT to become established and avoid the initial ‘teething’ phase that most trials experience, sampling for RECRUIT will not begin until the trial has been recruiting for approximately four months. Sampling to RECRUIT (and therefore audio-recording of trial consultations) will roll from trial site to trial site in blocks of up to three months' duration, with planned suspensions if accrual to RECRUIT allows. This will help to minimise the numbers of families who are approached but not selected for RECRUIT. Concentrated sampling at particular sites in time-limited blocks, with the possibility of planned suspensions, will minimise the impact of RECRUIT on MASCOT and the risk of overburdening particular trial sites. It will also facilitate liaison with the sites and assist recruiters in routine audio-recording of consultations.

8.5.1. Health Economics

Health economic data will be collected on primary and secondary health care contacts and medications prescribed. Although not the primary focus of the study, it will aim to incorporate patient and societal costs in terms of time lost to school by the children and time lost to work for the parents and carers. It will include any out of pocket expenses such as personal money spent on medications and aids and appliances. It is important to determine differences in the patient pathway as a result of different regimes.

The four week run-in period can be ignored in terms of the economics as the costs will be common across all patients.

For participants entering the randomised phase, a blank Health Economics (HE) questionnaire will be inserted into their hand held record at each visit for the patient and their carer/s to complete over the following weeks up until their next appointment. This should increase the reliability and accuracy of the data collected by decreasing the family's reliance on retrospective recall of information. The family will receive a telephone call from the RN prior to their visit to remind them to complete and bring along the record and questionnaire for review at their next study appointment. During the visit, the HE questionnaire pages will be removed from the record by the RN. The original will be sent to CTU within seven days and copies made for the Site File and provided to the family (if requested). A new, blank questionnaire will then be inserted into the record for use until the next contact with the study team. At T+24 weeks an extra copy of the HE questionnaire will be inserted into the back of handheld record. At the telephone contact at T+36 weeks, patients/carers will be asked to swap the two questionnaires over and enter the start date on the new questionnaire. At T+48 both questionnaires will be collected from the hand held record.

8.5.2. Quality of Life

The Paediatric Asthma Quality of Life Questionnaire (PAQLQ) should be the first questionnaire completed during the clinic visit and should precede any discussion with the research doctor or nurse. Ideally, children should be interviewed on their own and in a quiet room where there are no distractions. Parents/carers should be instructed to wait in another room if possible, where they can complete the Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ) while the child completes the PAQLQ. The child should be made to feel comfortable and relaxed but be aware that they need to complete the questionnaire carefully. Where the PAQLQ is interviewer administered (i.e. for children ten years of age and younger) then the questionnaires should be read out exactly as they appear on the form. They should not be reworded or paraphrased for the child, even if they ask for clarification. Children will be asked to base their responses on the past seven days and adults on the previous two weeks.

Two coloured cards (green and blue) will be provided with the PAQLQ, which list sets of response options appropriate to the different questions. The appropriate response card is listed with each question. The interviewer should explain both cards to the child, reading through each of the response options with the younger children and asking the older ones to read each of the responses aloud to ensure they understand them. Children should be reminded that they are only able to choose one option. The PACQLQ is in a self-administered format and carers should be instructed to follow the instructions on the questionnaire.

The research nurse should ensure that all questions have been answered. Once they have collected the completed questionnaires from the participant and their carer, they will make a copy and send the originals to CTU within seven days. The copy will be retained in the Site File. The questionnaires should, wherever possible, only be completed during the study visit .They must always be completed by the same caregiver who completed the first questionnaire and this should be the child's main carer.

9.3.1. Primary

Number of asthma exacerbations requiring treatment with short courses of oral corticosteroids over 48 weeks from date of randomisation.

9.3.2. Secondary

1. Quality of Life as measured by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) and the Paediatric Asthma Caregivers Quality of Life Questionnaire (PACQLQ)¹³
2. Time from randomisation to first exacerbation requiring treatment with a short course of oral corticosteroids
3. School attendance
4. Hospital admissions
5. Amount of rescue beta2 agonist therapy prescribed
6. Time from randomisation to treatment withdrawal (due to lack of efficacy or side effects)
7. Lung function at 48 weeks (as assessed by spirometry)
8. Cost effectiveness
9. Adverse events

9.6.1. Economic analysis

Economic analysis will focus on determining the differences in the patient pathways between the three groups in terms of their costs and benefits. Analysis will therefore take a number of different forms.

Incremental Cost Effectiveness Ratios (ICER) will be calculated against the base case:

• A Inhaled fluticasone propionate 100 micrograms twice daily plus placebo tablet once daily.

The other two scenarios:

• B Inhaled fluticasone propionate 100 micrograms and salmeterol 50 micrograms twice daily (combination inhaler) plus placebo tablet once daily.
• C Inhaled fluticasone propionate 100 micrograms twice daily plus montelukast 5mg tablet once daily will be compared against the base case.

ICERs calculate the ratio of the difference in cost to the difference in outcome between the two groups. In terms of outcome, the ICER will be based on the difference in the number of exacerbations between the groups. Further ICERs based on quality of life could also be calculated.

Cost effectiveness acceptability curves (CEACs) will be calculated for each of the three regimes showing the probability that each option is cost effective at different willingness to pay thresholds.

A subsidiary economic analysis may evaluate the cost of exacerbations in terms of the average cost per exacerbation and then cost the treatment alternatives in terms of exacerbations averted. This subsidiary analysis is a useful supplement to the main analysis. Cases averted are a useful tool for presentation of the data.

Adverse Event (AE)

Any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product.

Adverse Reaction (AR)

Any untoward and unintended response in a subject to an investigational medicinal product which is related to any dose administered to that subject.

Unexpected Adverse Reaction (UAR)

An adverse reaction the nature and severity of which is not consistent with the information about the medicinal product in question set out in:

• In the case of a product with a marketing authorization, in the summary of product characteristics for that product
• In the case of any other investigational medicinal product, in the investigator's brochure relating to the trial in question.

Serious Adverse Event (SAE), Serious Adverse Reaction (SAR) or Suspected Unexpected Serious Adverse Reaction (SUSAR)

Any adverse event, adverse reaction or unexpected adverse reaction, respectively, that:

• results in death
• is life-threatening^* (subject at immediate risk of death)
• requires in-patient hospitalisation or prolongation of existing hospitalisation^**
• results in persistent or significant disability or incapacity, or consists of a congenital anomaly or birth defect
• Other important medical events

^*‘life-threatening’ in the definition of ‘serious’ refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.

^**Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the hospitalisation is a precautionary measure for continued observation. Hospitalisations for a pre-existing condition, including elective procedures that have not worsened, do not constitute an SAE.

^***Other important medical events that may not result in death, be life-threatening, or require hospitalisation may be considered a serious adverse event/experience when, based upon appropriate medical judgment, they may jeopardise the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition

10.2.1. Include

• An exacerbation of a pre-existing illness
• An increase in frequency or intensity of a pre-existing episodic event/condition
• A condition (even though it may have been present prior to the start of the trial) detected after trial drug administration
• Continuous persistent disease or symptoms present at baseline that worsens following the administration of the study/trial treatment

10.2.2. Do Not Include

• Medical or surgical procedures – the condition which leads to the procedure is the adverse event
• Pre-existing disease or conditions present before treatment that do not worsen
• Situations where an untoward medical occurrence has occurred e.g. cosmetic elective surgery
• Overdose of medication without signs or symptoms
• The disease being treated or associated symptoms/signs unless more severe than expected for the patient's condition

10.2.3. Reporting of Pregnancy

Study participants will not routinely be tested for pregnancy as part of the trial screening process. Any pregnancy which does occur during the course of the study should be reported to the MCRN CTU immediately. The investigator should discuss the risks of continuing with the pregnancy with the patient and the possible effects on the foetus if they continue on trial treatment. It is at the investigator's discretion to decide whether the individual should be instructed to stop taking study drugs. All pregnancies that occur during trial treatment, or within seven days of finishing treatment, need to be followed up until completion and reported separately.

10.7.1. Non serious ARs/AEs

All such events, whether expected or not, should be recorded on an Adverse Event Form, which should be transmitted to the MCRN CTU within seven days of the form being due.

10.7.2. Serious ARs/AEs/SUSARs

SARs, SAEs and SUSARs should be reported within 24 hours of the local site becoming aware of the event. The SAE form asks for the nature of event, date of onset, severity, corrective therapies given, outcome and causality. The responsible investigator should sign the causality of the event. Additional information should be sent within 5 days if the reaction has not resolved at the time of reporting.

The MCRN CTU will notify the MHRA and main REC of all SUSARs occurring during the study according to the following timelines; fatal and life-threatening within 7 days of notification and non-life threatening within 15 days. All investigators will be informed of all SUSARs occurring throughout the study. Local investigators should report any SUSARs and/or SAEs as required by their local Research & Development (R&D) Office.

Minimum information required for reporting

• Study identifier
• Study centre
• Patient number
• A description of the event
• Date of onset
• Current status
• Whether study treatment was discontinued
• The reason why the event is classified as serious
• Investigator assessment of the association between the event and study treatment

1. The SAE form should be completed by the responsible investigator i.e. the consultant named on the ‘signature list and delegation of responsibilities log’ who is responsible for the patient's care. The investigator should assess the SAE for the likelihood that that it is a response to an investigational medicine. In the absence of the responsible investigator the form should be completed and signed by a designated member of the site trial team and faxed to the MCRN CTU immediately. The responsible investigator should check the SAE form, make changes as appropriate, sign and then re-fax to the MCRN CTU as soon as possible. The initial report shall be followed by detailed, written reports.
2. Send the SAE form by fax (within 24 hours or next working day) to the MCRN CTU: Fax Number: 0151 282 4721
3. The responsible investigator must notify their local R&D department of the event (as per standard local procedure).
4. In the case of an SAE the subject must be followed-up until clinical recovery is complete and laboratory results have returned to normal, or until the event has stabilised. Follow-up may continue after completion of protocol treatment if necessary.
5. Follow-up information is noted on another SAE form by ticking the box marked ‘follow-up’ and faxing to the MCRN CTU as information becomes available. Extra, annotated information and/or copies of test results may be provided separately.
6. The patient must be identified by trial number, date of birth and initials only. The patient's name should not be used on any correspondence.

10.8.1. Maintenance of Blinding

Systems for SUSAR and SAR reporting should, as far as possible, maintain blinding of individual clinicians and of trials staff involved in the day-to-day running of the trial. Unblinding clinicians may be unavoidable if the information is necessary for the medical management of particular patients. The safety of patients in the trial always takes priority. In each report, seriousness, causality and expectedness should be evaluated for all of the trial treatments unless criteria have been fulfilled (section 7.8) and unblinding has taken place. Cases that are considered serious, unexpected and possibly, probably or almost certainly related to one of the trial therapies (i.e. possible SUSARs) would have to be unblinded at the clinical trials unit prior to reporting to the regulator.

11.3.1. General

Informed consent is a process initiated prior to an individual agreeing to participate in a trial and continues throughout the individual's participation. Informed consent is required for all patients participating in MCRN CTU coordinated trials. In obtaining and documenting informed consent, the investigator should comply with applicable regulatory requirements and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Informed consent should only be taken by staff who are appropriately trained to do so and who have experience in providing information to minors.

Parental and age and stage-of-development appropriate Patient Information Sheet and Consent (PISC) forms, which will have been approved by an independent ethics committee (IEC), will be issued to potentially eligible patients and their families. The PISC will describe in detail the trial procedures (for both the run-in and randomised treatment phases), the trial interventions/products and potential risks and benefits of taking part in the study. All patients and their families will receive the appropriate version of the written information and be asked to read and review it. The PISC will emphasise that participation in the trial is voluntary and that the parent or legal representative^* may, without the minor being subject to any resulting detriment, withdraw them from the trial at any time by revoking the informed consent. The rights and welfare of the patient will be protected by emphasising to them that the quality of medical care will not be adversely affected if they decline to participate in this study. All parents/legally acceptable representatives and patients will be given the opportunity to ask questions and will be given sufficient time to consider trial entry before consenting. They should have the opportunity to discuss the study with their usual medical practitioner and/or family/friends prior to agreeing to participate. The consent form will request permission for the patient's General Practitioner to be informed of their registration into the trial and also permission for personnel involved in the research or from regulatory authorities to have access to the individual's medical records. A copy of the informed consent/assent document will be given to the patient and their legally acceptable representative for their records.

^*A mother always has legal responsibility for her child, however a father only has legal responsibility if he is married to the mother or has acquired legal responsibility for his child in the following ways:

• For children born before 1 December 2003, unmarried fathers can get parental responsibility by:
  • marrying the mother of their child or by obtaining a parental responsibility order from the court
  • registering a parental responsibility agreement with the court or by an application to court
• For children born after 1 December 2003, unmarried fathers can get parental responsibility by:
  • registering the child's birth jointly with the mother at the time of birth
  • re-registering the birth if you are the natural father
  • marrying the mother of their child or by obtaining a parental responsibility order from the court
  • registering with the court for parental responsibility

11.3.2. Obtaining Informed Consent

The consent process will be carried out by an appropriate researcher identified in the trial signature and delegation log. The consent process will be conducted by a researcher with training and experience with minors. The researcher delegated to obtain informed consent will be determined on a site by site basis, depending on the experience and knowledge of the individual staff at that site. Only personnel confident and competent to do so will be able to obtain informed consent. This can include PIs, other delegated investigators and research nurses. Where informed consent is being obtained by a research nurse, the patient and their family should have access to a clinician with expertise in paediatric respiratory medicine if they have any concerns about participation or any further questions that the nurse is unable to sufficiently answer.

Upon reviewing the PISC with the patient and their parent/s or legal representative, the researcher who is obtaining consent will fully explain the research study (both the run-in and randomised treatment phases) to the patient and their parent/legal representative and answer any questions they may have. They will discuss the objectives of the study and all potential benefits and inconveniences of taking part. They will clearly outline all of the responsibilities the patient and their family will be expected to meet if they agree to participate, including attendance at study visits and compliance with trial medications. A contact point where further information about the trial may be obtained will be provided. The patient and their family will be made aware that entry into the randomised phase of the trial is contingent on their continuing to meet the eligibility criteria following the four week run-in, as well as their continuing consent/assent to participate in the trial.

Both parental consent and the patient's assent, if appropriate, will be obtained prior to any study related procedures being carried out. The researcher and the parent/legal representative of the minor must personally sign and date the form. If capable, the patient should assent and personally sign and date the assent form. Assent forms do not substitute for the consent form signed by the patient's legally acceptable representative. Where the child is unable to provide assent, this should be documented in the patient's medical notes and recorded on a copy of the age and stage of development specific PISC. The original assent form should be filed in the medical notes and copies placed in the site file and forwarded to the MCRN CTU.

The original copy of the consent/assent form will be retained in the patient's medical notes and must be available for inspection. A copy will be returned to the MCRN CTU and one will also be placed in the Site File. A further copy of the signed consent/assent form will be provided to the child's parent/legally acceptable representative along with the PISC used during the recruitment consultation.

Following the four week run-in phase, any patients continuing to meet the eligibility criteria will progress to the randomised part of the trial. Once they have been found to be eligible, prior to randomisation, the researcher will reiterate previous written and verbal explanations about the trial and answer any further questions the family may have. The patient and their parent/s or legally acceptable representative will be asked to provide verbal consent (and assent, where appropriate) for their continued participation in the trial.

11.3.3. Informed Consent for DNA Collection

Consent for obtaining DNA in the form of saliva will be discussed initially at the T–4 study visit. All participants registered in the trial will be provided with a copy of a parental and age and stage of development specific PISC, approved by an IEC and developed specifically for the sub-study. They will have the opportunity to ask any questions and to discuss the sub-study with their usual medical practitioner and/or family/friends prior to making their decision.

Consent for participation in the genetic sub-study will be obtained at the T0 visit by the researcher identified in the site signature and delegation log. They will discuss the objectives of the study and all potential benefits and inconveniences of taking part. Participants and their families will be made aware that they are consenting for the DNA to be collected and stored for analysis at a later date. It will be made clear that the DNA specimen will be used only for analysis of specific genetic polymorphisms relating to asthma severity and outcomes and the steps that will be taken to maintain the confidentiality of the data.

Both parental consent and patient assent, if appropriate, will be obtained prior to the collection of the DNA sample. The research practitioner and the parent/legal representative of the minor must personally sign and date the form. If capable, the patient should assent and personally sign and date the assent form. Assent forms do not substitute for the consent form signed by the patient's legally acceptable representative.

The original copy of the consent/assent form will be retained in the patient's medical notes and must be available for inspection. A copy will be returned to the MCRN CTU and one will also be placed in the Site File. A further copy of the signed consent/assent form will be provided to the child's parent/legally acceptable representative along with the Patient Information Sheet relating to the trial.

13.5.1. Central Monitoring

The MCRN CTU is to receive a copy of the PISC within a week of randomisation. If consent forms are not forwarded regularly by a participating centre, the Trial Coordinator will conduct a site visit to check the presence of a signed PISC in the medical notes of all registered patients.

Data submitted to the database will be centrally monitored by the CTU to ensure, as far as possible, that CRF data collected are consistent with adherence to the trial protocol. Data will be checked for missing or unusual values (range checks) and checked for consistency within participants over time. Discrepancies that have been raised will be queried. The MACRO data management system will automatically keep a log of what data has been changed, the time of each change, and the person who changed it.

The Trial Coordinator will review rates of recruitment, missing outcome data, SAEs, ADRs, study withdrawals and losses to follow-up across sites, and remedial action taken as necessary. The Trial Coordinator may arrange site visits to undertake source data verification.

Standardised paper Case Report Forms (CRFs) should be sent to the MCRN CTU promptly. The Trial Data Manager will conduct data entry checks and use automated validation checks at data entry. A site visit will be conducted if inconsistencies, unresolved queries, missing data are consistently noted at a given site.

Monthly recruitment reports will be provided by the Trial Coordinator, monitoring reasons cited for consent refusal and querying reasons for slow recruitment. The TMG is charged with providing solutions to problems where possible.

The Trial Coordinator will keep a central protocol deviation log which will be updated with all deviations reported from trial sites. If the Trial Coordinator identifies significant and/or persistent non-compliance on the part of the PI, this will be documented in the monitoring report and the MCRN CTU team will discuss any further action required. A site visit will be conducted if primary and secondary measures are consistently missing from a given site. The Trial Coordinator will be in regular contact with the PIs in order to monitor the impact that the study may have on the running of the service.

13.5.2. Site Monitoring

Site monitoring may be deemed to be necessary as a result of central data checks. In order to perform their role effectively, a member of the MCRN CTU staff (usually the Trial Coordinator) may need direct access to primary data, e.g. patient records, laboratory reports, appointment books, etc. Since this affects the patient's confidentiality, this fact is included in the Patient Information Sheet and Informed Consent Form.

13.5.3. Confidentiality

Individual participants' medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited with the exceptions below.

Case report forms will be labelled with patient initials and a unique trial registration and/or randomisation number. DNA samples will be transferred to an external laboratory and will be identified by unique identifiers only. Medical information may be given to the participant's medical team and all appropriate medical personnel responsible for the participant's welfare.

Verification of appropriate informed consent will be enabled by the provision of copies of participants' signed informed consent/assent forms being supplied to the MCRN CTU by recruiting centres. This requires that name data will be transferred to the MCRN CTU, which is explained in the PISC. The MCRN CTU will preserve the confidentiality of participants taking part in the study and the University of Liverpool is a Data Controller registered with the Information Commissioners Office.

13.5.4. Quality Assurance and Quality Control of Data

QA includes all the planned and systematic actions established to ensure the trial is performed and data generated, documented/recorded and reported in compliance with applicable regulatory requirements. QC includes the operational techniques and activities done within the QA system to verify that the requirements for quality of the trial-related activities are fulfilled.

This trial has undergone a risk assessment, the outcome of which indicates that it is a low risk trial. As such, site visits will be conducted and source data verification performed only if indicated to be necessary as a result of central monitoring. To this end:

• The PI, RN and designated pharmacist from each centre will attend the trial launch meeting, coordinated by the MCRN CTU in conjunction with the chief investigator, which will incorporate elements of trial specific training necessary to fulfil the requirements of the protocol
• The Trial Coordinator is to verify appropriate approvals are in place prior to the initiation of a site and that relevant personnel have attended site specific training
• The internal QA process of the MCRN CTU involves routine audit of certain activities across all trials, including random checking of adherence to informed consent procedure (monitoring receipt of signed consent forms)
• The Trial Coordinator and Trial Statistician are to check safety reporting rates between centres
• The Trial Coordinator and Trial Statistician are to monitor screening, recruitment and drop out rates between centres
• The Trial Data Manager is to conduct data entry consistency checks and follow up data queries until resolved
• Independent oversight of the trial will be provided by the Data Monitoring Committee and independent members of the Trial Steering Committee

T–4

Where the T-4 visit is conducted at an outreach centre (i.e. a GP practice), if the patient is registered in the trial the PI will write the T-4 prescription for that patient. The RN/PI will arrange with the patient to collect the study medication from the outreach centre on a day agreed with both the patient and the dispensing pharmacy department. On receipt of the prescription, pharmacy will prepare the medication for dispensing. It will be placed in a container with a temperature monitor provided centrally through the MASCOT trial. The medication will be transported via the hospital pharmacy service which delivers hospital dispensed prescriptions to GP practices within the community. Two members of the NNUH pharmacy team will sign and date the accountability log to confirm that the prescription has been dispensed. The medication will be securely transported to the outreach clinic where the patient will collect their study medication.

T0

Where the T0 visit is conducted at an outreach centre (i.e. a GP practice), if the patient is found to be eligible for randomisation and wishes to continue in the trial, the PI will write a trial prescription which will be faxed to pharmacy. The RN/PI will arrange with the patient to collect the study medication from the outreach centre on a day agreed with both the patient and the dispensing pharmacy department. The patient will be allocated their randomisation number by pharmacy as per the standard process detailed in Section 7 and an appropriate treatment pack will be prepared for dispensing. It will be placed in a container with a temperature monitor provided centrally through the MASCOT trial. The medication will be transported via the hospital pharmacy service which delivers hospital dispensed prescriptions to GP practices within the community. Two members of the NNUH pharmacy team will sign and date the accountability log to confirm that the prescription has been dispensed. The medication will be securely transported to the outreach clinic where the patient will collect their medication.

T+8 onwards

The PI/RN will ensure that pharmacy have received a signed valid prescription at least 48 hours before the medication needs to be dispensed. On receipt of the prescription, pharmacy will ascertain the patient's randomised treatment allocation and dispense the appropriate trial treatment pack/s for that patient. The pack/s will be placed in a container with a temperature monitor provided centrally through the MASCOT trial. The medication will be transported via the hospital pharmacy service which delivers hospital dispensed prescriptions to GP practices within the community. Two members of the NNUH pharmacy team will sign and date the accountability log to confirm that the prescription has been dispensed. The medication will be securely transported to the outreach clinic where the patient will be attending for their study visit that day. The medication will then be given to the patient by the RN at the end of the visit if they are eligible and willing to continue to the next part of the study. If the patient is not eligible to continue in the trial or wishes to withdraw from trial treatment at that point, the dispensed medications will be returned to pharmacy for destruction. The RN will collect any previously dispensed used/unused medications from the patient and return them to the hospital pharmacy within five working days for destruction.

ELIGIBILITY CRITERIA SEARCH

1. Age range – 6–14 yrs 11/12 months (SHARED) – shared by all in total group (not incl or excl)

2. Asthma (H33) Any code (incls past/active)

OR children on bronchodilators and/or shorting acting corticosteroids.

No date range incl (SHARED)

3. Bronchodilaters – current prescriptions.

Try 1 script (issue) in last year (SHARED)

4^*. Not eligible (exclusion) if prescribed in the previous month and used currently Leukotriene Antagonists

Select drugs: Montelukast Zafilucast/Accolate

Issue (script) 1 in the last month

(EXCLUSION)

5^*. Exclusion not shared

Exclude long acting beta agonists (select beta agonist) if prescribed in the last previous month and used currently

Select drugs: Formoteral/fumerate

Seretride (combination flixotide+) Symbicort

Current: 1 script (issue) in the last month

(EXCLUSION)

6. Not shared

Exclude theophyline

Current last year

7. EXCLUSION

Cystic Fibrosis (CF) – C370

Cardiac congenital P6

Exclude P68 congenital heart disease

^*Please note that this criterion can be added on as an excluder when conducting the electronic search. However, depending on the time coding methods and the individual database, it may be easier to assess this during a manual notes search after the initial electronic search has been conducted to avoid any potentially eligible patients being prematurely excluded.

TO CREATE A SEARCH ON EMIS LV

Choose ST search & statistics

Select B – patient searches

Select A – build and perform a new search

Select A – search on today's practice population i.e. currently registered pop (SHARED)

Select A – add Feature

Select 2 – AGE upper 14, lower 6 (SHARED)

Select 2 – Classification Codes, type Read Code H33,

Select A – (Asthma^**) press return (answer Y to all lower codes)

Select A – no date range, A (SHARED)

Select A – add Feature

Select 7 – Drugs, when prompted ‘Search on all drugs Y/N’ enter N for No

Select B – search by drug group

Select 3 – Respiratory System Drugs

Select 3 – (corticosteroids for inhalation), press return (Y for all variants of drug group)

Press return (C current), press (A – all)

Enter date range 01/01/2008, press return, (today's date)

Press return (blank frequency)

Enter Y to continue, set operator as (SHARED)

NOW ADD IN CRITERIA FOR DRUG EXCLUSIONS

Select A – add Feature

Select 7 – Drugs, when prompted ‘Search on all drugs Y/N’ enter N for No

Select I – Ingredient or brand, type in part of the name of the drug e.g. ‘Monte’ press return

Select 1 – (montelukart sodium (G) (T)) press return, Enter – (Y to all variants), press return

Enter – (C – current) press return

Enter – (A – all)

Enter date range – (6 months ago), press return, (today's date)

Press return (blank frequency)

Enter Y to continue, set operator as B (EXCLUDE)

Select A – add Feature

Select 7 – Drugs, when prompted ‘Search on all drugs Y/N’ enter N for No

Select I – Ingredient or brand, type in part of the name of the drug e.g. ‘Salmet’ press return

Select 1 – (salmeterol xinafoate (G) (T)) press return, Enter – (Y to all variants), press return

Enter – (C – current) press return

Enter – (A – all)

Enter date range – (6 months ago), press return, (today's date)

Press return (blank frequency)

Enter Y to continue, set operator as B (EXCLUDE)

Select A – add Feature

Select 7 – drugs, when prompted ‘Search on all drugs Y/N’ enter N for No

Select I – Ingredient or brand, type in part of the name of the drug e.g. ‘Formo’ press return

Select 3 – (Formoterol Fumarate (G) (T)) press return, Enter – (Y to all variants), press return

Enter – (C – current) press return

Enter – (A – all)

Enter date range – (6 months ago), press return, (today's date)

Press return (blank frequency)

Enter Y to continue, set operator as B (EXCLUDE)

When you have entered the appropriate criteria enter Y to confirm that the features are correct (N if they are not and edit the search) always check your date range & operator status.

Save the search with an appropriate name, prefixed by ‘MASCOT’, to the directory for one off searches. Enter Y to run the search. A message in a yellow band will appear at the top of the screen when the search has completed.

To view the results go to S ‘Search results’, type MASCOT and press return. Select your search

Choose A – A table showing the distribution by age and sex.

Once you are happy with the group of patients the search has generated, via WP Word Processing module mail merge the MASCOT participant invitation letter template onto practice letter headed paper, including the patient's name & address details.

The envelope to be mailed out to the patient and their family should include:

• the participant invitation letter
• parent/guardian MASCOT Patient Information Sheet
• the age-specific MASCOT Patient information Sheet (optional)
• a stamped SAE for use when returning the reply slip to the local MASCOT team

REMEMBER – only appropriate practice staff can view identifiable patient data. MASCOT research nurses should not be accessing patient names or any data which could easily identify a patient.