Table 5 Summary of amendments

1.

29/01/16

1. Consent to contact forms

MAGENTA 8-15 assent to contact 11082015 d0.6

MAGENTA 16-17 consent to contact 11082015 d0.6 *

MAGENTA parent carer consent to contact 11082015 d0.6 *

The above 3 documents currently have a box for “research ID” this needs to be changed to “consent ID”. We are also changing the wording from “research nurse” to “research team”.

In addition, the 2 consent documents marked with * need a section where participants/ parents can document the participants date of birth.

We would therefore like to change the above three documents to:

MAGENTA 8-15 assent to contact 18112015 d0.7

MAGENTA 16-17 consent to contact 18112015 d0.7

MAGENTA parent carer consent to contact 18112015 d0.7

2. Consent to study forms for parents of participants age 16-17

Participants aged 16-17 do not need parents to consent on their behalf; however, parents are being asked to complete parental questionnaires and do need to provide consent to this research procedure. We have therefore designed the consent form:

MAGENTA parent carer consent to study (16-17) 18112015 d0.1

3. Consent to study forms

MAGENTA 16-17 consent to study 18112015 d0.5

MAGENTA parent carer consent to study 18112015 d0.5

We will use data collected during the feasibility study for the full scale trial. We need participants to give their consent and will now include the wording “I agree that data collected about me can be used in the full trial”. We are also changing the wording from “research nurse” to “research team”.

See new forms below:

MAGENTA 16-17 consent to study 23102015 d0.6

MAGENTA parent carer consent to study 23102015 d0.5

This info has also been included in: MAGENTA parent carer consent to study (16-17) 18112015 d0.1

4. Consent to discussion

MAGENTA 8-15 assent to record discussion 18112015 d0.7

MAGENTA 16-17 consent to record discussion 18112015 d0.7

We are changing the wording from “research nurse” to “researcher”.

Clearer instruction on how to complete the form have been provided with the line “Please answer the following questions by circling ‘yes’ if you agree”.

The line “I confirm that I would like to hear more information about this study” had been removed because it is unnecessary.

“I understand that I can switch off the recorder or stop the discussion without having to give a reason”. The wording of this line has been amended to make it more child-friendly.

The parental consent box has been removed from the 16-17 consent form, because it is unnecessary.

5. Protocol

We may carry out qualitative interviews via Skype. We have therefore added the following sentence to the protocol:

“Interviews will take place in clinic, in the participant’s home or via Skype.”

The wording “special clinical psychologist” has been changed to “specialist psychologist” in line with the services practice.

2.

31/03/16

The following amendments were made to the protocol:

1. Additional background information has been included. This provides further clarification on the current evidence based and better defines the treatments. The protocol has been changed from:

“NICE recommends that children with CFS/ME are offered either CBT, Graded Exercise Therapy (GET) or activity management effective in adults with CFS/ME but there is no evidence for the effectiveness or cost-effectiveness for paediatric CFS/ME. There is also limited evidence on the acceptability of GET for children with CFS/ME or on the best method for delivering GET in terms of intensity (frequency of sessions) and length of treatment (number of sessions and length of time for follow up).”

to:

“NICE recommends that children with CFS/ME are offered either Cognitive Behavioural Therapy (CBT), Graded Exercise Therapy (GET) or Activity Managemen t[5]. GET stabilises physical activity levels, before gradually increasing at a manageable rate. Activity management establishes a baseline for all activity (mainly cognitive, such as school and homework, in children and adolescents) which is then increased [5, 7]. There is good evidence for the effectiveness of CBT in children with CFS/ME [8,9,10]; however, there is no evidence for the effectiveness of GET in children although GET is moderately effective in adults [11]. There is also limited evidence on the acceptability of GET for children with CFS/ME or on the best method for delivering these interventions in terms of intensity (frequency of sessions) and length of intervention (number of sessions and length of time for follow up).”

2. The aims and objectives have been re-worded to offer more specific details. The protocol has been changed from:

• To investigate the recruitment process including eligibility assessment, the recruitment interview and the views of children and parents about the recruitment process.

• Assess the number of eligible children, the number of children approached, the number recruited and the number retained in the first 6 months of the study.

• To assess issues of retention and interviewing those who drop out of the study.

• Assess the acceptability (satisfaction and compliance) of graded exercise therapy and activity management.

• Assess the feasibility and acceptability of using accelerometers to measure physical activity in children with CFS/ME.

• Evaluate whether the two treatments are distinct and being delivered in a consistent manner across centres.

to:

• Assess the number of eligible children, the number of children approached, the number recruited and the number retained in the first 6 months of the study.

• Identify barriers and facilitators to trial recruitment with a view to addressing barriers where possible.

• Explore issues of retention and understand why people drop out of the study.

• Assess the acceptability (satisfaction and adherence) of GET and activity management.

• Assess the feasibility and acceptability of using accelerometers to measure physical activity in children with CFS/ME.

• Evaluate whether the two interventions are distinct and being delivered in a consistent manner across centres.

3. The protocol previously stated that the recruitment discussion would be carried out by a “research nurse”. This has been amended to enable any trained member of the research team to undertake these calls, therefore the wording is more generic e.g. “member of the research team” or “the recruiter”.

4. The protocol currently states that recruitment discussion will be carried out over the phone or face-to face. We have updated the protocol to indicate that the recruitment discussion may also take place over Skype. This is because the service is routinely using Skype and potential participants and their parents have requested this.

5. The protocol previously stated that activity management would be carried out by CFS/ME specialists that are not physiotherapists. The protocol has been amended to state that any activity management trained CFS/ME specialist, including physiotherapists, may deliver this intervention.

6. The protocol previously stated that graded exercise therapy (GET) would only be carried out by GET-trained physiotherapists. The protocol has been amended to state that any CFS/ME specialist who has been trained in GET (including occupational therapists, nurses, psychologists) may deliver this intervention.

7. The protocol previously stated: In both treatment arms, children, their parents/carers and the clinician providing treatment will choose the number of follow-up sessions (between 8 and 12) and the frequency of appointments (every 2–6 weeks) within a maximum length of treatment of 1 year.

The amended protocol offers estimations for frequency and duration and clarifies that trial intervention should be carried out in line with standard clinical practice:

In both treatment arms, children, their parents/carers and the clinician providing treatment will choose the number of follow-up sessions (estimated to be between 8 and 12) and the frequency of appointments (every 2–6 weeks), in line with standard clinical practice.

8. We have changed the protocol to indicate that therapist may offer intervention sessions via Skype. This is because this has become routine clinical practice and patients and parents have requested this. In this instance, sessions will still be audio recorded. Children will be asked to provide consent to the audio recording of treatment session on paper forms, to be returned by post, or on-line via the redcap system.

9. The protocol previously stated:

We will assume that the intervention is not acceptable for participants who DNA or have late cancellations for > 25% of follow-up appointments.

On the recommendation of the trial management group, this has been changed to:

We will assume that those who did not attend (or cancelled within 24 h) three or more consecutive appointments or 50% of appointments did not find the interventions acceptable.

10. The outcome measure EQ-5D-5 L has been changed to EQ-5D-Y. The EQ-5D-Y is designed and validated for use with younger populations. Both the trial management group and trial steering committee advised that the EQ-5D-Y should be used in this trial.

11. The trial management group recommended that wear diaries should only be sent to participants in the initial stages of the study to determine the validity of accelerometer data. Beyond this, the diaries would be an additional burden for participant with little added benefit. The protocol previously stated:

Participants will be asked to complete a log of wear time (time worn and time taken off) which can be integrated with their activity/exercise diaries.

This has been updated to:

In the initial stage of the study approximately 10 participants will be asked to complete a log of wear time (time worn and time taken off). This wear diary data will be compared against accelerometer data to check for the validity/ reliability of using accelerometers with young people with CFS/ME.

12. Further details about the analysis of accelerometer data have been provided. The following have been added:

The accelerometer data will be processed to identify mean minutes of sedentary, light and moderate to vigorous intensity physical activity per day using established accelerometer cut-off points and protocols16 24 . The mean accelerometer counts per minute, which provides an indication of the volume of physical activity in which the participant engages, will also be calculated using established methods.

13. We have changed the protocol to indicate that the qualitative interviews will also be offered over Skype. If the interview takes place over Skype,s children will be asked to provide consent on paper forms, to be returned by post, or on-line via the redcap system.

14. Stop-go criteria for the study has been added:

Proposed stop criteria for MAGENTA: We will not proceed to the full trial if at 12 months (end of August 2016), one of the following is true:

• We have recruited less than 70 children (~ 70% of the target specified) AND if the qualitative data collected suggests that we cannot improve recruitment by changing recruitment methods

• The 6-month follow-up is less than 80% and AND if the qualitative data suggests we cannot improve follow-up.

• The qualitative data suggests the interventions are not acceptable to children and/or their parents.

• If the DSMC recommend the trial is stopped for safety reasons and if the TSC agree with this decision.

15. Further details about safety analysis have been added. The following are now detailed:

Safety outcomes

For safety outcomes, we will prospectively collect serious and non-serious adverse events defined as any clinical change or illness reported at clinic or postal follow-up. We will define a serious deterioration in health as: a decrease ≥ 20 in SF-36-PFS or scores of “much” or “very much worse” on the Clinical Global Impression scale; clinician reported serious deterioration in health; or withdrawal from treatment because of feeling worse. Safety outcomes will be analysed by the Data and Safety Monitoring Committee (DSMC) and reported to the Trial Steering Committee.

Frequency of analyses

The first interim safety analyses will be at 10 months (before the trial transitions from the feasibility to full phase). The DSMC will decide on the second safety analyses which may be at 18 months or when 50% of children have been recruited. The safety analyses will be used to ensure that neither intervention arm is having a detrimental effect. These analyses will only investigate safety outcomes and will be conducted by an independent statistician with results provided to the Data and Safety Monitoring Committee.

Data and Safety Monitoring Committee (DSMC): (3 independent experts in CFS/ME, statistics and trials) will have unblinded access to the data to make recommendations to the TSC on whether there are safety reasons to stop the trial.

16. The protocol previously gave a target sample size for all three sites combined. The new protocol offers a target sample-size for each site.

17. The protocol previously stated that the feasibility study would recruit for 13 months; this has been amended to 12 months.

3.

27/07/16

1.Changes to wording in the protocol

• We have updated the Background section of out protocol to incorporate further studies in the field. We have changed “no evidence” to “little evidence”, and we have now included references to Lim and Lubitz (2002), Gordon and Lubitz (2009) and Gordon et al (2010).

• We have corrected a typo “on” to “of”

• We have changed the wording through from “child” or “children” to know say “Child and adolescent” or “children and adolescents” or “young person” or “young people” or “participants.” This more accurately describes our study population.

• We have made additional comments about the exclusion criteria section, to provide further definition and explanation. This has changed from: “Children will be excluded if they:

- are too severely affected to attend hospital appointments (and require a domiciliary assessment);

- are referred for CBT at their first clinical assessment;

- are unable to attend follow-up appointments; “

To:

“Children and adolescents will be excluded if they are severely affected. NICE defines severe CFS/ME as individuals who are unable to do activity for themselves, or carry out minimal daily tasks only, they have severe cognitive difficulties and depend on wheelchair for mobility 5; or are referred for CBT at their first clinical assessment or are unable to attend clinical sessions. Eligibility assessment will be carried out by the clinician at assessment and confirmed by the recruiting researcher.”

2. Amendments to health economics forms

We have had a poor response rate to our health economic forms, and we want to address this issue during the feasibility stage. We have been working closely with our Trial Management Group and our Health Economists and have developed a second version of the baseline, 6- month and 12-month questionnaires. The new forms continue to capture our primary outcomes. However, we have removed unnecessary questions, streamlined others, changed wording and have re-structured the forms to make them more user-friendly. We have attached both the original versions and second versions of these forms.

We have changed the wording in the protocol to reflect changes. From:

“Both parents will be asked to complete 3 inventories on-line at baseline, 6 and 12 months follow-up including:

socioeconomic status (baseline only); an adapted 4 item Work Productivity and Activity Impairment Questionnaire (General Health V2.0 [WPAI:GH])30 and an adapted existing healthcare resource use questionnaire to measure health service use (e.g. GP or specialist care), educational service (e.g. school counsellor) and travel costs.”

To:

“Both parents will be asked to complete 3 inventories on-line at baseline, 6 and 12 months follow-up including: an adapted 6-item Work Productivity and Activity Impairment Questionnaire (General Health V2.0 [WPAI:GH])30 and an adapted existing healthcare resource use questionnaire to measure health service use (e.g. GP or specialist care), educational service (e.g. school counsellor) and travel costs.”

3. Closing down the Cambridge site

We are unable to recruit from the Cambridge site because there is no support for recruitment and the clinical team is unable to deliver the trial as per protocol.

Our protocol has been amended. It now states that we will be recruiting from Bath and Newcastle only.