What is the Feasibility of the ISTEP Exercise Test in Boys With Haemophilia
Condition: Hemophilia
MeSH terms: Hemophilia A
Study type: Interventional

Summary: 
      This study will be used to assess the feasibility and sensitivity of using the iSTEP, to
      assess exercise capacity in boys with haemophilia.

      The feasibility criteria to be explored includes:

        1. Recruitment to target number or better

        2. The test procedure is completed within an allocated time (1-2 hours) and by 90% of
           participants without serious adverse events

        3. 90% of participants achieve a sufficient exercise response (85% maximum heart rate
           (HRmax))

        4. Calculation of estimates of minimum clinically important differences and variability for
           sample size calculations and responsiveness to severity of haemophilia and orthopaedic
           status The iSTEP exercise test will be compared to a more commonly used exercise test
           the modified shuttle walk test (10m- MSWT). Muscle strength (using myometry) will also
           be tested and compared to exercise performance for any relationships. Physical activity
           levels will also be assessed to obtain some baseline measurements of physical activity
           levels in this patient population, which are currently not very well known. The
           overarching aim of this current study is also to establish a robust and sensitive
           exercise test and to gain an understanding of the effects of physical activity levels
           and muscle strength on exercise capacity in this population.
    

Detailed description: 
      Identification of potential participants Eligible participants will be identified from the
      clinical patient database in the Haemophilia Centre at Great Ormond Street Hospital (GOSH)
      for Children NHS Trust. Potential participants will then be randomly selected. A simple
      randomisation approach will be employed using a computer random number table to select
      potential participants from the database. The parents / legal guardians will then be
      approached initially by the investigator via telephone to provide a brief verbal explanation
      of the research study and ask if they would be happy to receive a patient information sheet
      prior to their next clinic appointment. Should they be interested in participating in the
      study they will receive, by post, the PIS (one for parents and a separate age appropriate
      version for children) at least one week prior to their next clinic appointment. This will
      allow for a 'cooling-off' period of a minimum of one week for the potential participants. The
      researcher will then be available for questions by telephone or at the participant's next
      clinic appointment.

      For the normal healthy control exercise test comparison population, data will be obtained
      from the existing iSTEP healthy control data collected as part of the iSTEP study from
      children in primary schools in London. This sample of 30 participants will be matched to the
      haemophilia group in terms of sex, age, body mass and stature.

      Participant Recruitment

      Consent of participants:

      Most study recruits will be unable to give consent to participate due to their age. If the
      family have indicated that they are interested in participating in the study then at an
      agreed time (likely the next clinic appointment) one of the investigators from the research
      team will meet with the child participant and parent / legal guardian to complete the consent
      and assent forms as appropriate. The investigator will further explain the study procedures
      to the parent and child, why they are being asked to consider to be a part of the study and
      the associated risks and benefits of being included. The parent and child will then be given
      an opportunity to ask any further questions. The child/parent/legal guardian will then be
      asked to confirm if they agree to take part in the study. If consent is agreed a parental
      consent form will be completed by the parent/guardian and a copy will be provided. If the
      child assents then they will be asked to sign an assent form. If at any point during the
      study process the parent/guardian does not consent to inclusion in the study or the child
      withdraws their assent, then any data collected will be destroyed. Any decision to refuse or
      withdraw from the study will in no way influence the services that they receive.

      Discussion with parents about the project will be undertaken with the child present. Once the
      child's parent/guardian has given consent, the child must also indicate that they do not
      object to participating in the research activity and understand what is involved. This
      participant 'assent' will be sought from participants in concordance with the legal
      requirements in England as set out in the following documents:

        -  Children Act 1989

        -  Medical Research Council (2004). MRC Ethics Guide: Medical research involving children.
           Version 3.2 May 2007 A signed participant assent form will be completed and a copy will
           be provided (Appendix 3).

      The participant's medical team will be informed that they have volunteered to participate in
      this study, through verbal handover and documentation within the medical notes. Non-clinical
      members of the research team will only be able to access the participant's medical records
      once signed consent of this specific item has been provided.

      The evaluation of the recruitment process will include recording of percentages of refusals
      to consent and stated reasons, as part of the feasibility aspect of this study. This will
      inform the design of future studies with this group with regards to approach and recruitment
      protocols. Confidentiality Data collection and storage will be undertaken in accordance with;
      The Caldicott Principles, Data Protection Act 1998 and Confidentiality: NHS Code of Practice
      2003. The non-clinical members of the research team will only access data once consent has
      been provided from the parent/s. To ensure participant's confidentiality, data will be made
      anonymous by allocating a study participant number to identify their data. The research team
      will be the only ones to know the identity of each individual against his or her study
      number. All data will be recorded on a GOSH Trust computer under an electronic folder with
      restricted access for the investigators involved in the trial, electronic files will be
      encrypted and password protected. During the phases of data collection and analysis, only the
      chief investigator and research team will have access to the raw data and research findings.
      On completion of the research, data will be summarised and de-identified findings will be
      disseminated through publication in an appropriate professional journal and/or conference
      presentation.

      Should a participant experience exacerbation to any joint pain during the exercise trial
      process, they will be able to stop and rest at any time. Should they feel unable to continue
      they will be able to withdraw from the study. The iSTEP is an exercise test that uses a step,
      which is tailored to the participant's height. It becomes incrementally more difficult every
      2 minutes over the 10 minutes of the test, as the participant has to step up and down in time
      with a metronome (on audio track). The test ends when the participant is too tired to
      continue (see iSTEP protocol below), falls out of time with the metronome for stepping or at
      the end of the 10 minutes (that includes all 5 levels). Heart rate is taken at rest (before
      test), immediately afterwards and 3 minutes after the test.

      The 10m- Modified Shuttle Walk Test (10m-MSWT) is a fitness bleep test that is also
      incremental. There are 25 levels, each level lasts 1 minute. The audio track guides the test,
      the bleeps at the beginning of the test are spaced widely apart (e.g. 20seconds to walk 10m
      in the first level). The time between bleeps becomes shorter every minute so that the
      participant will have to start fast walking then jogging at approximately level 6. At level
      10 onwards the participant will need to run to keep in time with the bleeps. The test
      finishes when the participant is unable to continue due to , fatigue, breathlessness, or is
      unable to keep up with the bleeps. Heart rate is taken at rest, immediately after the test
      and 3 minutes after the test is finished (protocol below). Muscle myometry: uses a device to
      measure muscle power and is commonly used in research. The participant will be asked to push
      against resistance as strongly as they are able and the maximal power is calculated by the
      device (protocol below). Accelerometry: Activity will be measured using the ActiGraph GT3X,
      an accelerometer that measures volumes and patterns of activity. The ActiGraph has been
      extensively validated in children. A 15-second sampling epoch will be selected in order to
      optimize the ability to capture the sporadic nature of children's activity. Children will be
      asked to wear the accelerometer on an belt on the right hip for seven consecutive days during
      all waking hours. Accelerometers will be provided to families on the testing day and they
      will be asked to return it as soon as possible after the monitoring period (7days) using a
      supplied pre-paid envelope.

      PROTOCOLS:

      iSTEP Protocol Preparation

        -  The explanation to the participant is located on the pre-recorded audio track

        -  They will be required to step up and down in time with a metronome.

           - The height of the step is standardised for each child and will be based on
           approximately 50% of the length of the child's fibula.

        -  There is a bell to start. Thereafter the audio-track emits a metronome bleep at set
           speeds for 2 minutes at regularly spaced intervals.

        -  After every 2 minutes, the speed of stepping is increased by a small increment, so the
           participant steps progressively faster; the change in incremental stepping speed is
           indicated by a bell bleep.

        -  The first speed of walking is referred to as LEVEL 1, the second as LEVEL 2, and so on.
           Each level lasts for 2 minutes and the audio-recording continues for 5-levels (10
           minutes in total). Each level contains a number of steps the number of which is dictated
           by the speed of that level.

        -  The first level reciprocally stepping up and down at a rate of 36

        -  To help the participant establish the first very slow speed of stepping, the operator
           steps alongside for the first time.

           4. End point of the test

        -  If the participant completes the 10 minutes (5 levels of the test) the test is
           completed.

        -  The end point of the test may be determined by the operator when:

             -  Inability to maintain rhythm with the metronome, progressive speeding up and
                slowing down for >30 seconds

             -  Loss of coordination

             -  Light headedness

             -  Extreme exhaustion

             -  Sudden pallor

             -  Undue signs of distress including severe wheezing or chest pain 10M MODIFIED
                SHUTTLE WALK TEST (25 LEVELS) PROTOCOL GENERAL INSTRUCTIONS Similar guidance to
                participants as provided for iSTEP Starting the test

        -  There is a triple bleep to start. Thereafter the audio-track emits a single bleep at
           regularly spaced intervals. The participant should aim to be at the opposite end to the
           start by the time the bleep sounds.

        -  After first minute, the speed of walking is increased by a small increment, so the
           participant walks progressively faster; the change in incremental speed is indicated by
           a triple bleep.

        -  The first speed of walking is referred to as LEVEL 1, the second as LEVEL 2, and so on.
           Each level lasts for 1 minute and the audio-recording continues for 25-levels. Each
           level contains a number of shuttles (10m in length), the number of which is dictated by
           the speed of that level. End point of the test

        -  The end point of the test may be determined by the participant:

      When he or she becomes too breathless to maintain the required speed

      • The end point of the test may be determined by the operator when: Undue signs of distress
      including severe wheezing or chest pain Failure of the patient to complete the shuttle in the
      time allowed. This test takes approximately 10-15 minutes, dependant on participant. MUSCLE
      MYOMETRY PROTOCOL A hand held dynamometer will be used to record the force produced by a
      maximum voluntary isometric contraction (MVIC) of the knee extensors, and ankle dorsi and
      plantar flexors. This test will take 5-10 minutes as part of their routine clinical
      examination. The total time required of the participant, on top of the routine clinic visit
      will be approximately 1 hour 30 minutes.

      A14-1. In which aspects of the research process have you actively involved, or will you
      involve, patients, service users, and/or their carers, or members of the public? Design of
      the research Management of the research Undertaking the research Analysis of results
      Dissemination of findings None of the above Give details of involvement, or if none please
      justify the absence of involvement.

      Parents and children were approached to provide comments and changes to the PIS forms in
      wording and design. In addition they provided opinion upon the potential burden of the of
      undertaking the testing. They reported that they did not feel the testing protocol sounded
      too onerous on top of normal clinical assessment.
    

Intervention name(s): iSTEP exercise testing
Intervention type(s): Other
Intervention description(s): iSTEP 10 minute step test, up and down on a commercial standard 3-height adjustable step Undertaking the 10m-MSWT 20-30 minutes Procedure takes place on testing track at Great Ormond Street Hospital; a 5 minute walk from the Haemophilia Centre. One of the research team accompanies the family with child to the track and will accompany them back to the Centre once testing is finished. Muscle Myometry 10 minutes, carried out by one of the research team at the end of the physiotherapy clinical assessment in the Haemophilia Centre. Wearing of accelerometer (activity/ step counter)7 days Device will be set up and provided at the end of the testing on the day of attendance at clinic. They will be instructed to wear this throughout the week at home when they are awake (at least 8 hours). Haemophilia Joint Health Score (HJHS) - a standardised outcome measure of joint health in people with Haemophilia, undertaken by the Clinical Specialist Physiotherapists in Haemophilia.
Other intervention name(s): 10 metre Incremental Shuttle Walk Test; Muscle Myometry; Accelerometry; Haemophilia Joint Health Score (HJHS)
Intervention model: Single Group Assignment
Intervention model description: Each child with haemophilia will undertake both the iSTEP exercise test and a modified shuttle walk test (10m-MSWT) in a randomised order on the same day with a washout period of at least 1 hour. This data will then be compared to previously collected normative data for the iSTEP test from healthy school age children from the original iSTEP development and validation study (Rand et al, 2015).
The second component will include the feasibility of collecting standardised lower limb clinical muscle myometry measurements. The third component will be to explore the viability of collecting physical activity level data, in this population over a 7 day period using an accelerometer. This will be evaluated by monitoring the adherence to accelerometry wear. The value of the data will also be used to determine if it is useful at informing other aspects of fitness for boys with haemophilia.
Masking: None (Open Label)
Primary purpose: Basic Science