1. Marina Di Marco Principal Neuromuscular Physiotherapist
Clinical Trials in DMD
Marina Di Marco
Principal Neuromuscular Physiotherapist

2. The changing landscape of research in DMD
Emily Crossley and Alex Johnson (co-founders of Duchenne UK and parents of children with DMD) were disappointed that clinical trials were being turned down in the UK because of lack of capacity.
In July 2015, a workshop co-hosted by Prof Kate Bushby, the global neuromuscular network , Treat-NMD, the NIHR and representatives from Pharmaceutical Industry and the NHS met with the common goal of finding a resolution to this issue.
By September 2015, the Newcastle Plan, a 5 year strategy to increase funding to sites throughout the UK was put in place.

3. The changing landscape of research in DMD
Patients and their families want a greater say in trials. This includes:
Which trials we bring to the UK (exon skipping, anti- inflammatory, anti-fibrotic etc)
The way in which the trials are designed
Where the trials are and the travelling involved

4. The views of patients and their families
Everyone who wishes to participate in a clinical trial should have the opportunity to do so
Time is of the essence
Early access to medication.
Trials for patients living with DMD once they are wheelchair dependent
Research and clinical management combined
What is worse than not having treatment is having treatment that cannot be accessed due to the length of time approvals take within the NHS

5. Clinical Trials are good for parents, patients and clinicians
Drive standards of care upwards
Become visible in the field of research
Patient confidence
Standards of care
Patient commitment

6. What does this mean for physios
Physiotherapists are the key clinical evaluators in many trials
The outcome measures will determine the success of a trial
We use standardised assessments that are reliable, repeatable, comparable (NSAA including the 10m walk / run and the RFF), 6MWT, 4SC, PUL, 9HPT, MFM and respiratory measures
Myometry (HHM, Dynamometer)
Goniometry
Anthropometric measures such as height and weight. In some trials we measure height twice and take the average
Assessments are videoed for QC purposes; In some trials there are 40 study sites so following the protocol to the letter is essential

7. Who are suitable for the trial?
Inclusion and Exclusion Criteria
Willingness to participate and attend all appointments
Assessments must be undertaken at the same time each visit
Child must be able to understand and participate in all of the assessments
Child must be able to focus and to repeat each task until a reliable measurement is recorded
Child can be coached through each task
Trials cost a lot of money: only screen children who will be suitable for the trial with the ability to complete the trial outcomes at each visit. Sometimes a pre-screen is necessary
If a child fails screening, it does not reflect well on the research team

8. What is the difference between the different phases of trials?
Phase I trials: This is when we start to bring trials to human volunteers.
Phase I trials are when we evaluate a drugs safety and toxicity at different dose levels. We determine the drug pharmokinteics. Before a drug can exert any effect on the body, it has to be absorbed into the body systems. We need to find out what is the best dose of the drug with the fewest side effects. Small numbers are required.
Phase II trials: This is where we will evaluate the drug effectiveness
The drug effectiveness is ready to be evaluated in people with the disease or condition being studied. Phase II studies will determine the common short term adverse effects and risks associated with the drug. At this stage new combinations of the drug can be tested.

9. Phase III Trials
Phase III trials compare the new drug to the typical standard of care
These trials assess the side effects of each drug and which drug works better. Phase III trials enroll larger numbers of patients i.e. 100+
Patients are randomized to the new drug or the standard treatment. There can be more than two treatment groups in phase III trials. The control group gets the standard-of-care treatment. The other groups get a new treatment. No one knows the trial group they are in until the end of the trial and this can be frustrating for some patients.
Every patient in a phase III study is watched closely. The study will be stopped early if the side effects of the new drug are too severe or if one group has much better results. Phase III clinical trials are often needed before the FDA will approve the use of a new drug for the general public.

10. Phase IV Trials
Phase IV trials test new drugs approved by the FDA. The drug is tested in several hundreds of patients. This allows for better research on short-lived and long-lasting side effects and safety. For instance, some rare side effects may only be found in large groups of people. We can also learn more about how well the drug works and if it’s helpful when used with other treatments.

11. What drug trials are we involved in in RHC, Glasgow?
FOR-DMD
VBP15-004
TAM-DMD
Sarepta Essence

12. FOR-DMD
Finding the Optimum Regimen of steroids in Duchenne Muscular Dystrophy: double blind randomized trial to find optimum steroid regimen (phase IV trial)
An international multi-centre double blind parallel group, months comparing three corticosteroid regimens in wide use in DMD:
Daily prednisolone (0.75mg/kg/day)
Intermittent prednisolone (0.75mg/kg/day, 10 days on / 10 days off)
Daily deflazacort (0.9mg/kg/day)

13. VBP15-004 Investigational product is Vamorolone
A Phase IIb randomised Double blind, Parallel group, Placebo and Active controlled study with double-blind extension to evaluate the long term efficacy, safety and tolerability of Vamorolone in ambulant boys with Duchenne Muscular dystrophy.

14. Tam DMD
A multi-centre randomised double blind, placebo controlled, phase III safety and efficacy 48 week trial.
The purpose of the trial is to evaluate if Tamoxifen shows positive effects on muscle function and muscle force in comparison to placebo in patients with DMD i.e. Can Tamoxifen reduce muscle function decline?

15. Sarepta essence
A Double-Blind, Placebo Controlled, Multicentre Study with an Open-Label Extension to evaluate the Efficacy and Safety of SRP and SRP 4053 in Patients with Duchenne Muscular Dystrophy.
Primary Objective: Timed function test

16. Summary The way in which we conduct clinical trials is changing
Parents and their families are steering many areas of research working in partnership with Pharma, Education and the NHS
Screening and recruiting the correct patient cohort is key for a successful clinical trial
Clinical Evaluators have key roles in providing assessments that are standardised
To be successful, committed families and a cohesive research team are essential