June 7/8, 2013
In February, 2013 EMA (Europeans Medicines Agency) released draft “Guidelines on the clinical investigation of medicinal products for the treatment of Duchenne and Becker muscular dystrophy” open for comment. This is the result of advances in basic and clinical research with an ever increasing number of clinical trials, recruiting small numbers of patients for these studies. This has raised a number of issues to include study design, the choice of appropriate efficacy endpoints, the definition of reliable surrogate outcome measures as well as the need for subgroup analyses with respect to the heterogeneous patient population and the duration of trials (keeping in mind, some interventions may not demonstrate the full impact of an intervention within the context of a 48 week trial). Treat NMD and UPPMD (International PPMD groups) have been working together over these last weeks and months to prepare a formal response to the guidance.
Tools for measuring –conceptual framework- measures that can follow disease progression. These tools are indicative of the types of tools that have been used for clinical trials and large multi-center natural history studies. The committee recognized that if tools are to be used in clinical trials, they need to be shown to be valid, reliable, and sensitive to change at a particular point in the disease state. These outcome measures should have been used in multi-center trials and shown to be prognostic of future changes in the disease.
The table below depicts a range of outcome measures that have been used during the early stage of the disease (under 5), during the ambulant stage, early non-ambulant stage and late non-ambulant stage. This list details the major test that have been used and the age range for the outcome measure. However, this is not an exhaustive list. Not all of the tools listed below have had adequate validity, reliability, and sensitivity to change data to be used as a primary outcome in the current regulatory climate. The choice of tools will depend upon the therapy tested, the stage of the disease, and the whether the outcome measure has been shown to have a well-developed conceptual framework, and be valid, reliable and sensitive for the given population.
- Bayleys III locomotor scale. Age range is one month-42 months.
- Griffiths locomotor scale. Age range is birth-4.5 years.
- NorthStar Ambulatory Assessment. Age range is 3.5 years until non-ambulatory.
- MRC manual muscle testing (MMT) of strength. Age range is 4 years and older.
- 6-minute walk test (6MWT). Acceptable age range is 4-5 years until non-ambulatory
- NorthStar Ambulatory Assessment. Age range is 3.5 years until non-ambulatory.
- Timed Function Test (TFT) of activities (lie-to-stand, sit-to-stand, climb 4 stairs, walk/run 10 M). Age range is 4-5 years until non-ambulatory.
- PODCI (pediatric outcomes data collection instrument). At younger ages the PODCI is a proxy measure of functional activities by parent or caregiver at ages 4-11. At older ages the PODCI is a person-reported outcome measure (PROM)age ages 11 and older.
- Respiratory function tests (Forced vital capacity, Peak cough flow, maximum inspiratory pressure [MIP], and maximum expiratory pressure [MEP]). Ages 6 and older.
- Manual muscle testing (MMT) Age range is 4 years and older.
- Quantitative muscle testing (QMT). Age range is 5 years and older.
Non-Ambulant: (< 3 years nonambulant) and late (> 3 years nonambulant.
- Patient reported outcome for Upper Limb (PUL)
- Quantitative strength testing (pinch test, grip test, elbow extensors, elbow flexors, etc.)
- Quantitative measure of reachable workspace which measures shoulder movement
- Quantification of for non-ambulatory patients, especially elbow and digit movement
- Respiratory function tests (Forced vital capacity, Peak cough flow, maximum inspiratory pressure [MIP], and maximum expiratory pressure [MEP]).
- Patient reported outcome measures developed by Nathalie Goemans. In non-ambulatory patient, there are 3 specific domains that are considered – high level (shoulder) mid (elbow) and distal (wrist and finger).
- EK scale
What we are learning:
- That all deletions are not alike. That boys with exon 45 deleted (skipping 44) have a more mild phenotype and are intermediate Duchenne or Becker.
- That very young boys are abnormal even when they are doing some of the skills in a similar way as other children their own age. Part of the problem is that the boys are acquiring skills as part of their normal development, while they are losing skills at the same time due to the progression of the disease. As a result, a function may appear stable for a time even as strength is decreased. Therefore, we need to develop outcome measures that will be able to tease out these issues. In some of the outcome measures this can be done by comparing Duchenne boys to typically developing able-bodied controls. This is similar to CDC growth charts of height and weight.
- The 6-minute walk test (6MWT) have been shown to be valid, reliable, and sensitive to change. During a 48-week time period, it can sensitively measure by changes due to age and therapeutic intervention during the ambulant stage. The 6MWT has been shown to be a prognostic measure of future changes in the progression of the disease, has been used in several natural history studies, and has been used in both multi-center pharmaceutical studies and multi-center natural history studies. The 6MWT is useful as an outcome and predictive of ambulation, that it correlates to Timed Function Testing (TFT) as well as the North Star (NSAA)
- Outcome measures for the upper limbs and non-ambulatory stage is not so clear. However, recent work has developed potential outcome measures with the characteristics to be valid for clinical trials. Over the past three years, tests have been developed to test upper limb activities (PULS), shoulder motion (quantification of reachable workspace), elbow and digit motion, and patient-reported outcomes for the non-ambulatory patient. These measures are conceptually sound, and have been shown to be valid and reliable. More work needs to be done to show that they are sensitive to change and have utility in a multi-center trial or natural history study.
- Quantitative muscle testing (QMT) has been shown to be a valid, reliable, and sensitive measure of strength. Its usefulness in a 48-week trial in Duchenne will depend upon whether the drug has a large enough of an effect to demonstrate a change in strength in Duchenne boys.
- Respiratory function testing has been shown to be valid, reliable, and sensitive in some populations. Its usefulness in a 48-week trial in Duchenne will depend upon whether the drug has a large enough of an effect to alter the respiratory function. That grip/pinch testing correlates with respiratory function.
- Recently, several different patient reported outcome (PRO) measures have been assessed in natural history studies of Duchenne. These include the PODCI, PedsQL, PedsQL neuromuscular module, NeuroQol, and patient reported outcome measures developed by Nathalie Goemans. Each PRO has several different domains/categories. Although all of these measures are valid and reliable, only the PODCI has been shown to be sensitive to change over a 48-week period. The PedsQL measures have not shown change over time. The other measures (NeuroQol, Natalie Goemans’ upper extremity measure) have not yet been assessed for sensitivity to change in a large multicenter study over a year period.
- Patients needing exon 51 skip are in the majority of the Duchenne population (13%). The number of patients needing other exons skipping compounds (44, 45, 50, 53) include exponentially less patients
- That we need to utilize novel trial designs that involve patients at every stage of the condition
- That we need to explore testing methodologies in terms of their predictive value on progression of the disease in different domains, such as arm function, use of non-invasive ventilation and survival