1 2 aim

#apaperaday: Functional trajectories before and after loss of ambulation in Duchenne muscular dystrophy and implications for clinical trials

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Functional trajectories before and after loss of ambulation in Duchenne muscular dystrophy and implications for clinical trials

The pick is from @PLOSONE by McDonald et al on the trajectories of upper limb and respiratory functions during the transition period around loss of ambulation. DOI: 10.1371/journal.pone.0304099

Duchenne is a progressive muscle wasting disease where patients lose ambulation, upper limb function and respiratory and heart function. Trials for Duchenne are challenging, due to the fact that there is not one outcome measure that can capture all disease stages.

The focus so far has been on ambulatory patients – which runs the risk of a small label for approved drugs (if you only test in ambulatory patients, you do not know the benefit risk ratio in non ambulatory patients). Outcome measures for upper limb and respiratory function exist

However, usually trials looking into these outcomes focus completely on non-ambulatory patients. Here authors argue that patients might already lose respiratory and upper limb function during the transition phase from ambulatory to early non-ambulatory.

To test this they analyzed a natural history dataset (PRO-DMD-01, aka the BioMarin/Prosensa natural history data) which include 269 patients, 219 of whom were ambulatory at baseline, and 51 of those who lost ambulation during the follow up.

Loss of ambulation occurred on average at 12.7 years (7-18.5 years) and at that time the predicted forced vital capacity (FVC) was 79% and the performance upper limb score (PUL) had a mean score of 64 (is the maximum score).

The group losing ambulation before age 12 was less likely to be on daily steroids and had a shorter time on steroids. These individuals also had a lower FVC and %predicted FCV score and more ankle contractures. PUL scores were the same with those losing ambulation after age 12.

Authors show that the trajectories of the PUL and FCV are very variable between patients after loss of ambulation. However, on average patients lose 5.6% % predicted FCV per year before losing ambulation and 10.7% after; For PUL this is 2.3 vs 3.8 points per year, respectively.

Authors note that these differences (decline before and after loss of ambulation) do not significantly differ. This is probably due to the variability between patients and the relatively small number of patients included.

Authors looked at upper limb and FCV milestones. At the time of loss of ambulation, 50% of patients had a % predicted FVC of less than 80% and all patients reached this milestone within 2 years after losing ambulation. For PUL, 75% had a PUL entry score <6 at loss of ambulation.

PUL entry score is a score of 6 items to assess basic function – the maximum score is 12. Within 1.5 years after losing ambulation, all patients reached the entry score <6 for the PUL. Taking 10 seconds or more in the 10-meter walk/run test predicted loss of ambulation within 1 year.

In North Star Ambulatory Assessment (NSAA) the inability to stand on 1 leg & to step up/down 1 step were also predictive of losing ambulation. Authors discuss that the analysis shows that patients start losing respiratory and upper limb function already before losing ambulation.

They argue that this means that when a clinical trial uses respiratory function or PUL outcome measures the sponsors do not have to restrict themselves to only ambulatory patients, but can include those who are in the transition phase as well.

They also argue that time to event scores (e.g. % predicted FVC or getting below a score on the PUL or a PUL subscale) might be good ways to measure clinical benefit. They propose a composite score – the multidomain response index may be an alternative (if this is realistic).

Authors discuss that the patients who lose ambulation later were significantly heavier. This could be because they are more likely to be on daily steroids and/or because they have used steroids longer (so side effect related, not per se the cause of walking longer).

Authors discuss that a positive aspect of their analysis is that they used a prospective natural history dataset rather than retrospective analysis. However, the sample size was limited. So more work is needed to confirm the findings.

However, I think the message that sponsors should think less black and white about loss of ambulation and ambulatory vs non-ambulatory when designing trials is an important one.