Two ALS Staging Systems May Be Useful Assessment Tools in Clinical Trials

Two amyotrophic lateral sclerosis (ALS) staging systems — the King’s and the Milano-Torino’s, known as MiToS — may effectively assess changes in patients’ clinical progression and treatment responses, a study suggests.

The data also supported the previously reported complementary nature of these two systems, showing that the King’s was more sensitive to changes during early to mid-disease, while the MiToS system captured differences at later stages of ALS.

These findings support the use of both staging systems as assessment tools in ALS clinical trials, the researchers said.

The study, “Clinical staging in amyotrophic lateral sclerosis: analysis of Edaravone Study 19,” was published in the Journal of Neurology, Neurosurgery & Psychiatry.

Most ALS clinical studies rely on changes in the total ALSFRS-R score — the results of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised — as their main goal.  However, this type of functional scales may not place sufficient focus on key milestones in disease progression, researchers say.

Notably, ALS staging systems — such as the King’s and MiToS systems, which capture the observed progressive loss of independence and function in ALS — could potentially offer useful additional and complementary information to functional scales.

The King’s clinical staging system assesses the anatomical spread of ALS, based on the number of affected regions — brain stem (bulbar) and arms and legs — as well as late-stage nutritional and respiratory failure. Notably, the bulbar region of the brain controls the muscles involved in swallowing, speaking, and breathing.

Scores in the King’s system range from 1 for early disease with one region involved, to 4, for late disease, with stage 5 being death.

In turn, the MiToS functional staging system comprises six stages, based on the number of functional domains with loss of independent function. This scale ranges from stage 0 being normal function to stage 5 being death.

These staging systems were shown to be complementary in previous studies, with the King’s system having “greatest resolution in early to mid-disease and MiToS showing higher resolution for later stages of disease,” the researchers wrote.

Now, a team from Mitsubishi Tanabe Pharma America (MTPA), along with colleagues in the U.S., the U.K., and Italy, evaluated the potential utility of the King’s and MiToS systems as clinical tools by retrospectively analyzing data from the Phase 3 Study 19 (NCT01492686).

That completed study compared the safety and effectiveness of MTPA’s Radicava (edaravone) against a placebo in 137 ALS patients. The participants were randomly assigned to receive six cycles of either Radicava or a placebo, directly into the bloodstream, for 24 weeks (nearly six months).

A total of 123 participants completing treatment — 65 on Radicava and 58 on a placebo — entered the study’s extension part, in which all received Radicava for an additional six months.

Results from the first part of the study showed that six months of treatment with Radicava significantly slowed patients’ functional decline, by 33% as assessed with the ALSFRS-R, compared with a placebo.

The extension study findings suggested that those always on Radicava continued to experience slower disease progression, while patients previously on a placebo started to benefit from the therapy.

In the current analysis study, the scientists used the ALSFRS-R scores of Study 19’s participants to determine their King’s and MiToS stages and assess the proportion of patients showing disease progression based on these staging systems.

The results showed that, at study entry, all participants were at MiToS stage 0 (normal function) and about 80% were at King’s stage 1 or 2 — bulbar only to bulbar and upper limb involvement.

Both the King’s and MiToS staging systems appeared to detect differences in clinical progression between patients on continuous Radicava treatment and those initially assigned to a placebo.

Particularly, the King’s system captured greater, but not statistically significant differences in the first six months of the study (the placebo-controlled part), with fewer Radicava-treated patients showing disease progression (42%) compared with those given a placebo (55.9%).

In addition, Radicava appeared to show the greatest effects in slowing the transition from King’s stage 1 to stage 2, which “may be particularly important to patients, as this is when disability is relatively low” and health costs are less, the researchers wrote.

In contrast, the MiToS system appeared to capture later differences between patient groups.

These differences reached statistical significance when considering disease progression of at least two stages, which occurred more than twice as often among patients starting Radicava later on (23.5%) than among those on continuous Radicava treatment (10.1%).

Even though Study 19 was not designed to assess effects on clinical staging, these findings suggest that both ALS staging systems may be useful assessment tools in clinical trials, the investigators said.

“The independent and complementary nature of the 2 systems, one tracking anatomical spread of disease (the King’s Clinical Staging System) and the other focusing on loss of function (the MiToS system), means they can provide different insights that may be particularly important in counselling patients on the potential benefits of therapy,” the team wrote.

Notably, the MiToS system is currently being used as the main goal in a Phase 2 trial (Eudract no. 2014-005367-32) called PROMISE, and the King’s system as a secondary goal in the Phase 2 MIROCALS study (NCT03039673). The MIROCALS trial is ongoing in France and the United Kingdom, while PROMISE is underway in Italy.

Data from these ALS trials will also help to determine the true value of these staging systems as key clinical assessments.