Relapses Can Obscure Quality-of-life Ratings in Trials

Experiencing disease relapses after receiving a placebo in a clinical trial may change the perception of health in participants with neuromyelitis optica spectrum disorder (NMOSD) and lead to an underestimation of the disease’s impact on quality of life, a study shows.

This effect — known as “response shift” — may result in less pronounced differences in self-reported quality of life between placebo and treatment groups and subsequently underestimate a therapy’s benefits.

These findings also highlight the need for improved self-reported quality of life measures that better capture aspects that become more important when a person experiences a relapse.

The study, “Response-shift effects in neuromyelitis optica spectrum disorder: a secondary analysis of clinical trial data,” was published in the journal Quality of Life Research.

While clinical trials are designed to provide unbiased estimates of treatment outcomes, in some cases “a treatment may have an unarguable benefit on objective outcomes but a less clear impact on more subjective outcomes,” the researchers wrote.

These discrepancies may be explained by the presence of so-called response-shift effects, which refer to the idea that a change in health status may alter a person’s standards, values, or conceptualization of some concepts such as “quality of life.”

Increasing evidence suggests that these response-shift effects can influence clinical trial results, either overestimating or underestimating treatment benefits, and several studies have tested for their presence in clinical trials.

The PREVENT Phase 3 trial (NCT01892345) evaluated the safety and effectiveness of Soliris (eculizumab, by Alexion Pharmaceuticals) against a placebo in 143 adults with NMOSD who tested positive for autoantibodies against the naturally produced AQP4 protein.

Present in at least two-thirds of NMOSD cases, these abnormal antibodies promote the activation of specific complement system pathways, which contribute to nerve cell damage and are targeted by Soliris. The complement system is a set of more than 50 blood proteins that contribute to the body’s natural immune defenses.

PREVENT’s top-line data showed that Soliris-treated patients had a significantly lower risk of relapse, compared with those given a placebo, meeting the trial’s main goal. These positive findings supported the therapy’s approval in several countries for NMOSD adult patients with AQ4P autoantibodies.

However, less pronounced or null benefits were observed in subjective, or self-reported, measures, including the European Quality of Life 5-Dimension 3-Level (EQ-5D-3L), which assesses a patient’s health state in five domains: mobility, self care, usual activities, pain/discomfort, and anxiety/depression.

In the new study, researchers at DeltaQuest Foundation assessed whether response-shift effects could explain the discrepancies between results of objective and subjective measures in the PREVENT study. Of note, DeltaQuest is a non-profit organization focused on innovative quality-of-life research.

Since current methods to detect response-shift effects rely on a relatively large number of patients, the researchers developed a new and more appropriate approach for smaller patient samples, such as those included in PREVENT.

Given that Soliris was highly effective at preventing relapses, the team analyzed whether both treatment groups (Soliris vs. placebo) and the relapse status (no relapse vs. clinician-assessed relapse vs. relapse assessed by an independent panel) drove response-shifts in these patients.

If the data suggested the presence of such effects, the team would conduct further analysis to examine any perception changes to certain quality of life aspects (recalibration) and such changes over time (reprioritization), as well as whether certain measures captured unique quality-of-life aspects that distinguished the groups (reconceptualization).

Results showed that PREVENT participants changed the way they thought about health based on treatment- and relapse-related experiences, through recalibration, reprioritization, and reconceptualization.

“We found that, among [placebo] patients and as relapse criteria became more specific and rigorous, commonly accepted clinical and demographic indicators explained less well the patients’ QOL [quality of life] ratings,” the researchers wrote.

These response-shift effects resulted in better-than-expected quality of life ratings — likely underestimating the impact of placebo and relapse on quality of life, and reducing the differences between data from the placebo and Soliris groups.

As such, “the benefit of [Soliris] is likely even greater than what was documented in the pivotal clinical trial, extending to subjective outcomes,” the researchers wrote.

“We conclude that there are other aspects of QOL that become more important when one experiences a relapse,” the team wrote, adding that these aspects are not well captured with currently used measures.

Using additional quality of life measures or developing improved tests may help to determine “exactly what ‘health’ means after relapse,” the researchers concluded.