Epub: Sormani et al. Time to first relapse as an endpoint in multiple sclerosis clinical trials. Mult Scler. 2012.
BACKGROUND: The increasing number of effective therapies to treat
MS raises ethical concerns for the use of placebo
in clinical trials, suggesting that new clinical trial design strategies
are needed.
BACKGROUND: The increasing number of effective therapies to treat
MS raises ethical concerns for the use of placebo
in clinical trials, suggesting that new clinical trial design strategies
are needed.
OBJECTIVES: To evaluate time to first relapse as an endpoint for MS clinical trials.
METHODS: A
recently-developed model fitting the distribution of time to first
relapse in MS was used for simulations estimating the sample sizes of
trials using this as an outcome, and for comparison with the size of
trials using the annualized relapse rate (ARR) as the primary outcome.
recently-developed model fitting the distribution of time to first
relapse in MS was used for simulations estimating the sample sizes of
trials using this as an outcome, and for comparison with the size of
trials using the annualized relapse rate (ARR) as the primary outcome.
RESULTS:
Trials based on time to first relapse were feasible, requiring sample
sizes that were similar or even smaller than if the study was based on
ARR instead. In the case of low ARR (0.4 relapses/year), as is expected
in future trials, the 1-year trials designed to detect a treatment
effect of 30%, with 90% power, require fewer MSers when based on time
to first relapse (470 MSers/arm) than if based on ARR (540
MSers/arm).
Trials based on time to first relapse were feasible, requiring sample
sizes that were similar or even smaller than if the study was based on
ARR instead. In the case of low ARR (0.4 relapses/year), as is expected
in future trials, the 1-year trials designed to detect a treatment
effect of 30%, with 90% power, require fewer MSers when based on time
to first relapse (470 MSers/arm) than if based on ARR (540
MSers/arm).
CONCLUSIONS:
Our simulations show that time to first relapse is not less powerful
than ARR in MS trials; thus, this measure would be a potentially useful
primary outcome offering the advantage of an ethically sound design, as
the MSers randomized to placebo can then switch to the active drug,
once they relapse. A potential drawback is the loss of information for
other endpoints collected at fixed time points.
Our simulations show that time to first relapse is not less powerful
than ARR in MS trials; thus, this measure would be a potentially useful
primary outcome offering the advantage of an ethically sound design, as
the MSers randomized to placebo can then switch to the active drug,
once they relapse. A potential drawback is the loss of information for
other endpoints collected at fixed time points.
“This analysis supports what we have been saying for sometime we need to be more imaginative in how
we undertake trials so that they can speed up the thoughput of new
drugs and expose fewer MSers to trial conditions. Let’s hope the regulators see the advantage of this!”
Isn't it possible that somebody moving from no treatment/ineffective treatment relapses v quickly?Because the effective new treatment will not work at once
That may be the case with some treatments in that it takes time to maximise its effect. Also rememeber none of the new treatments are 100% effective
Even if a drug is immediately effective, can it stop a relapse that is already brewing (just about to break out)?
No. Relapses destined to happen in in the next 6-8 weeks are likely to happen. We suspect the process that drives a relapse starts weeks to months before the relapse occurs. For example, Natalizumab which is probably the most effective licensed drug for highly active MS at present only starts being effective, compared to placebo, after 2 months.
Then relapses in the first 6-8 weeks after the start of a trial should be discounted/ignored