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pro - act contains data from 17 als clinical trials spanning more than 20 years .
the most common measurements of progression in pro - act ( and als trials in general ) are versions of the amyotrophic lateral sclerosis functional rating score ( alsfrs ) .
five trials in pro - act used the original alsfrs , 4 used the currently favored revised version ( alsfrs - r ) , and 3 measured both .
the plateau analysis described below was obtained using alsfrs , which maximized available sample size .
reversal analyses were obtained using alsfrs - r , which make them more comparable to contemporaneous studies .
additional pro - act details including participant demographics and disease characteristics have been published previously . to examine longitudinal als progression in pro - act , we generated histograms of alsfrs changes at 6 , 12 , and 18 months of trial participation . since studies in pro - act gathered data on different schedules , we used windows to approximate these intervals .
for example , the 6-month point was defined as the closest available time point to 180 days that occurred between 150 and 210 days . to determine the potential for als reversals
, we looked at rolling 180-day intervals with least 4 alsfrs - r data points , applied a least - squares fit , and determined the slope , intercept , and 95% confidence interval .
we plotted the percentage of participants who ever experienced any periods of alsfrs - r improvements of 14 points , and how long these lasted for intervals of up to 360 days . to ensure that positive or negative treatment effects did not influence findings
, all analyses were repeated using only data from pro - act participants assigned to placebo groups .
all the data in pro - act are de - identified ; it was thus not possible to locate participants again and reconsent them for this study .
all the data in pro - act are de - identified ; it was thus not possible to locate participants again and reconsent them for this study .
for the 6-month analysis , there were 3,132 participants available , and 25% did not decline .
for the 12-month analysis , there were 2,105 participants available , and 16% did not decline . for the 18-month analysis , there were 1,218 participants available , and 7% did not decline .
these histograms show the natural history of pooled resource open - access als clinical trials ( pro - act ) participants ' amyotrophic lateral sclerosis functional rating score ( alsfrs ) changes at intervals of 6 months ( a ) , 12 months ( b ) , and 18 months ( c ) . in terms of potential als reversals
, least - squares analysis showed that 14% of 1,343 participants had a 180-day interval where their alsfrs - r slope was greater than zero .
plotting periods of alsfrs - r improvements of 14 points vs the length of those periods out to 360 days confirmed that small als reversals are not uncommon , especially over shorter follow - up intervals ( data not shown ) .
large sustained als reversals , however , are rare . fewer than 1% of patients with als ever experienced reversals of 4 or more alsfrs - r points lasting 12 months . repeating these analyses in
only placebo - treated participants showed no significant differences in the frequencies of als reversals .
figure 2 presents selected pro - act participants ' alsfrs - r scores over time .
the region of the graph detected in the above analysis as an als reversal is highlighted .
some of these reversals ( for example , participant a ) are mainly the result of a single data point ( in this case the last data point ) .
other reversals show a slow , steady improvement over time ( for example , participant b ) .
these graphs show 2 individual pooled resource open - access als clinical trials participants ' amyotrophic lateral sclerosis functional rating score  revised ( alsfrs - r ) scores over time .
the portion of the curve picked up as an amyotrophic lateral sclerosis reversal is highlighted .
some of these reversals appear to be the result of a single data point ( participant a , last data point ) .
others include multiple incrementally improving data points , which are potentially more interesting ( participant b ) .
the table compares available demographics between participants with and without reversals ( as defined by the least - squares method ) .
the mean alsfrs - r score at the start of a reversal was 37 ( standard deviation 16.08 ) ; thus slow progressors ( those with high alsfrs - r score and long disease duration ) appear more likely to experience a reversal . age and onset site were not associated with reversals .
these data confirm previous case series , showing that als progression is variable , and extend our knowledge by showing that a high percentage of patients in a large database experience als plateaus . while brief plateaus are more common than longer ones , some of these last as long as 18 months . in light of this information ,
responder analyses that interpret stable disease over short intervals as evidence of treatment benefit must be met with skepticism .
these data also show that some patients with als experience a reversal of their disease .
some of these are the result of a single data point being significantly different than the prior ones .
these may suggest an als mimic syndrome , an endogenous mechanism that is able to compensate for the disease , a deleterious exogenous environmental influence that was removed , or even an undocumented treatment that is working .
our leading hypotheses are that there may be an antibody - mediated als mimic syndrome , perhaps related to lrp4 antibodies , or a polymorphism that confers resistance to an als pathway allowing regeneration to occur at a faster rate than degeneration . supporting the latter , there are polymorphisms associated with slow als progression .
genetic resistance allows some patients to unexpectedly control other fatal diseases such as hiv . to test these hypotheses
, we will gather als reversals and measure their antibody levels and whole - exome sequencing . when we find reversals that are temporally correlated with an alternative therapy
, we will try the same therapy in others to see if anyone else gets better .
first , the demographics of participants in als trials ( and thus those in pro - act ) differ from those of nonparticipating patients .
second , the pro - act database does not contain information about educational level , cognitive status , or the year when the original data points were collected ; it is thus not possible to use pro - act to determine how these might influence disease progression .
third , while als reversals were more common in men and those with longer disease duration ( and probably slower progression ) , it is difficult to know how much importance to ascribe to these findings .
our definitions of als reversals are somewhat arbitrary ; thus comparison of demographics and disease characteristics between those with and without a reversal runs the risk of dichotomania . finally , we measured als progression using the alsfrs and alsfrs - r . while these are the most commonly used measures of disease progression in als clinics and in current trials , they are unlikely to be perfectly sensitive to motor neuron loss .
more sensitive als biomarkers are being sought and will eventually further illuminate the course of als progression . until these arrive , the alsfrs and alsfrs - r remain useful , but we urge caution in interpreting plateaus or small reversals in these as evidence of treatment effects .
bedlack : study concept and design , writing . t. vaughan : analysis and interpretation , critical revision of the manuscript for important intellectual content .
p. wicks : study concept and design , critical revision of the manuscript for important intellectual content .
j. heywood : study concept and design , critical revision of the manuscript for important intellectual content .
e. sinani : analysis and interpretation , critical revision of the manuscript for important intellectual content .
r. selsov : analysis and interpretation , critical revision of the manuscript for important intellectual content . e.a .
macklin : analysis and interpretation , critical revision of the manuscript for important intellectual content .
d. schoenfeld : analysis and interpretation , critical revision of the manuscript for important intellectual content .
m. cudkowicz : study concept and design , critical revision of the manuscript for important intellectual content .
a. sherman : analysis and interpretation , critical revision of the manuscript for important intellectual content .
the patientslikeme research team has received research funding ( including conference support and consulting fees ) from abbvie , accorda , actelion , amgen , astrazeneca , avanir , biogen , boehringer ingelheim , genentech , genzyme , janssen , johnson & johnson , merck , novartis , sanofi , and ucb .
the patientslikeme r&d team has received research grant funding from kaiser permanente , the robert wood johnson foundation , sage bionetworks , the aku society , and the university of maryland .
r. bedlack has research grants from the als association , motor neurone disease association , and cytokinetics ; serves on the dsmb for brainstorm cell ; and is a paid consultant for the als association and neuraltus pharmaceuticals .
e. macklin serves on dsmbs for acorda therapeutics , lantheus medical imaging , and shire human genetic therapies and receives research support from the adolph coors foundation , als association , als therapy alliance , als therapy development institute , autism speaks , biotie therapies , muscular dystrophy association , and michael j. fox foundation .
a. sherman receives research support from the als association , muscular dystrophy association , american academy of neurology , als finding a cure foundation , and prize4life .
objective : to determine the frequency of amyotrophic lateral sclerosis ( als ) plateaus and reversals in the pooled resource open - access als clinical trials ( pro - act ) database.methods:we analyzed amyotrophic lateral sclerosis functional rating scale ( alsfrs ) and alsfrs  revised ( alsfrs - r ) data from pro - act participants . 
 the frequencies of participants experiencing plateaus ( periods where scores did not change ) were calculated over 6- , 12- , and 18-month epochs . the percentage of participants ever experiencing reversals ( periods where scores improved ) of different lengths were also calculated and plotted.results:over 6 months , 
 25% of 3,132 participants did not decline . over 12 months , 16% of 2,105 participants did not decline . over 18 months , 
 7% of 1,218 participants did not decline . 
 small als reversals were also common , especially over shorter follow - up intervals ; 14% of 1,343 participants had a 180-day interval where their alsfrs - r slope was greater than zero . 
 fewer than 1% of participants ever experienced improvements of 4 or more alsfrs - r points lasting at least 12 months.conclusion:als plateaus and small reversals are common , especially over brief intervals . in light of these data , stable disease , especially for a short period of time , should not be interpreted as an als treatment effect . 
 large sustained als reversals , on the other hand , are rare , potentially important , and warrant further study .