Abstract: For the original Cochrane Review, the review authors identified two RCTs involving 54 participants with ALS receiving NIV. There were no new RCTs or quasi-RCTs at the first update. One new RCT was identified in the second update but was excluded for the reasons outlined below. Incomplete data were available for one published study comparing early and late initiation of NIV (13 participants). We contacted the trial authors, who were not able to provide the missing data. The conclusions of the review were therefore based on a single study of 41 participants comparing NIV with standard care. Lack of (or uncertain) blinding represented a risk of bias for participant- and clinician-assessed outcomes such as quality of life, but it was otherwise a well-conducted study with a low risk of bias. The study provided moderate-quality evidence that overall median survival was significantly different between the group treated with NIV and the standard care group. The median survival in the NIV group was 48 days longer (219 days compared to 171 days for the standard care group (estimated 95% confidence interval 12 to 91 days, P = 0.0062)). This survival benefit was accompanied by an enhanced quality of life. On subgroup analysis, in the subgroup with normal to moderately impaired bulbar function (20 participants), median survival was 205 days longer (216 days in the NIV group versus 11 days in the standard care group, P = 0.0059), and quality of life measures were better than with standard care (low-quality evidence). In the participants with poor bulbar function (21 participants), NIV did not prolong survival or improve quality of life, although there was significant improvement in the mean symptoms domain of the Sleep Apnea Quality of Life Index by some measures. Neither trial reported clinical data on intervention-related adverse effects. Moderate-quality evidence from a single RCT of NIV in 41 participants suggests that it significantly prolongs survival, and low-quality evidence indicates that it improves or maintains quality of life in people with ALS. Survival and quality of life were significantly improved in the subgroup of people with better bulbar function, but not in those with severe bulbar impairment. Adverse effects related to NIV should be systematically reported, as at present there is little information on this subject. More RCT evidence to support the use of NIV in ALS will be difficult to generate, as not offering NIV to the control group is no longer ethically justifiable. Future studies should examine the benefits of early intervention with NIV and establish the most appropriate timing for initiating NIV in order to obtain its maximum benefit. The effect of adding cough augmentation techniques to NIV also needs to be investigated in an RCT. Future studies should examine the health economics of NIV. Access to NIV remains restricted in many parts of the world, including Europe and North America. We need to understand the factors, personal and socioeconomic, that determine access to NIV.

Plain-language summary: In this updated review, we examined the evidence from two randomised trials of NIV in ALS involving a total of 54 participants. One of the trials, which studied when to start NIV, provided no usable data. A third trial, identified in a clinical trials register, currently has no published results. Complete data were only available from a single trial of 41 participants. The results of this trial provided moderate-quality evidence that NIV significantly prolongs survival, and low-quality evidence that it improves or maintains quality of life compared to standard care. Median survival was increased by an estimated 48 days, from 171 to 219 days. The survival benefit from NIV was much greater in people with ALS in whom the muscles used for speaking, chewing, and swallowing (bulbar muscles) were either unaffected or only moderately weak. Among these 20 participants, the median survival with NIV was increased by an estimated 205 days (216 days with NIV, compared to 11 days with standard care). Quality of life was also maintained in participants with mild to moderate bulbar weakness. In the 21 participants with severe bulbar weakness, NIV did not prolong survival or maintain quality of life scores, although a sleep-related symptoms score improved. Neither trial reported on adverse effects. Participants and clinicians were aware of the treatment groups, which can influence quality of life assessments. More trials of NIV versus standard care in ALS are unlikely as it would not be ethical to withhold NIV. Future studies should examine early intervention with NIV and determine the best time to start it. The evidence is up to date to January 2017.