APPENDIX SIX
Respiratory Issues in Clinical Trials

I. Methods and Techniques of Pulmonary Measurement.

1. There are no evidence based data as to which pulmonary measurement is most robust. Vital capacity (FVC or VC) is less variable than measurement of peak pressures, arterial blood gases or serum chloride.
2. There are no published data supporting VC over FVC, and this is an important issue to resolve.
3. There are no published data related to use of masks or mouthpieces. However, these devices can influence pulmonary measurement. Their use should be standardized and devices should not be changed or introduced during the trial.
4. Pulmonary testing personnel should be well trained and demonstrate adequate test-retest reliability. Their interaction with the patient should be standardized.
5. There is a learning effect for the patient in the measurement of pulmonary function, and this must be factored into trial design.

II. Clinical Factors Which Can Influence Respiratory Status

1. There are data that non-invasive ventilation can relieve patient symptoms and prolong survival. There are no data to determine when to introduce non-invasive ventilation. The individual investigator should have control over how to manage patients with respect to non-invasive ventilation. Accordingly, in future trials it is important to obtain data to develop standards for the timing of instituting non-invasive ventilation.
2. There are also data that enhanced nutrition by gastric feeding may influence respiratory function and prolong survival. As above, there are no published standards of practice but investigators should do what is best for the patient, and data for standards are needed.
3. Coexistent pulmonary disease should be treated by best medical care, but should not be an exclusion criterion.

III. Respiratory Measures as Outcome Variables

1. Non-invasive ventilation and gastric feeding may alter respiratory measurements. Accordingly, their introduction may represent an endpoint. This must be stipulated before the trial begins.
2. Non-invasive ventilation and gastric feeding may have significant therapeutic effects, which must be considered in trial design, especially when survival is the outcome measure.

IV. Future Research

1. More research is needed to determine the best measure of pulmonary function for clinical trials.
2. There is a clear need for determining the influence of non-invasive ventilation and gastric feeding, and their timing, upon functional measurements and survival in ALS/MND.

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