Harmonized standard operating procedures for administering the ALS functional rating scale-revised

Abstract The ALS Functional Rating Scale-Revised is the most commonly used primary outcome measure in current ALS clinical trials. While rigorous training and certification is generally recognized as critical to reliable performance, differences have existed between training in the two groups responsible for most training in ALS outcome measures. We present a harmonized standard operating procedure which is intended to further reduce response variability by the use of identical training in North America and Europe.

The ALS Functional Rating Scale was introduced as an outcome measure for ALS trials in 1996, when it was used as a secondary outcome measure in a clinical trial of CNTF in patients with ALS (1).The original scale was a 10 item instrument assessing bulbar function, fine motor function, gross motor function, and respiratory symptoms.Respiratory function was assessed in only a single question, and the scale was revised to include 2 additional respiratory questions, which was used as a secondary measure in a trial of BDNF (2).It has been extensively investigated subsequently, and found to predict clinically relevant outcomes such as survival and pulmonary function, show excellent reproducibility, and be equivalent whether obtained in person or by telephone.Since 1996, the ALSFRS or ALSFRS-R has been used in 38 clinical trials enrolling more than 100 participants, including 19 as the primary outcome measure (3).
The ALSFRS and ALSFRS-R were designed to be administered using a structured interview, during which the evaluator probes the participant responses, both to verify responses and accurately place the participant status within a 5 point scale.
Because of this interactive method of administration, training evaluators to perform this assessment is critical both for reproducibility within and across participants.Over the last 20 years, this training has been designed and implemented by two main groups: the Northeast ALS Clinical Trials Consortium (NEALS) in collaboration with individuals at Upstate Medical University in Syracuse and later at the Barrow Neurological Institute in Phoenix, and ENCALS/TRICALS coordinated by individuals at UMC Utrecht, the Netherlands.
The NEALS consortium first conducted standard training and certification of performance in conjunction with a trial of topiramate in ALS (4).This was followed by NEALS administered trials of celecoxib, lithium, ceftriaxone, creatine and PB/Turso (5)(6)(7)(8)(9).The same training group has also performed training and certification activities for the ALSFRS-R and other outcome measures for industry sponsored trials of dexpramepexole, tirasemtiv, azanezumab, reldesemtiv, NP001, and tofersen (10)(11)(12)(13)(14)(15)(16)(17).During this time frame, study specific training manuals and standard operating procedures were generated which varied slightly in detail, but which have remained very consistent in the previous 5 years.
Since 2016, ENCALS/TRICALS have also trained and certified assessors in the administration of the ALSFRS at the annual ENCALS/TRICALS meetings.This was done in parallel with the training and certification of the careful performance of other outcome measures used in clinical trials, such as vital capacity, dynamometry, Edinburgh Cognitive Assessment Scale (ECAS) and King's staging.Training and certification were conducted in investigator-initiated studies, such as TUDCA, lithium (on UNC13a risk genotypes), and Triumeq, as well as industry-sponsored studies, such as ORARIALS, RT001, PHOENIX, DAZALS and ADORE (e.g.(12,(18)(19)(20)).The ENCALS/TRICALS training was based on the standard operating procedure (SOP) developed in 2015.The initial training consists of a face-to-face training with a video score exam.Since 2017, an online training platform has been included as part of the training process to be able to provide (an update of) training more often.
While the NEALS and ENCALS/TRICALS training instruction and certification process are similar, important differences have been noted that have the potential to alter scoring.Several examples are presented here.In item 1, the ENCALS/TRICALS SOP mandates a specific score if a participant requires repetition for speech to be understood 25% of the time; the NEALS SOP assigns this score if repetition is required on a daily basis.For item 2, a specific score for salivation requires the participant reporting that they use a tissue to dab their mouth 25% of the time or more, while the NEALS SOP has no numeric criterion.Item 10 asks about dyspnea, or shortness of breath; the ENCALS/TRICALS scoring mandates the lowest possible score if noninvasive ventilation is used at all, while the NEALS SOP instructs the evaluator to score this item according to how a participant feels when noninvasive ventilation is not being used.Each of these items would be potentially scored differently depending on these instructions.Scoring for other questions also have differences, but are minor compared to the differences of the examples noted above.Table 1 shows all prior differences between the ENCALS/TRICALS SOP and the NEALS SOP, with the final harmonized wording also shown.
Given the multinational character of many current and planned clinical trials, and the fact that a single evaluator is very likely to receive training both according the NEALS and the ENCALS/TRICALS SOPs, the developers and trainers from the two groups felt it was imperative to train evaluators in a consistent manner.For this reason, meetings were held during the summer of 2022 to harmonize training and certification practices.As the ALSFRS-R remains the most commonly employed primary outcome measure for ALS trials, we believe that it is critical that this harmonized set of instructions be available to the ALS community and present them here.We hope that this SOP will be adopted universally; this will improve consistency and reliability of administration of a tool that remains the mainstay of ALS clinical trials.

ALS Functional Rating Scale Revised (ALSFRS-R) Standard Operating Procedure (SOP)
This SOP is designed to help standardize the administration of the ALSFRS-R The ALSFRS-R is a scale designed to assess daily function as rated by the participant with the assistance of a trained evaluator.The questions should be asked broadly; based on the response, the evaluator should probe to validate the response and help the participant determine which of the choices for each question are most appropriate.The goal of the evaluator is to help the participant determine accurately their level of function, not to push the response to either a higher or lower score.If the scale is administered over the telephone and the participant is unable to respond because of significant bulbar impairment, a caregiver should relay the questions and responses without interpretation.The participant should be able to hear the questions directly, so use of speaker phone is preferred.
As a general rule, "help" means help from a caregiver or a device or appliance.For example, use of a handrail, ankle foot orthosis (AFO) or walking stick would count as help with walking.
For each question, responses should be recorded according to the closest level within each 5 point list, in which 4 reflects normal function or no change from prior to onset of any symptoms of ALS, and 0 reflects no function.
Occasionally, participants provide responses clearly at odds with the observed function of the participant.In such cases, clarification can be asked; for example "You report normal speech but I am hearing significant slurring."In most cases, the participant will modify their responses; however if the participant persists in their report of function, their assessment must be recorded.
Some questions may ask about functions that are no longer being performed, even though the participant thinks they might be able to do so.In such situations the rater should score according to what is being performed, not what hypothetically could be performed.In cases of temporary disability (such as a cast on an arm) the evaluator should rate according to what the patient is able to do at the current time.
The same evaluator should perform the evaluation on a given patient throughout the course of a study.Dietary consistency changes are defined as: Food needs to be mashed, liquidized, or cut into smaller pieces to allow swallowing, drinks need thickener, or some foods are avoided in favor of others that are easier to swallow.Rate 1, if the participant cannot maintain weight by oral intake due to swallowing issues, whether or not a feeding tube is in place.Rate 0, if the participant reports no oral intake (NPO).This status requires parental or enteral feeding.NPO means they are not swallowing anything (not even sips of coffee or other drinks; if they do so for reasons of taste, it must be suctioned or spit out).Item 4: HANDWRITING Ask ''How are you writing using your dominant hand?''Rate without use of any assistive devices, such as foam tubing &/or mechanical aids due to finger weakness.If such devices are used routinely, ask how writing is without their use.If participant is unsure, either ask them to demonstrate, or rate as 0. Handwriting refers to either printing or cursive; however, if there has been a switch from one to the other, grade as 3 or less.Rate 4, if there is no change from prior to onset of ALS symptoms.Rate 3, if all words are legible, while using a normal pen, but there is a change in writing.Rate 2, if some words cannot be read but others can.Rate 1, if the participant can only write their name or sign, but other writing is illegible.If the participant has not written other words except their name or signature recently and therefore cannot answer the question further, score as 1.Rate 0, if the participant cannot hold a pen in a normal writing position.

Item 5a: CUTTING FOOD AND HANDLING UTENSILS (patients without gastrostomy)
Ask "How are you with cutting food or handling utensils?"If a participant has a gastrostomy but it is not the primary method of caloric intake, treat as "without gastrostomy".Rate 4, if there is no change from prior to onset of ALS symptoms, and there has been no change in the type of utensil used (for example chopsticks to knife and fork, or tendency to use a spoon now).Rate 3, if there is some difficulty either cutting food or holding utensils, but the participant is able to do this independently.Rate 2, if occasional assistance is needed for cutting food, but the participant is independent for the task otherwise.Use of altered utensils constitutes assistance and is rated 2. Rate 1, if assistance is required at least half the time for cutting but not for feeding.For example, if food must be cut but the participant can feed themselves otherwise, rate as 1.
If the participant cannot cut foods but still try to feed themselves and succeed at least occasionally, rate as 1.Rate 0, if assistance is needed for all aspects of feeding.
If a participant chooses not feed themselves for any reason rate as 0. If a participant feeds themselves without the use of their arms, rate as 0.
Item 5b: CUTTING FOOD AND HANDLING UTENSILS (alternate scale for patients with gastrostomy) Ask "How are you with handling the gastrostomy fastenings and fixtures?"If someone has a gastrostomy and it is the primary method of caloric intake, treat as "with gastrostomy"."Normal" means that there is no difficulty at all with any manipulations.T Bunte: has nothing to declare.G Kittle: has nothing to declare.
Rate 2, if dietary consistency changes are required.
Harmonized standard Operating procedures for administering the ALS Functional Rating Scale-Revised 31 Item 11: ORTHOPNEA Ask "Can you sleep lying down flat or do you need to be propped up?" Score based on difficulty regardless of the apparent underlying cause (for example, needing to sleep sitting up because of excessive saliva scores 1).Treat a hospital style bed in which the back can be raised independently as if pillows were in place of the raised section.Rate 4, if sleep position has not changed from prior to onset of ALS symptoms.Rate 3, if there is difficulty falling asleep, or if the participant wakes because of breathlessness but they do not use more than two pillows, or if they have changed their sleeping position (i.e. from supine to the side, prone to side, etc.).Rate 2, if more than two pillows are needed.Rate 1, if the participant sleeps sitting up in bed or in a chair.Rate 0, if using nocturnal BiPAP or any form of NIV and the participant NEVER sleeps without device.If the participant uses BiPAP or other form of NIV, but sometimes sleeps without it, select the number that best describes the participant's orthopnea when sleeping without device.Item 12: RESPIRATORY INSUFFICIENCY Ask:"Do you use noninvasive ventilation?"This question refers to any sort of noninvasive technique, including CPAP but excluding cough assist devices.Any use of NIV for any reason is rated at most 3. Rate 4, if the participant does not use noninvasive ventilation.Rate 3, if Intermittent use during the day or night.Rate 2, if intermittent use during the day and continuous at night.Rate 1, if using NIV continuously, during night and day, defined as more than 22 hours per day for 7 consecutive days.
Continuous use of ventilation is defined as use for more than 22 hours daily for 7 consecutive days.Under these circumstances, rate as 0.