Appendix E-1: Study Procedures

Subjects

Subjects were recruited through three individual tertiary care centers that specialize in the treatment of individuals with ALS. Subjects were included if they 1) had a diagnosis of clinically definite, probable, or probable with laboratory-supported ALS, based on the El Escorial criteria;[1] and (2) were in the early stages of ALS. To ensure subjects were in the early stages of ALS, we used several criteria. First, physical signs and symptoms had to indicate subjects were in Stage 1 or 2, as determined by Sinaki and Mulder staging criteria.[2] Individuals in these stages may have mild to moderate weakness in certain, few muscles, and can perform normal life activities with no or mild limitations. We also only enrolled subjects with a forced vital capacity (FVC) of 90% predicted or greater and an ALS Functional Rating Scale (ALSFRS) score of 30 or greater. Clinically, we have found that those with a FVC less than 90% of predicted and/or an ALSFRS score less than 30 tend to be individuals who are further along in the disease process. We felt these individuals may not be have been able to physically participate in a 6-month study protocol, thus they were excluded.

Those who were enrolled in an on-going ALS pharmaceutical trial were not eligible to participate in the study. We also excluded subjects who: (1)had a history of neuromuscular dysfunction not related to ALS, (2) had a concomitant medical problem that would pose a safety problem or would interfere with the person’s ability to participate in the intervention; and, (3) who were unwilling or unable to comply with the assigned group protocol.

Interventions

After random assignment, subjects in both the usual care and resistance exercise groups were prescribed an exercise program by a research physical therapist. The prescribing therapist was not blinded to group assignment. Subjects in the usual care group received a program consisting of upper and lower extremity stretching exercises targeting the following muscle groups: gastrocnemius, hamstring, quadriceps, ankle dorsiflexors, shoulder flexors, extensors, adductors, and abductors. Subjects were instructed to hold each stretch for a count of 30 seconds and to repeat each exercise 5 times. They were asked to complete the exercise program once daily.

Subjects in the resistance exercise group were also given the stretching exercise program outlined above. In addition, each subject was prescribed an individualized, progressive, moderate intensity and moderate load resistanceupper and lower extremity exercise program using a training repetition maximum(RM) target. This technique involves initially determining anRM weight as a training load, the weight at which a muscle can move through range of motion using good form and technique, a specific number of times. For example, a "1-RM" is the maximal amount of weight that can be lifted only one timeand signifies an individual's maximum lifting capacity. For healthy individuals who are novice exercisers and for special populations, it has been suggested that a 1-RM not be used to determine the training load, because lifting maximal weight may induce muscle soreness and increase the risk of more serious muscular injury.[3] Studies have indicated that training with loads corresponding to 1- to 6-RM (i.e., the maximal amount of weight that can be lifted 1 to 6 times, respectively) were most conducive to increasing maximal dynamic strength,[4],[5] and greatest strength gains appear to result from resistances yielding 4- to 10- RM (and, mostly 5- to 6-RM).5,[6],[7]

Because safety was our primary concern and the subjects were completing their exercise program at home without supervision from a physical therapist, a moderate intensity and moderate load (3 sets of 5 repetitions based on initial 6-RM load) were chosen. A 6-RM weight was determined individually for each muscle group exercised. Subjects were asked to perform 5 repetitions at the full 6-RM weight, 5 repetitions at 75% of the 6-RM weight, and 5 repetitions at 50% of the 6-RM weight for each muscle group. This procedure is the reverse of the three-bout Delorme system and is designed to decrease resistance as muscle fatigue develops, in attempts to diminish the detrimental effects of fatigue (Oxford technique).[8] The following muscle groups bilaterally were targeted: shoulder flexors, shoulder abductors, shoulder extensors, elbow flexors, elbow extensors, hip flexors, hip extensors, knee flexors, knee extensors, and ankle dorsiflexors. However, resistance exercise protocols were developed according to patient tolerance and limitations. For example, if the subject could not move the limb through available range of motion against gravity (e.g., muscle strength grade less than 3), no exercise was prescribed for that muscle group. Subjects were asked to perform the resistance exercise program three times per week, and the exercise program was modified throughout the study period by the physical therapist, according to patient tolerance.

Subjects were asked to demonstrate the exercises to the prescribing therapist at the initial baseline session and were provided with written instructions and diagrams of the exercises.

Compliance

In order to monitor exercise side effects and the degree of compliance to the prescribed exercise program, subjects completed exercise logs, were telephoned every two weeks and interviewed during the monthly re-assessment.

Study participants were asked to record whether they exercised, what exercises they completed and if they noticed any side effects of exercise, such as increased muscle cramping, pain, fatigue, or fasciculations in their logs. Compliance was determined by the non-blinded PT through review of the exercise logs, bi-weekly telephone contact, and with questioning during the monthly re-evaluation visits. Compliance was categorized as "high” for completing at least 75% of the exercises in a month, as "moderate" for completing 50 % to75% of the exercises in a month, “low” for completing less than 50% of the exercises in a month, and "non- compliant" for doing none of the exercises in a month.

Baseline and Study Assessments

On the baseline visit, prescription and over-the-counter medication, and exercise history were recorded. All outcome assessments were completed by a second research physical therapist blinded to group assignment, at baseline and then every month for up to a period of 6 months. The physical therapists whoinitially prescribed the exercise programs were unblinded to group assignment and were responsible for collecting the logs, making the telephone contacts, interviewing subjects about exercise side effects and compliance, and revising the exercise program. The subjects were not blinded to the type of the exercise program and were instructed not tell the evaluators who were blinded to the type of the exercise program, about their group assignment. The blinded physical therapistdid not discuss potential results of the study outcomes with the subjects and the data analysis was blinded to group.

Three subjects in the usual care group and four subjects in the resistance exercise group had been engaged in low intensity aerobic exercise activity, of at least 10 minutes or more induration, before entering the study. These subjects were instructed that they could continue with this type of exercise if they chose, but were to inform the prescribing therapist of any changes. Two subjects in the control group and four subjects in the experimental group were engaged in light resistance exercises prior to entry into the study. The two subjects in the control group were asked to stop the resistance exercises and the subjects in the experimental group were asked to follow the study protocol, rather than their own exercise protocol, as a requirement of randomization into the study.

Primary Outcome Measure

Function

The ALSFRS, the most-widely used and extensively validated global functional scale for ALS, was used to assess the primary outcome.[9] Subjects’ function for 10 items are rated on a scale from 4 (normal function) to 0 (unable to attempt the task). TheALSFRS has been found to correlate positively with objective measures of upper (U/E) and lower extremity (L/E) muscle strength and has been found to be valid and reliable for measuring the decline in function that results from loss of muscular strength.9 Because the ALSFRS examines bulbar and breathing function, in addition to U/E and L/E function, we also examined the combined U/E and L/E sub-scale scores (items 4 to 9), in addition to total ALSFRS scores

Secondary Outcome Measures

Fatigue

Fatigue was measured using the Fatigue Severity Scale (FSS).[10] The FSS assesses fatigue using nine statements that ask subjects to rate the degree of severity of fatigue. Lower scores indicate less fatigue and/or less problems caused by fatigue. No fatigue scales have been validated in individuals with ALS, however, the FSS has been found to be valid and reliable for individuals with multiple sclerosis.10

Quality of life

Quality of life was measured using the SF-36.[11] The SF-36 is a valid and reliable generic health-related quality of life instrument that has been utilized in ALS clinical trials. It consists of 36 items representing eight general health concepts: physical functioning (P-F), role disability due to physical-health problems (R-P), bodily pain (BP), general health perceptions (GH), vitality (V), social functioning (SF), role disability due to emotional problems (R-E) and general mental health (MH).

Other Measures

Because the effects of resistance exercise have not been thoroughly studied in individuals with ALS, we choose to evaluate two additional measures every month to closely monitor for signs of adverse effects of exercise.

Maximum Voluntary Isometric Contraction

Changes in muscle strength were monitored monthly throughout the study period using Maximum Voluntary Isometric Contraction (MVIC)[12] which has been validated and widely used in many clinical trials.[13],[14] MVIC is currently considered to be the most direct technique for investigating motor unit loss, and has been used extensively for evaluating muscle strength in individuals with ALS for the past 15 years. Its range and sensitivity have been validated by several natural history studies,[15],[16] and MVIC has been shown to strongly correlate with progressive weakness in the ALS population.16 Data were normalized, summed and averaged to yield an U/E and L/E megascore, using the method described by Andres et al.12 Raw scores were standardized relative to normative population values, using predicted force and SD based on age, gender, weight, and height: z-score = muscle force (kg) – predicted force (kg)/SD of the predicted force (kg).

Forced Vital Capacity

Forced vital capacity was evaluated using a hand-held Puritan-Bennett spirometer. Three measurement trials for FVC were obtained and the best trial was recorded. FVC has been found to be a sensitive parameter of respiratory function for individuals with ALS,[17],[18] and an increased rate of FVC decline is prognostic of imminent respiratory failure.18

REFERENCES

[1] The World Federation of Neurology Research Group on Neuromuscular Diseases, Subcommittee on Motor Neuron Disease. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Jour of Neuro Sci 1994;124 (Suppl):96-107.

[2] Sinaki M, Mulder DW. Rehabilitation techniques for patients with amyotrophic lateral sclerosis. Mayo Clin Proc. 1978;53:173-178.

[3] Braith R, Graves J, Leggett S, Pollock M. Effect of training on the relationship

between maximal and submaximal strength. Med Sci Sports Exerc1993; 25:132-138.

[4] Campos GER, Luecke TJ, Wendeln HK, et al. Muscular adaptations in

response to three different resistance-training regimens: specificity of repetition

maximum training zones. Eur J Appl Phys. 2002;88:50-60.

[5] Weiss LW, Coney HD, Clark FC. Differential functional adaptations to short-term

low-, moderate-, and high-repetition weight training. J Strength Cond Res.1999;13: 236-241.

[6] Berger, RA. Optimum repetitions for the development of strength. Res. Q. 1962;33:334–338.

[7] O’Shea, P. Effects of selected weight training programs on the development of strength and muscle hypertrophy. Res. Q. 1966;37:95–102

[8] Zinowieff AN. Heavy resistance exercise: The Oxford technique. Br J Phys Med 1951; 14:129-133.

[9] The ALS CNTF Treatment Study (ACTS) Phase I II Study Group. The amyotrophic lateral sclerosis functional rating scale: assessment of activities of daily living in patients with amyotrophic lateral sclerosis. Arch Neurology 1996;53:141-147.

[10] Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale: Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46:1121-1123.

[11] Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 Health Survey: Manual and Interpretation Guide. Boston: Health Institute, New EnglandMedicalCenter, 1993.

[12] Andres PL, Hedlund W, Finison L, Conlon T, Felmus M, Munsat TL. Quantitative motor assessment in amyotrophic lateral sclerosis. Neurology. 1986;36:937-41.

[13] Sanjak M, Paulson D, Sufit R, Reddan W, Beaulieu D, Erickson L, Shug A, Brooks BR. Physiologic and metabolic response to progressive and prolonged exercise in amyotrophic lateral sclerosis. Neurology. 1987;37:1217-20.

[14] Kilmar DD, McCrory MA, Wright NC, Aitkens SG, Bernauer EM. The effect of a high resistance exercise program in slowly progressive neuromuscular disease. Arch Phys Med Rehabil. 1994;75:560-3.

[15] Ringel SP, Murphy JR, Alderson MK, et al. The natural history of amyotrophic lateral sclerosis. Neurology. 1993;43(7):1316-1322.

[16] Brooks BR, Sufit PL, DePaul R. Design of clinical therapeutic trials in amyotrophic lateral sclerosis. Adv Neurol. 1991;56:521-546.

[17] Griggs RC, Donohoe KM, Utell MJ, Goldblatt D, Moxley RT 3rd. Evaluation of pulmonary function in neuromuscular disease. Arch Neurol. 1981;38(1):9-12.

[18] Fallat RJ, Jewitt B, Bass M, et al. Spirometry in amyotrophic lateral sclerosis. Arch Neurol. 1979;36:74-80.