ALS Trials and the ALSFRS-R

Learn about past difficulties with clinical trials for ALS treatments, and the ALS Functional Rating Scale–Revised (ALSFRS-R) as a tool for evaluating the decline in physical function over time.

Overview of ALS Trials

Over the past 2 decades, results from most clinical trials for ALS treatments have been discouraging. A snapshot of prescription medications indicated for the treatment of ALS shows a 22-year gap been riluzole, the first FDA-approved treatment, and RADICAVA® (edaravone), the only FDA-approved treatment option shown to slow the loss of physical function in a pivotal clinical trial.1-3

Overview of ALS Treatment Clinical Trials Overview of ALS Treatment Clinical Trials
ALS patient with cane standing next to ALS patient in wheelchair

ALS clinical trials have been challenged by the heterogeneity of disease progression.2,4

For example, if the trial evaluates a broad patient population, including those who have minimal or no decline on the ALSFRS-R during the study period, it is very difficult to show a treatment effect.5

About the ALSFRS-R

The ALSFRS-R is considered to be a gold standard used to measure ALS trial outcomes

The ALS Functional Rating Scale–Revised (ALSFRS-R) is a validated, questionnaire-based tool for evaluating decline in function over time.6,7

green checkmark in green circle

The ALSFRS-R is considered to be a gold standard used to measure ALS trial outcomes.8

ALS clinical trials are increasingly focused on physical function in addition to survival.9,10

75%
of current clinical trials (6 out of 8) use the ALSFRS-R as an outcome measure.11

Understanding the ALSFRS-R

The ALSFRS-R consists of 12 items in 4 domains. Each item is scored between 4 and 0, for a maximum score of 48.12

Tap on each item below to see the point descriptions.

Tap on each item below to see the point descriptions.

Swipe

BULBAR

Speech
4Normal
3Detectable speech disturbance
2Intelligible with repeating
1Speech combined with nonvocal communication
0Loss of useful speech
Consider what a 1-point loss may mean within each item.
Salivation
4Normal
3Slight but definite excess of saliva in mouth; may have nighttime drooling
2Moderately excessive saliva; may have minimal drooling
1Marked excess of saliva with some drooling
0Marked drooling; requires constant tissue or handkerchief
Consider what a 1-point loss may mean within each item.
Swallowing
4Normal
3Early eating problems—occasional choking
2Dietary consistency changes
1Needs supplemental tube feeding
0NPO (exclusively parenteral or enteral feeding)
Consider what a 1-point loss may mean within each item.

FINE MOTOR

Handwriting
4Normal
3Slow or sloppy; all words are legible
2Not all words are legible
1Able to grip pen but unable to write
0Unable to grip pen
Consider what a 1-point loss may mean within each item.
Cutting Food (patients without gastrostomy)
4Normal
3Somewhat slow and clumsy, but no help needed
2Can cut most foods, although clumsy and slow; some help needed
1Food must be cut by someone, but can still feed slowly
0Needs to be fed
Consider what a 1-point loss may mean within each item.
Cutting Food (patients with gastrostomy)
4Normal
3Clumsy, but no help needed
2Some help needed with closures and fasteners
1Provides minimal assistance to caregiver
0Unable to perform any aspect of task
Consider what a 1-point loss may mean within each item.
Dressing and Hygiene
4Normal
3Independent and complete self-care with effort or decreased efficiency
2Intermittent assistance or substitute methods
1Needs attendant for self-care
0Total dependence
Consider what a 1-point loss may mean within each item.

GROSS MOTOR

Turning in Bed
4Normal
3Somewhat slow and clumsy, but no help needed
2Can turn alone or adjust sheets, but with great difficulty
1Can initiate, but not turn or adjust sheets alone
0Helpless
Consider what a 1-point loss may mean within each item.
Walking
4Normal
3Early ambulation difficulties
2Walks with assistance
1Non-ambulatory functional movement only
0No purposeful leg movement
Consider what a 1-point loss may mean within each item.
Climbing Stairs
4Normal
3Slow
2Mild unsteadiness or fatigue
1Needs assistance
0Cannot do
Consider what a 1-point loss may mean within each item.

RESPIRATORY

Dyspnea
4None
3Occurs when walking
2Occurs with one or more of the following: eating, bathing, dressing (ADL)
1Occurs at rest, difficulty breathing when either sitting or lying
0Significant difficulty, considering using mechanical respiratory support
Consider what a 1-point loss may mean within each item.
Orthopnea
4None
3Some difficulty sleeping at night due to shortness of breath. Does not routinely use more than two pillows
2Needs extra pillow in order to sleep (more than two)
1Can only sleep sitting up
0Unable to sleep
Consider what a 1-point loss may mean within each item.
Respiratory Insufficiency
4None
3Intermittent use of BiPAP
2Continuous use of BiPAP during the night
1Continuous use of BiPAP during the night and day
0Invasive mechanical ventilation by intubation or tracheostomy
Consider what a 1-point loss may mean within each item.

The ALSFRS-R was used to assess the primary endpoint in the pivotal trial for RADICAVA®.3,a

aMean change in ALSFRS-R at 24 weeks.

ALSFRS-R point changes

Based on data from the PRO-ACT database, the average rate of ALSFRS-R decline is 1.02 points/month.13

Calendar image of one month and arrow image showing about one point drop on ALSFRS-R

Due to the heterogeneity of ALS, each patient's individual decline may vary widely, with some patients losing 0 to 1 point/month and others losing up to 6 points/month.14


A report concerning a survey of 65 members of the Northeast ALS Consortium (NEALS) concluded that a treatment that resulted in a

20%-​25%
or greater change in the slope of the
ALSFRS-R is clinically meaningful.15

    References:
  1. Mitsumoto H, Brooks BR, Silani V. Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved? Lancet Neurol. 2014;13:1127-1138.
  2. Su XW, Broach JR, Connor JR, et al. Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research. Muscle Nerve. 2014;49:786-803.
  3. RADICAVA Prescribing Information. Jersey City, NJ: Mitsubishi Tanabe Pharma America, Inc.; 2018.
  4. Takei K, Watanabe K, Yuki S, et al. Edaravone and its clinical development for amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(sup1):5-10.
  5. Edaravone (MCI-186) ALS 16 Study Group. A post-hoc subgroup analysis of outcomes in the first phase III clinical study of edaravone (MCI-186) in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(sup1):11-19.
  6. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. J Neurol Sci. 1999;169(1-2):13-21.
  7. Leigh PN, Swash M, Iwasaki Y, et al. Amyotrophic lateral sclerosis: a consensus viewpoint on designing and implementing a clinical trial. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004;5(2):84-98.
  8. ALS Worldwide. A Paradigm Shift in ALS/MND Clinic Care: Best Practices from the Patient Perspective. http://alsworldwide.org/assets/team/staff/cvs/alsww_clinic-book-web_copy.pdf. Published 2014. Accessed June 21, 2019.
  9. Miller RG Brooks BR, Swain-Eng R, et al. Quality improvement in neurology: amyotrophic lateral sclerosis quality measures. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15:165-168.
  10. Eisen A. Motor neurone disease. In: Turner MR, Kiernan MC, eds. Landmark Papers in Neurology. 1st ed. Oxford, United Kingdom: Oxford University Press; 2015:264.
  11. Clinicaltrials.gov. Clinical study information. Accessed May 28, 2019.
  12. The ALS C.A.R.E. Program. Center for Outcomes Research, University of Massachusetts Medical School. http://www.outcomes-umassmed.org/ALS/alsscale.aspx. Accessed May 28, 2019.
  13. Atassi N, Berry J, Shui A, et al. The PRO-ACT database: design, initial analyses, and predictive futures. Neurology. 2014;83:1719-1725.
  14. Proudfoot M, Jones A, Talbot K, et al. The ALSFRS as an outcome measure in therapeutic trials and its relationship to symptom onset. Amyotroph Lateral Scler Frontotemporal Degener. 2016;17:414-425.
  15. Castrillo-Viguera C, Grasso DL, Simpson E, et al. Clinical significance in the change of decline in ALSFRS-R. Amyotroph Lateral Scler. 2010;11(1-2):178-180.
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Important Safety Information

Hypersensitivity Reactions

Radicava® (edaravone) is contraindicated in patients with a history of hypersensitivity to edaravone or any of the inactive ingredients in Radicava®. Hypersensitivity reactions (redness, wheals, and erythema multiforme) and cases of anaphylaxis (urticaria, decreased blood pressure, and dyspnea) have been reported. Patients should be monitored carefully for hypersensitivity reactions, and if they occur, discontinue Radicava®, treat per standard of care, and monitor until the condition resolves.

Sulfite Allergic Reactions

Radicava® contains sodium bisulfite, and may cause allergic type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown, but occurs more frequently in asthmatic people.

Most Common Adverse Reactions

Most common adverse reactions (at least 10% and greater than placebo) are contusion, gait disturbance, and headache.

Pregnancy

Based on animal data, Radicava® may cause fetal harm.

Geriatric Use

No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

To report suspected adverse reactions or product complaints, contact Mitsubishi Tanabe Pharma America, Inc., at 1-888-292-0058. You may also report suspected adverse reactions to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Indication

Radicava® is indicated for the treatment of amyotrophic lateral sclerosis (ALS).

Please see full Prescribing Information.

For more information about RADICAVA®, call 1-888-292-0058.