Physiotherapy-Based Measures (HINE, CHOP INTEND, HMFSE) For People With SMA and How They Are Used to Monitor Treatment Outcomes

Summary

To prove or disprove that a new medication is helpful in treating a condition, pharmaceutical companies use outcome measures (i.e. measurements of the effect of a medication on patients). This article summarises what is known about some of the more commonly used outcome measures in SMA (i.e. HINE, CHOP INTEND, HMFSE), and how both these and individuals who have SMA would be expected to progress without treatments.

When trying out a new medication it is up to the drug companies to find evidence that the medication is doing what they think it will do to individuals with the condition.  

Outcome measures

Outcome measures are tools used to measure the success or failure of a drug being trialled. These results are sent to the organisations (like the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)) which decide on licencing of the medication, and therefore whether it can be sold in that area of the world. Outcome measures can be any activity which is capable of measuring how a condition progresses. Among other things, these may be:

  • Physiotherapy-based (e.g. how far can you walk in six minutes?)
     
  • Blood or tissue (biopsy) based (e.g. does the level of SMN protein go up or down?)
     
  • Imaging based (e.g. on an Magnetic Resonating Image (MRI) scan, do the muscles show a difference over time?)
     
  • Special test based (e.g. does the electrical signal from muscle increase or decrease?)
     
  • Opinion based (e.g. does the individual experiencing the condition have a better quality of life?)

Not all outcome measures are as good as others in trying to prove or disprove that the medication has an effect. The ideal outcome measure would be:

Non-invasive Involves nothing entering the body and shouldn’t place any burden (such as pain) on individuals with the condition if they take part in the trial.
 
Reliable The results should be the same no matter who performs the experiment (i.e. if a different physiotherapist did it, they would get the same results).
 
Sensitive The measure should be able to detect changes in the disease over a defined period of time. It is no use doing a study over one year if you wouldn’t have expected any worsening of the condition over that period anyway. Often this is the problem with conditions like SMA, as they can be very slow to progress. 
 
Validated The outcome measure should have been used by many studies and found to be a useful measurement, along with the other qualities in this table.
Clinically relevant

This means that if the condition changes as a result of giving the medication, the measure to show this should mean something to the person with the condition. An example of a very clinically relevant measurement would be how far a participant can walk in six minutes. If a person who couldn’t walk more than 1 metre before the treatment can now walk for 300 meters, that would be very clinically relevant and important. Using imaging which suggests the condition gets better with a medication is only clinically relevant if the individual is also more able to do the things that are important to them.

Cheap The smaller cost, the better, as drug companies are more likely to fund trials that are cheaper to run. If an outcome measure is really cheap, they may do it more often and this can speed up trials if results are positive. 
 

When a pharmaceutical company sets out a clinical trial, outcome measures are usually split into three types:

  • Primary outcome measure – this is the most important outcome measurement and is the one they have chosen to show the treatment has or hasn’t worked.
     
  • Secondary outcome measures – these may be useful outcome measures that give important supporting information.  This may be used to add further evidence of how the drug does work (if the primary outcome measurement was positive), or alternatively it may be used to inform pharmaceutical companies as to whether the treatment has worked at all. For example, in a trial, individuals didn’t improve in how far they could walk (primary outcome measure) but all of the MRI scans showed improvements in the muscle (secondary outcome measure). It may be that this trial stopped too soon and that another year may begin to show a difference in walking distance.
     
  • Exploratory outcome measures – these are ideas for outcome measures which could be used in the future. Often this is a way of making sure they are tried out fairly on a big group of participants, rather than running a separate trial to try them out.

SMA physiotherapy outcome measures and how they would be expected to progress without treatment

SMA is a condition that affects a wide range of ages with wide ranging impacts, so physiotherapy outcome measures vary considerably between people with different types of SMA. Also, younger participants will not be able to carry out instructions and will have different measurements that are important to them.

Additionally, it’s important when considering new treatments to have a baseline against which to measure outcomes. This is often called the ‘natural history’ of the condition.

This section looks at three of the most common physiotherapy scales used to measure outcomes and what ‘natural history’ they have indicated.

HINE (Hammersmith Infant Neurological Examination)

  • What is it and how is it scored?

The HINE score is only used in children up to the age of 2 years. It is a physiotherapy-based assessment designed to be as easy as possible to measure. HINE looks at developmental tasks a baby is expected to be able to do and scores them for each. There are eight parts to it:

  • voluntary grasp,
  • head control,
  • ability to kick whilst lying on back,
  • rolling,
  • sitting,
  • crawling,
  • standing,
  • walking.

Each of these parts is scored out of up to four. The total score for each varies as some tasks (i.e. crawling) may have more stages before successfully being able to do the task. The total score is out of 26.

You can see a simplified summary of what is measured and scored, here.

Usually researchers are most interested in two things: the average score of infants at the end of the study, and how much the score may have changed. HINE is also used to look at other conditions such as cerebral palsy1, Infants at risk of developmental problems2, and premature babies3.

  • What has been reported as the usual score for an infant with SMA Type 1 without drug treatment over time?

De Sanctis and colleagues looked at 34 infants with SMA (Type 1) using the HINE assessment4. They found a difference between infants who began with weakness at less than 6 months compared to infants who were older when symptoms began. The younger group scored 0 on all of the different parts and didn’t increase their score over the 12 months of the study. No infants improved in their score over time. Some of the infants affected at a later age may have achieved a score of one in head control, kick, and voluntary grasp. None improved their ability, and the majority reduced in score over the time of the study.

CHOP INTEND (Children’s Hospital Of Philadelphia Infant Test Of Neuromuscular Disorders)

  • What is it and how is it scored?

CHOP INTEND was developed to be used on children from 3 months to over four years. It was developed by looking at babies with SMA Type 15. The score uses 16 parts and scores infants on how well they can perform certain movements. Each one is scored from 0 to 4, with 0 being no response/ability to perform the movement and 4 being ‘complete response’ (being able to perform the task).

You can see a simplified summary of what is measured and scored, here.

  • What has been reported as the usual score for an infant with SMA Type 1 without drug treatment over time

Unlike other assessment tools, CHOP INTEND was developed with SMA evaluation in mind. Kolb and colleagues found that infants with SMA Type 1 scored much lower on average (20) than unaffected infants of the same age (50)6. In a natural history study looking at infants with Type 1 SMA, the following graph was shown to highlight the course of how infants score over time. Each line represents an infant and their score on this test over time. As infants get older their score slowly declines, though as the graph shows, there is a lot of variation between individuals as to how quickly this happens7.

From Kolb SJ, Coffey CS, Yankey JW, et al. Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study. Each line shows the change in an individual child’s CHOP INTEND score over time.

HMFSE - Hammersmith Functional Motor Scale—Expanded

  • What is it and how is it scored?

This test was developed to look at older children with SMA, such as Type 2 and 3. The scale includes several scores that would only be expected in children who can walk. Another advantage of this scale is that it can be used after a child has lost the ability to perform a task or become unable to walk. The HFMSE includes 13 parts, and broadly relates to developmental movement milestones such as rolling, crawling, standing, walking, jumping and even climbing stairs. The test is scored from 0-2 and is out of 6610.

You can see a simplified summary of what is measured and scored, here.

  • What has been reported as the usual score for an infant with SMA without drug treatment over time (‘natural history’)?

One study looking at how SMA progresses in Type 2 and 3, the HMFSE score, has been seen to fall by about half a point (0.56) over a year11. Another study found that the score doesn’t just fall by the same amount each year as individuals get older and that this varies; they also found that over a two and a half year period the score fell by almost 2 (1.71). It is difficult to compare these studies as there will be differences in how the trials were run; this includes things such as age of participant, and how able they were at the beginning of the trial12.

Conclusions

To date there have been many ways to show how SMA progresses. This is important when designing trials and allows drug companies or universities to show that a medication or other treatment or intervention makes a difference. Without these ways of putting a number on how much a condition has progressed, new therapies wouldn’t be approved.

References

  1. Romeo, D. M., Ricci, D. , Brogna, C. and Mercuri, E. (2016), Use of the Hammersmith Infant Neurological Examination in infants with cerebral palsy: a critical review of the literature. Dev Med Child Neurol, 58: 240-245. doi:10.1111/dmcn.12876
     
  2. Pane, M. , Coratti, G. , Sansone, V. A., Messina, S. , Bruno, C. , Catteruccia, M. , Sframeli, M. , Albamonte, E. , Pedemonte, M. , D'Amico, A. , Bravetti, C. , Berti, B. , Brigati, G. , Tacchetti, P. , Salmin, F. , de Sanctis, R. , Lucibello, S. , Piastra, M. , Genovese, O. , Bertini, E. , Vita, G. , Tiziano, F. D., Mercuri, E. and , (2019), Nusinersen in type 1 spinal muscular atrophy: Twelve‐month real‐world data. Ann Neurol. doi:10.1002/ana.25533
     
  3. Maitre, Nathalie L. et al. Implementation of the Hammersmith Infant Neurological Examination in a High-Risk Infant Follow-Up Program. Pediatric Neurology, Volume 65, 31 - 38
     
  4. Chin, E. Y., Baral, V. R., Ereno, I. L., Allen, J. C., Low, K. and Yeo, C. L. (2019), Evaluation of neurological behaviour in late‐preterm newborn infants using the Hammersmith Neonatal Neurological Examination. J Paediatr Child Health, 55: 349-357. doi:10.1111/jpc.14205
     
  5. De Sanctis R, Coratti G, Pasternak A, et al. Developmental milestones in type I spinal muscular atrophy. Neuromuscul Disord. 2016;26(11):754–759. doi:10.1016/j.nmd.2016.10.002
     
  6. Glanzman AM, Mazzone E, Main M, et al. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord. 2010;20(3):155–161. doi:10.1016/j.nmd.2009.11.014
     
  7. Kolb SJ, Coffey CS, Yankey JW, et al. Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study. Ann Clin Transl Neurol. 2016;3(2):132–145. Published 2016 Jan 21. doi:10.1002/acn3.283
     
  8. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014;83(9):810–817. doi:10.1212/WNL.0000000000000741
     
  9. http://investors.avexis.com/phoenix.zhtml?c=254285&p=irol-newsArticle&ID=2344283) accessed on the 30th of June 2019.
     
  10. Ramsey D, Scoto M, Mayhew A, et al. Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool. PLoS One. 2017;12(2):e0172346. Published 2017 Feb 21. doi:10.1371/journal.pone.0172346
     
  11. Mercuri E, Finkel R, Montes J, et al. Patterns of disease progression in type 2 and 3 SMA: implications for clinical trials. Neuromuscul Disord. 2016;26(2):123-131.
     
  12. Kaufmann P, McDermott MP, Darras BT, et al. Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology. 2012;79(18):1889-1897.