Objeto de la investigación

Clinimetrics are characterised as ‘…arbitrary ratings, scales, indexes, instruments or other expressions that have been created as ‘’measurements’’ for those clinical phenomena that cannot be measured in the customary dimensions of ‘’laboratory data’’.’ These rating scales have been developed in order to be used to describe the clinical condition of patients with a disease process (Feinstein, 1987). The clinical changes due to the disease progression can be covered by recording elements of impairment, disability and/or handicaps (Brooks, 1997). Clinimetric scales, as a measure of a complex clinical phenomenon, usually contain multiple items representing different aspects of a disease such as pathology, impairment, disability and handicap, the combination of which varies in the different ALS clinical functional rating scales developed over the last two decades (Brooks, 2002). Most of these scales require either the patient’s self-reporting or the clinician’s reporting of the

51 | P a g e current functional state, referable to the four major anatomical domains involved in ALS (bulbar, breathing, arms and legs) in an ordinal-scaled questionnaire. In addition, attributes being measured in clinimetric scales need to vary over the entire range of clinical presentation among patients in order to provide adequate coverage of clinimetric scale score variability. Hence, limited variability of attributes may not be representative of the whole population (Brooks, 2002), although it might be more sensitive to reflect the change of function.

Reliable clinimetric scales need to fulfil i) consistent intra-rater reliability (or so-called test-retest reliability) in assessments of a patients with stable condition by the same assessor at different occasions, either being tested in the clinic or via telephone, ii) consistent inter-rater reliability across examiners, iii) the ability to detect change over time within a patients, i.e. the clinimetric scale score responsiveness, and iv) good clinimetric scale score sensitivity to detect clinically differences between groups. Table 1.6 summarises markers related to function which are used in ALS trials (Cudkowicz et al., 2004).

One of the most widely used clinimetric scale in ALS is the ALS Function Rating Scale_Revised (ALSFRS_R), a revised version of ALSFRS, which strengthens the ALSFRS with regard to the assessment of respiratory function (Cedarbaum et al., 1999). In a study of 267 ALS patients in the clinic, 4.4-fold increased risk to death or tracheotomy was found in patients with baseline ALSFRS_R score below the median (38), suggesting ALSFRS_R score is a good predictor of survival (Kaufmann et al., 2005) and its progression rate at diagnosis was found to subordinate to the score itself in another study (Kimura et al., 2006).

Progression rate measured by ALSFRS_R between i) First symptom to First examination, ii) the whole follow-up period, and iii) within 100 days during follow-up were all found correlate with survival time (Kollewe et al., 2008). Hence, the ALSFRS_R is currently widely used as a screening measure for entry into clinical trials and as a sensitive outcome measure with sufficient validation to be recommended as a primary endpoint (Leigh et al., 2004). Indeed, a new endpoint for ALS was recently introduced, which combines survival time and change in the ALSFRS_R score as co-primary endpoints, the Combined Assessment of Function and Survival (CAFS) (Berry et al., 2013). CAFS provides a balanced analysis of a drug which might have preferential benefit on function and survival, a powerful

52 | P a g e

Table 1.6 Summary of current clinimetrics in use in ALS.

Measures Method Pros and cons Reference

Muscle Strength Maximum Voluntary Isometric Contraction (MVIC) Quantify the strength of individual muscle groups and normalise the score to obtain megascores. Numerically continuous data.

Fixed device with strain gauges

Good intra- and inter-rater reliability; has been used as primary outcome measure in clinical trials. Inconsistent association with survival found in different trials. Long testing time (approximately 45 minutes), expensive equipment, vigorous training for evaluators required, nor applicable for home visit, not usable for very weak muscles, high dropout rate in the trials using MVIC as an outcome measure

(Andres et al., 1986; Cudkowicz et al., 2004; Hoagland et al., 1997)

Hand-held dynamometre

Been validated against MVIC with good correlation; good intra-rater reliability; portable; inexpensive; shorter testing time.

(Beck et al., 1999; Cudkowicz et al., 2004) Manual Muscle

Testing (MMT)

Using the Medical Research Council (MRC) grading scale. Ordinal qualitative data.

Trained evaluators and standardised patient positioning required; speed, low cost, but low sensitive to change in muscle strength.

(Cudkowicz et al., 2004; Lakes and Group, 2003) Pulmonary function

Forced vital capacity (FVC)

Volume of air forcefully expired in one breath, reported as a percentage of a predicted vital capacity based on the height, gender and age.

Widely available, non-invasive, and portable. Baseline FVC and the rate of decline in FVC are predictive of survival. The decline of FVC overtime is a sensitive measure of disease progression. However, this test is difficult to perform in patients with significant bulbar symptoms.

(Cudkowicz et al., 2003; Kaufmann et al., 2005; Magnus et al., 2002; Varrato et al., 2001) Maximal Inspiratory Pressure (MIP)

The maximal negative pressure at the mouth after complete exhalation by single sustained maximal inspiratory effort against an occluded airway.

Widely available, non-invasive, and portable, but increased variability in patients with bulbar involvements.

(Black and Hyatt, 1969; Cudkowicz et al., 2004)

Maximal Expiratory Pressure (MEP)

The maximal positive pressure measured in the mouth after inhalation to total lung capacity followed by a maximal expiratory effort against an occluded airway

Widely available, non-invasive, and portable, but increased variability in patients with bulbar involvements.

(Black and Hyatt, 1969; Cudkowicz et al., 2004)

Functional rating scales: access the activities of daily living (ADL) Appel ALS rating

scale

Evaluate 5 categories: Bulbar,

Respiratory, Muscle Strength, Lower limbs and Upper limbs function, ranging from 30 (normal) to 164 (maximum impairment).

Simple, validated, sensitive. Rate of change in the score is a predictor of survival. Several team members required to finish the test; time-consuming. Difficult to use in severely affected patients. Unclear relation to function.

(Appel et al., 1987; Haverkamp et al., 1995)

ALS Functional Rating Scale (ALSFRS)

Evaluate 4 motor areas (fine motor, gross motor, bulbar, and respiratory) in 10 questions, score ranging from 40 (normal)

The first functional scale independent to strength testing. Good correlation with survival and other measures. Disproportionate weighing of limb and bulbar measurements to respiratory dysfunction.

53 | P a g e to 0 (worst function) ALS Functional Rating Scale_Revised (ALSFRS_R)

Evaluate 4 motor areas (fine motor, gross motor, bulbar, and respiratory) in 12 questions, score ranging from 48 (normal) to 0 (worst function)

The revised test of ALSFRS. Currently the most widely used functional test in ALS clinical trials. The rate of progression of ALSFRS_R from onset of disease is a predictor of survival time.

(Cedarbaum et al., 1999; Gordon et al., 2010; Kaufmann et al., 2007) Combined Assessment of Function and Survival (CAFS)

A recently developed endpoint which combines two primary outcomes: the ALSFRS_R and survival.

Has been applied in a phase II and phase III study, and show CAFS may provide a balanced analysis for a testing drug with disproportionate effect on function and survival, which weights mortality as the most clinically important outcome. However, CAFS scores between treatment groups cannot be compared across trials directly and it requires sophisticated analysis of the data for function arm and survival arm.

(Archibald et al., 2011; Berry et al., 2013; Cudkowicz et al., 2011; Ferreira-Gonzalez et al., 2007; Rudnicki et al., 2013; Wittkop et al., 2010)

54 | P a g e statistical analysis, and yet prevent false-positive results from drugs beneficial in function but detrimental in survival (Berry et al., 2013). If CAFS can be further validated in more trials, then it may help to improve design and outcome of clinical trials in ALS.