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Guanfacine Hydrochloride Extended Release (Intuniv XR) Tablets: For the Treatment of Attention-Deficit/Hyperactivity Disorder [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2015 Jul.

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Guanfacine Hydrochloride Extended Release (Intuniv XR) Tablets: For the Treatment of Attention-Deficit/Hyperactivity Disorder [Internet].

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APPENDIX 5VALIDITY OF OUTCOME MEASURES

Objective

To describe the scales used in the guanfacine extended release studies and report minimal clinically important difference (MCID) estimates, where available.

Findings

Table 18Summary of Scales Used in the Included Studies

ScaleRaterDescriptionMinimum Important DifferenceComments
ADHD-RSInvestigator18 items (range 0 to 3 points each)
Total range: 0 to 54 (lower score represents fewer symptoms)
18 items are grouped into two subscales: hyperactivity-impulsivity and inattentiveness
Various views exist:
  • 30% mean total score change difference between treatment groups44
  • Between-treatment difference of 5.2 to 7.7 points39
Parent and teacher versions exist, but in the included studies, the investigator version was used.
CPRS-RParent48 items (range 0 to 3 points each)
Lower score represents fewer symptoms
Measures: conduct problems, learning problems, psychometric problems, impulsivity and hyperactivity, and anxiety
Not definedAbbreviated versions of the Conners’ scales were used in some studies (e.g., Study 301)

The primary outcome of Study 307 was the Oppositional Subscale of CPRS-R (long version)
CTRS-RTeacher38 items (range 0 to 3 points each)
Lower score represents fewer symptoms
Measures: hyperactivity, conduct problems, emotional overindulgence, anxious-passiveness, asocial behaviour and daydreaming-attendance problems
Not defined
CGI-S and CGI-IInvestigatorAt baseline, the CGI-S is used on a scale of 1 (no symptoms) to 7 (very severe symptoms).
Subsequently, the CGI-I is used on a scale of 1 to 7 where 1 to 3 means improvement, 4 means no change, and 5 to 7 means worse
Various opinions exist:
  • CGI-I of 1(very much improved) or 2(much improved)44
  • 1 point difference on CGI-S correlates with 8 to 10 points on ADHD-RS45
  • 2 level improvement on CGI-I correlates with 50 to 60% improvement on ADHD-RS45
WFIRSParentMeasure of functioning. Six domains: family, learning and school, life skills, child’s self-concept, social activities, and risky activities
50 questions (score 0 to 3 for each, total score up to 150)
Not defined
HUI2/3ParentHUI2 range (−0.03 to 1.0)
HUI3 range (−0.36 to 1.0)
Various opinions exist. The developers of the scales cite the following range:
0.03 to 0.0546,47
These scales not previously used in clinical studies of ADHD, according to the manufacturer.
CHQCHQ-P50: patient or caregiver
CHQ-CF87: children 10 or older
CHQ-P50 (50 items)
CHQ-CF87 (87 items)
Domains include: physical functioning, role/social limitations, bodily pain, general health perception, role/social limitations, self-esteem, mental health, general behaviour, emotional impact on the parent and time impact on the parent, family activities, and family cohesion. Scores range from 0 to 100, the higher scores indicating better HRQoL.
Not defined

ADHR-RS = ADHD Rating Scale-IV; HRQoL = health related quality of life; HUI2/3 = Health Utilities Index Mark 2 and 3; CHQ = Child Health Questionnaire; WFIRS = Weiss Functional Impairment Rating Scale; CGI-S/I = Clinical Global Impression – Severity of Illness/Improvement; CPRS-R = Conners’ Parent Rating Scale–Revised; CTRS-R = Conners’ Teacher Rating Scale–Revised.

ADHD Rating Scale-IV

The ADHD Rating Scale-IV (ADHD-RS) rates the 18 symptoms of ADHD as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) on a four-point (0 to 3) scale from “never” to “always” and on a number of related scales.44 (Total score range is 0 to 54.) It can be completed by the parent (P-home form) or the teacher (school form) or the investigator on the basis of information provided by the teacher or parent (PI). The scale has high utility for multiple applications due to its quick completion, ease of scoring, and sensitivity to treatment. There is a large, ethnically and geographically representative normative base, consisting of parents and teachers’ ratings of approximately 2,000 children and youths 5 to 18 years old. Test-retest reliability is good, but there is low agreement between teachers’ and parent’s assessments. Differences between scores on the parent and the investigator versions are small.48 There is considerable evidence of discriminant validity between children and youths with ADHD and clinical controls and between subtypes. Sensitivity and specificity appear to be suboptimal and can lead to misclassification of patients on screening. Utility in children under 5 years of age and adults has not been established.49

Some publications have suggested that a 30% mean total score change, or 5.2 to 7.7 points’ difference between treatment groups represents a MCID.39,44 Some studies have defined a responder as a patient who has achieved a mean score of 2 from all items on this scale. This reflects a reduced frequency of symptoms, occurring on average “sometimes.”44

Conners’ Rating Scales

The Conners’ Rating Scales were initially developed to assess a wide variety of children’s behaviour problems. The Conners’ Rating Scale–Revised (R) contains items that are specific to DSM-IV defined ADHD. Normative data are available from parent and teacher ratings of children in the US and Canada, with values presented separately by gender for different age groups from three to 17 years. There is also an Adolescent Self-Report available, which includes 12 items regarding adolescent behaviour.49

Conners’ Teacher Rating Scale–Revised

This scale is used by clinicians and researchers to assess teachers’ perception of children’s behaviour in the classroom. This scale has 38 items rated using a four-point Likert scale (ranging from 0 for not at all true to 3 for very much true). It contains six scales and assesses behaviour along the dimensions of hyperactivity, conduct problems, emotional overindulgence, anxious-passiveness, asocial behaviour, and daydreaming-attendance problems.50 There is a large, ethnically and geographically representative normative base, consisting of teachers’ ratings of 1,702 youths, in separate cohorts of three to seven, eight to 12, and 13 to 17 years of age. It has moderate test-retest reliability but high sensitivity and specificity. The CTRS–R has excellent clinical utility and provides reliable, valid, and convenient means of measuring teachers’ perceptions but should constitute only one component of the evaluation process and should not be solely relied upon for making clinical decisions.51

Conners’ Parent Rating Scale–Revised

This scale is used by clinicians and researchers to assess parents’ perception of children’s behaviour in the classroom. This scale has 48 items rated using a four-point Likert scale (ranging from 0 for “not at all true” to 3 for “very much true”). The Conners’ Parent Rating Scale–R contains five scales and assesses the behaviour of children along dimensions of conduct problems, learning problems, psychometric problems, impulsivity and hyperactivity, and anxiety. It has low to adequate one year test-retest reliability, adequate one year test-retest reliability for the impulsivity/hyperactivity factor, and low inter-parent inter-rater reliability.50

Clinical Global Impression–Severity of Illness/Improvement

At baseline, the investigator rates the severity of symptoms on a seven-point scale at baseline from 0 to 6 (0 = no symptoms and 6 = “very severe” symptoms). In subsequent assessments, the patient’s improvement is measured relative to baseline using a seven-point scale from 1 to 7 (1 = “very much improved” and 7 = “very much worse”). This can then be converted to a dichotomous measure, grouping those who improved (“very much improved” and “much improved”) and those who did not (all other categories).

There is no widely accepted definition of a clinically relevant response for ADHD. A reduction of 30% in a severity scale score (e.g., ADHD-RS) is likely to equate to a CGI of 1 (“very much improved”) or 2 (“much improved”) and has been used as a clinically relevant measure of response in some studies.44

Child Health Questionnaire

The Child Health Questionnaire (CHQ) is a multi-dimensional generic measure of health-related quality of life (HRQoL) that can be used with children as young as five years of age. It measures 11 domains of health. Physical domains include physical functioning, role/social limitations as a result of physical health, bodily pain and discomfort, and general health perception. Psychosocial domains include role/social limitations as a result of emotional-behavioural problems, self-esteem, mental health, general behaviour, emotional impact on the parent, and time impact on the parent. Separate domains measure impact on family activities and family cohesion. Scores for the domains and items range from 0 to 100, the higher scores indicating better HRQoL. Summary scores have a mean of 50 and standard deviation of 10. The CHQ has undergone extensive validation and normative data testing.52

Weiss Functional Impairment Rating Scale–Parent Report

The Weiss Functional Impairment Rating Scale–Parent Report is a 50-item parent-rated measure of functioning across six domains: family, learning and school, life skills, child’s self-concept, social activities, and risky activities. Each item is rated using a four-point Likert scale ranging from 0 (never or not at all) to 3 (very often or very much) and then summed to provide domain and total scale scores.53

Health Utility Index Mark 2 and Mark 330,47

The Health Utility Index Mark 2 (HUI2) and Mark 3 (HUI3) are generic health profiles and preference-based systems for measuring health status and HRQoL, and for producing utility scores. They describe the experience of patients undergoing therapy; long-term outcomes associated with disease or therapy; the efficacy, effectiveness, and efficiency of health care interventions; and the health status of general populations.

The self-administered, parent-assessed version of the HUI2 and HUI3 that was used in several guanfacine trials consists of 15 questions required to classify a patient’s health status. Three additional questions were included to capture additional information of use for health status measurement surveys.

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