A Safety, Efficacy and Tolerability Study of Sativex for the Treatment of Spasticity in Children Aged 8 to 18 Years

The spasticity 0-10 NRS was completed daily at bedtime using a paper study diary. The difference between spasticity and spasm was clearly explained to the caregiver. The primary caregiver was asked the following question: "This question is about your child's muscles and how soft or tight/hard they have felt today. Think carefully about how your child's muscles have felt today and circle a number from 0 to 10 that best describes this, where: 0 = 'my child's muscles have felt totally relaxed' and 10 = 'my child's muscles have felt the tightest/hardest they have ever felt'". A reduction in score indicates an improvement in condition.

The mean spasticity 0-10 NRS score of the last 7 days of the baseline period was used for a patient's mean baseline score. The mean 0-10 NRS score of the last 7 days prior to completion/withdrawal was used for a patient's mean end of treatment score.

This study looked at the MTS in the worst affected limb only. The same limb was assessed at each visit, preferably also by the same examiner.

The MTS used the following criteria:

• Individuals were positioned in the sitting position to test the upper extremities and a supine position to test the lower extremities
• Three speed definitions:

• V1 is slow as possible
• V2 speed of limb falling under gravity
• V3 moving as fast as possible
• The MTS describes R1 and R2. R1 is the angle of muscle reaction; R2 is the full passive range of movement.
• R2 is measured at V1 and R1 at V3. R2-R1 = dynamic tone component of the muscle. The relationship between R1 and R2 estimates the relative contributions of spasticity compared to contracture.

A reduction in score indicates and improvement in condition.

Participants were tested in the supine position and participants were instructed to relax. Muscle groups in the ankle, knee, hip, shoulder, elbow and wrist were rated on a scale of 0 = No increase in muscle tone, 1 = Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion when the affected part(s) is moved in flexion or extension, 1+ = Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the range of movement (ROM), 2 = More marked increase in muscle tone through most of the ROM, but affected part(s) easily moved, 3 = Considerable increase in muscle tone, passive movement difficult, 4 = Affected part(s) rigid in flexion or extension. The MAS was performed by the same examiner at each visit, where possible. A reduction in score indicates an improvement in condition.

The sleep quality 0-10 NRS was completed at the same time each day, ideally when waking in the morning. This questionnaire was designed to record the level of sleep disturbance. The primary caregiver was asked the following question: "This question is about how badly your child slept last night. Please mark a number from 0 to 10 that indicates how bad your child's sleep was where: 0 = My child had a night of non-stop sleep and 10 = My child was unable to sleep at all". A reduction in score indicates and improvement in condition.

The PPP is a 20-item behaviour rating scale designed to assess pain in children with severe neurological disability. Each item is scored on a four point scale of 0 to 3 as occurring 'not at all' (zero) to 'a great deal' (three) in the given time period. The total score therefore will range from 0 to 60. The questionnaire was designed to be completed by the child's primary caregiver and was completed at each assessment visit during the study. A reduction in score indicates an improvement in condition.

The cerebral palsy QOL-Child QoL questionnaire (aged 4-12 years) is a 66-item questionnaire that looks at eight important domains of life including friends and family; participation; communication; health; special equipment; pain and bother; access to services; and parents' health. Completed by the primary caregiver it assesses how the caregiver thinks the child feels about these aspects of their life. The numbers range from one (very unhappy) to nine (very happy).

The teen questionnaire (aged 13-18 years) comes with two questionnaires, one to be completed by the participant, if applicable, and one by the primary caregiver. The first seven sections of the questionnaire are identical and look at seven important domains of life including friends and family; school; participation; communication; health, special equipment and pain and bother. The caregiver questionnaire has an additional section which looks at access to services.

Increases in score indicate an improvement in condition.

The comfort questionnaire was completed at the same time each day, i.e. bedtime in the evening. The caregiver was asked to reflect on the whole day and record the longest number of minutes at any one time over which their child was able to sit in comfort for, without moving position. An increase in time indicates an improvement in condition.

The CDI 2 contains 28 items, each of which consists of three statements (each scored 0-2 [0=best outcome, 2=worst outcome]). For each item, the participant is asked to select the statement that best describes his or her feelings. The assessment is designed for a variety of situations, including schools, child guidance clinics, pediatric practices, and child psychiatric settings. If the participant is unable to complete the questionnaire, the questionnaire will be left blank.

A reduction in score indicates an improvement in condition.

The SF-36-II is a 36 item questionnaire that measures eight multi-item dimensions of health: physical functioning (10 items) social functioning (two items) role limitations due to physical problems (four items), role limitations due to emotional problems (three items), mental health (five items), energy/vitality (four items), pain (two items), and general health perception (five items). There is a further unscaled single item asking respondents about health change over the past year. For each dimension item scores are coded, summed, and transformed on to a scale from 0 (worst possible health state measured by the questionnaire) to 100 (best possible health state). An increase in score indicates an improvement in condition.

The main caregiver was asked to assess the change in the participant's condition. Questions were rated on a seven-point scale: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The caregiver was asked:

"How have the participant's general functional abilities changed since Visit 2?" (i.e. change from baseline).

The number of participants for each marker is presented.

The main caregiver was asked to assess the change in the participant's condition. Questions were rated on a seven-point scale: Very much worse, Much worse, Minimally worse, No change, Minimally better, Much better, Very much better. The caregiver was asked:

"How has the participant's ease of transfer changed since Visit 2?"(i.e. change from baseline).

The number of participants for each marker is presented.

The number of participants who reported an adverse event during the randomised treatment part of the study is presented.