The TIM study was a prospective, double-blind, randomized, multicenter, parallel-group, phase 3 study conducted in 45 sites across 14 countries worldwide. Eligible patients were randomized 1:1:2 to three parallel incobotulinumtoxinA dose groups, respectively: low dose: 4 units/kilogram (U/kg) body weight (BW), maximum total dose 100 U; mid dose: 12 U/kg BW, maximum total dose 300 U; high dose: 16 U/kg BW, maximum total dose 400 U.
Two LL clinical patterns were selected for treatment for each patient, one of which was required to be pes equinus on one side of the body. The patterns chosen by the investigator reflected the patient’s clinical need for therapy, with consideration given to the severity of the involved spastic muscles of the clinical pattern, subject age/weight and muscle size, activity, and experience from previous BoNT treatments. In the bilateral group, patients were treated for pes equinus on both sides of the body (Fig.1 A). In the unilateral group, patients were treated for pes equinus and ipsilateral flexed knee or adducted thigh. In this group, patients with an AS score 2 in the flexed knee and/or adducted thigh had one pattern chosen for treatment based on the investigator’s judgement. Each clinical pattern was treated with half of the total incobotulinumtoxinA dose (2, 4, or 8 U/kg incobotulinumtoxinA with a maximum dose of 50, 150, and 200 U, respectively, per clinical pattern). The muscles treated for each clinical pattern are specified in Fig. 1 A.
At the initial screening visit, each patient was evaluated medically for inclusion in the study, including Gross Motor Function Classification System (GMFCS) classification, AS score, and presence of pain; participants were also questioned about past and concomitant medications within the last 4 weeks, and prior BoNT-A medications. After a 14-day screening period which allowed investigators to check each subject’s eligibility for study participation, treatments were administered during two consecutive double-blind injection cycles, each followed by 12–36 weeks of observation (Fig.1 B), giving an overall study duration of 26–74 weeks. The injections were administered according to the study’s standardized treatment plans with predefined dose ranges and injection-site numbers for each muscle. Equal injection volumes were administered in all dose groups (total volume up to 8 mL; 4 mL/clinical pattern), with dose ranges and injection volumes adjusted for patients with 25 kg BW. At least one form of technical guidance (ultrasound, electrical stimulation, or electromyography) was required for injections, and site-individualized local anesthesia and/or analgosedation protocols could be employed as needed.
Eligibility for reinjection was assessed regularly from 12–36 weeks post-injection. The treatment plan defined for the first injection cycle was continued in the second injection. Patients were eligible for re-treatment if they had an investigator- and patient-agreed clinical need for reinjection in the LL(s) and clinical patterns chosen at the injection visit of injection cycle 1, and an AS score 2 in the treated clinical pattern. For patients with an AS score of 1, the investigator decided whether to re-treat. The injection interval was flexible and based on clinical need. The time to reinjection for each of the three incobotulinumtoxinA dose groups was analyzed descriptively.
Participants were allowed to maintain prior usual and concomitant therapies. These included nonpharmacological therapies such as physical therapy, orthotic management other than casting and rehabilitation, and pharmacological treatments, such as muscle relaxants and antidepressants. Patients who completed the TIM study had the option of enrolling in the open-label Treatment with IncobotulinumtoxinA in Movement Open Label (TIMO) study with 4 further injection cycles.
Two LL clinical patterns were selected for treatment for each patient, one of which was required to be pes equinus on one side of the body. The patterns chosen by the investigator reflected the patient’s clinical need for therapy, with consideration given to the severity of the involved spastic muscles of the clinical pattern, subject age/weight and muscle size, activity, and experience from previous BoNT treatments. In the bilateral group, patients were treated for pes equinus on both sides of the body (Fig.
At the initial screening visit, each patient was evaluated medically for inclusion in the study, including Gross Motor Function Classification System (GMFCS) classification, AS score, and presence of pain; participants were also questioned about past and concomitant medications within the last 4 weeks, and prior BoNT-A medications. After a 14-day screening period which allowed investigators to check each subject’s eligibility for study participation, treatments were administered during two consecutive double-blind injection cycles, each followed by 12–36 weeks of observation (Fig.
Eligibility for reinjection was assessed regularly from 12–36 weeks post-injection. The treatment plan defined for the first injection cycle was continued in the second injection. Patients were eligible for re-treatment if they had an investigator- and patient-agreed clinical need for reinjection in the LL(s) and clinical patterns chosen at the injection visit of injection cycle 1, and an AS score 2 in the treated clinical pattern. For patients with an AS score of 1, the investigator decided whether to re-treat. The injection interval was flexible and based on clinical need. The time to reinjection for each of the three incobotulinumtoxinA dose groups was analyzed descriptively.
Participants were allowed to maintain prior usual and concomitant therapies. These included nonpharmacological therapies such as physical therapy, orthotic management other than casting and rehabilitation, and pharmacological treatments, such as muscle relaxants and antidepressants. Patients who completed the TIM study had the option of enrolling in the open-label Treatment with IncobotulinumtoxinA in Movement Open Label (TIMO) study with 4 further injection cycles.
