The population involved will be children (either BoNT-A treatment-naïve or pre-treated) with multifocal spasticity of the upper and lower limb due to cerebral palsy, scheduled to receive at least one dose of 16 U/kg (maximum 400U) of IncobotulinumtoxinA. No stratification by gender or age is planned.~Our main aim will be to investigate the efficacy of IncobotulinumtoxinA in the treatment of both BoNT-A naïve and pretreated children for upper and lower limb spasticity using a dose titration approach over three injection cycles, with a flexible observation period after injection of 12 to 20 weeks and a total duration of exposure up to 60 weeks.~Our secondary aim will be to investigate the safety of IncobotulinumtoxinA in the treatment of both BoNT-A naïve and pretreated children for upper and lower limb spasticity using a dose titration approach over three injection cycles, with a flexible observation period after injection of 12 to 20 weeks and a total duration of exposure up to 60 weeks.~Treatment procedures BoNT-A has been established as effective and safe (Level A recommendation) for the treatment of childhood spasticity in CP [18]. It acts in the cytosol of nerve endings and inhibits the release of acetylcholine at neuromuscular junctions by cleaving the synaptosomal-associated protein of 25kDa, which is required for vesicle docking and, consequently, neurotransmitter release. BoNT-A injections guided by ultrasonography are allowed into the spastic muscle affected limbs of both body sides.~Considering a dose of 16 U/kg (maximum 400U) licensed for OnabotulinumoxinA and a conversion ratio of 1:1 between OnabotulinumtoxinA and IncobotulinumtoxinA was defined the following dose for cycle 1 according to Law 648/96. Dose titration was defined according to the previous evidence in adults coming from the Tower study [10].~In cycle 1, a total body dose of 16U/kg (maximum 400U) of IncobotulinumtoxinA will be injected into the spastic muscles of the affected limbs.~In cycle 2, a total body dose of 19U/kg (maximum 475U) of IncobotulinumtoxinA will be injected into the spastic muscles of the affected limbs. If a dose of 19U/kg is not justified (i.e., for clinical or safety reasons) but BoNT-A treatment is still needed (according to the clinical condition of patients) the same dose injected in cycle 1 (16U/Kg; maximum 400U) may be administered in the cycle 2.~In cycle 3, a total body dose of 22U/kg (maximum 550U) of IncobotulinumtoxinA will be injected into the spastic muscles of the affected limbs. If a dose of 22U/kg is not justified (i.e., for clinical or safety reasons) but BoNT-A treatment is still needed (according to the clinical condition of patients) the same dose injected in cycle 2 (19U/Kg; maximum 600U) may be administered in the cycle 3 (if the patient has been treated with 16U/kg in cycle 2, a dose of 19U/kg may be injected in cycle 3).~As to cycles 2 and 3, the following clinical and safety issues will be considered to not justify the dose increase to 19U/kg or 22U/kg: full achievement of the goals set on the GAS as a consequence of a clinically significant reduction of treated muscle tone (quantifiable in at least 1 point on the AS); occurrence of the adverse events reported in paragraph 7 (risks and benefits) and not included in the withdrawal criteria.~Concomitant therapies~Co-administration of the following drugs will not be allowed during the study period:~Aminoglycoside antibiotics~Spectinomycin~Agents interfering with neuromuscular transmission (e.g. tubocurarine-type muscle relaxants)~4-Aminoquinoline~Anticholinergic drugs~AbobotulinumtoxinA (Dysport) and OnabotulinumtoxinA (Botox) Thus, in case these drugs will be needed/administered, the patient will have to withdraw from the study.
Prospective, open-label, non-randomized, single-arm, dose titration, phase II study.~The study will consist of three injection cycles. In each, an injection visit is followed by an observation period of 12 to 20 weeks.~During cycle 1, a total body dose of 16U/kg (maximum 400U) of IncobotulinumtoxinA will be injected into the spastic muscles of the affected limbs.~During cycle 2, a total body dose of 19U/kg (maximum 475U) of IncobotulinumtoxinA will be injected into the spastic muscles of the affected limbs. If a dose of 19U/kg is not justified (i.e., for clinical or safety reasons) but BoNT-A treatment is still needed (according to the clinical condition of patients) the same dose injected in cycle 1 (16U/Kg; maximum 400U) may be administered in the cycle 2.~During cycle 3, a total body dose of 22U/kg (maximum 550U) of IncobotulinumtoxinA will be injected into the spastic muscles of the affected limbs. If a dose of 22U/kg is not justified (i.e., for clinical or safety reasons) but BoNT-A treatment is still needed (according to the clinical condition of patients) the same dose injected in cycle 2 (19U/Kg; maximum 475U) may be administered in the cycle 3.