INcobotulinumtoxina in ChIldren Upper and Lower Limb sPasticITy (INCIPIT)

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.

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.

Eligibility Criteria:
Inclusion Criteria:

* Patients with upper and lower limb spasticity due to cerebral palsy
* Gross Motor Function Classification System (GMFCS) from Level II to Level V
* Selected target clinical pattern diagnosed by a qualified health care professional (i.e. physiatrist)
* Focal spasticity scored at least 2 points on the Ashworth scale (AS) in the joints associated with the selected target clinical pattern
* Patient deemed by the investigator to require a total body dose up to 22U/kg (maximum 550U) during the study period
* In the case of children pretreated with BoNT-A, time from the last injection at least 5 months
* Informed consent signed by parents or legal guardian.

Exclusion Criteria:

* Participation in other trials
* BoNT-A treatment contraindicated
* Therapy with anticoagulants or other substances that could have an anticoagulant effect
* Girls of childbearing potential (defined as females post menarche)
* Presence of fixed contractures, or bony deformities of the affected limbs
* Previous treatment of spastic muscles with nerve penalization
* Other neurological or orthopaedic conditions involving the affected limbs.

Specific vulnerable populations:

* institutionalized patients will not be included
* girls of childbearing potential (defined as females with a history of menarche) will not be included.

Withdrawal criteria for single patients:

* Serious adverse event (SAE)
* Development of dysphagia and/or aspiration pneumonia.
* Withdrawal of consent
* Inability to follow the study according to its design and time points
* Co-administration of aminoglycoside antibiotics, spectinomycin, 4-aminoquinoline, anticholinergic drugs, AbobotulinumtoxinA, OnabotulinumtoxinA or other agents interfering with neuromuscular transmission (e.g., tubocurarine-type muscle relaxants).