Clinical trial NCT02604186: Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
Official title: Botulinum Toxin in Patients With Hereditary Spastic Paraplegia: a Randomized, Double-blind, Placebo-controlled, Crossover Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Hereditary Spastic Paraplegia
Keywords: Spasticity
Botulinum Toxin
Hereditary Spastic Paraplegia
Lead sponsor: University of Campinas, Brazil
Sponsor class: OTHER
Collaborators: name: Conselho Nacional de Desenvolvimento Científico e Tecnológico
name: Cristália Produtos Químicos Farmacêuticos Ltda.
First posted: 2015-11-13
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Hereditary spastic paraplegias constitute a heterogeneous group of diseases with the common predominant feature of spasticity of the lower limbs. The clinical picture is composed of difficulty walking, exaggerated deep reflexes, pathological reflexes such as the Babinski sign, sphincter disturbances and various degrees of weakness as well as sensory disturbances.

Spasticity is the symptom that provoques greater incapacity. Although there have been recent advances in the genetic and pathogenic characterization of SPG there is scarcity of therapeutic options. The Botulinum Toxin (BTx) is a well established treatment for movement disorders such as cervical dystonia, blepharospasm, and arm spastic following stroke.

Therefore, the investigators propose the execution of a randomized, double-blind, placebo-controlled, crossover study to evaluate the efficacy of the treatment with Btx over SPG patient's gait. The primary outcome measure will be gait velocity with the 10 meter walking test 8 weeks after injection. Each participant will be submitted to one injection session of Btx and one of placebo (consisting of sterile sodium chloride), each one separated by a period of 6 months. The primary and secondary outcomes will be evaluated by a blind investigator 8 weeks after each injection session.

Detailed description: Introduction

Hereditary spastic paraplegias (SPG) constitute a heterogeneous group of diseases with a common predominant feature: spasticity of the lower limbs and difficulty walking. The neurologic examination reveals spasticity, exaggerated and pathological reflexes, such as the Babinski sign, and minor hypoesthesia. Spasticity is more evident when the patient walks than during passive movement. Weakness may or may not be present, and typically is less disabling than spasticity, especially during the initial years of the disease. The increase in tonus leads to reduced amplitude of movement and abnormal posture, altogether leading to a very slow gait, falls and articular deformities. Clinically, SPG is divided into pure and complicated forms. The first one is characterized by almost exclusive dysfunction of the pyramidal tracts. Minor sensory and sphincter disturbances are also present. The complicated subtypes encompass a wide variety of associated features such as ataxia, cognitive decline and vision loss. Genetically, SPGs are divided into autosomal dominant, autosomal recessive and X-linked forms. Pure forms are mostly inherited in an autosomal dominant manner, whereas the autosomal recessive forms mostly manifest as complicated forms. Although useful clinically, this genotype-phenotype correlation is not always true. The most used SPG classification is based on the locus that harbors the mutated gene. Each subtype is designated by the initials SPG, followed by a number that corresponds to a specific gene. The gene number is established following the chronological order of identification of each locus.

The discovery of new genes and the unraveling of molecular pathways of SPGs have lead to a better understanding of the disease in the past few years. Despite that, there are very few treatment options . There is no placebo-controlled clinical trial performed to assess any therapeutic intervention for SPG. Oral anti-spastic agents such as baclofen and tizanidine are frequently employed. When the response is inadequate, or there are significant side effects, botulinum toxin injections may be attempted. The substance blocks liberation of acetylcholine from the pre-synaptic cleft. With less activation of the nicotinic receptors at the post-synaptic junction the muscle contraction is inhibited. Botulinum Toxin (Btx) is a first-line treatment for movement disorders such as cervical dystonia, blepharospasm, and spastic arm following stroke. Studies with Btx in patients with SPG are limited to small open-label case series, and there is no solid evidence that patients actually benefit from this therapy. The rationale basis for its use is based on the well established knowledge that Btx reduces muscle tonus. The functional impact on gait, on the other hand, is not well known, as well as the impact this treatment could produce over symptoms such as fatigue and pain.

Justification Spasticity is the most disabling manifestation in patients with SPG. Although there have been recent advances in the genetic and pathogenic characterization of the disease, there is scarcity of therapeutic options. The use of oral anti-spastics is limited by frequent side effects such as somnolence and drowsiness. Therefore, the investigators designed a randomized, double-blind, placebo-controlled, crossover trial to evaluate the efficacy and safety of Btx injections in patients with SPG. The primary outcome measure will be gait velocity assessed through the 10 meter walking test 8 weeks after injection. Each participant will be submitted to one injection session with Btx and one with placebo (consisting of sterile sodium chloride), each one separated by a period of 6 months.

Objectives General Objective To evaluate the effects of Btx compared to placebo injections in a cohort of patients with SPG. The primary outcome will be increase in gait velocity, a measure that reflects functional gain. Secondary outcomes will include measures of spasticity, pain and fatigue.

Specific Objectives

* To investigate whether Btx injections improve maximum gait velocity in patients with SPG compared to injections of placebo.
* To investigate the effects of the treatment versus placebo over the following functional measures: Spastic Paraplegia Rating Scale (SPRS), Visual Analogic Pain Scale, Brief Pain inventory, Modified fatigue impact scale, Ashworth Spasticity and muscle strength (through the Medical Research Council Scale) for adductors and triceps surae muscles.

Methods Patients Selection Patients will be selected during regular consultations at two University Hospitals in Brazil: the University of Campinas (UNICAMP) and the Federal University of Paraná (UFPR).

Sample size Estimate The sample size calculus was based on a recent exploratory study (Niet, 2015) where 15 patients with autosomal dominant spastic paraplegia were submitted to Btx injections at the triceps surae. This provoked and increase in gait velocity of 9% after 4 weeks and of 12% after 18 weeks. Estimating a 12% effect for an alfa value of 0.08 and a p value of 0.05, the investigators obtained a N of 54 individuals after correcting for possible losses (approximately 10%). The Stata version 13.1 was used for the estimates.

Procedures All patients recruited will be randomized to receive injections of Prosigne (Botulinum Toxin A) or a Placebo solution (sterile Sodium Chloride 0.9%). Each patient in the treatment group will receive 400 units of botulinum toxin. 100 units will be injected at adductors at each leg and 100 units will be applied in each triceps surae bilaterally. The botulinum toxin as well as the placebo solutions will be prepared by a blind investigator. Prosigne will be diluted with sterile sodium chloride (10U/0.2mL). Within 24 to 28 weeks of the first treatment groups will be switched. Those patients that received botulinum toxin will receive a placebo solution and vice-versa (crossover point). During the study, all patients will be oriented to maintain the ongoing use of medications. They will receive an explanatory sheet regarding stretching exercises, at least one month before receiving treatment, and will be trained by a physiotherapist to execute those exercises twice a week.

Data analysis and interpretation Patients will be evaluated by an experienced and blind neurologist regarding the efficacy parameters of the study. This evaluation will take place immediately before each treatment section and 8 weeks after it. The primary outcome measure will be maximum gait velocity. Each patient will be asked to walk a 10 meter distance barefooted 3 times, as fast as he can. The average velocity between the 3 trials will be used as the final measure. Assistive devices are permitted. Spastic Paraplegia Rating Scale (SPRS), Ashworth modified spasticity scale, medical research council scale for muscular strength (for adductors, thigh and triceps surae muscle groups), visual analogic scale of pain, brief pain inventory and the modified fatigue impact scale, together with the 10 meter comfortable walking velocity, will be evaluated at the same day as the primary outcome measure and will serve as secondary outcome measures.

Eligibility criteria: Inclusion Criteria:

* Age between 18 and 80 years
* Clinical diagnosis of Hereditary Spastic Paraplegia
* Ability to walk at least 10 meters: Assistive devices are permitted

Exclusion Criteria:

* Wheelchair bound patients
* Additional neurological symptoms that may significantly impact gait such as ataxia, polyneuropathy or dementia.
* Fixed tendon contractures
* Antecedents of allergy or adverse reaction to botulinum toxin
* Pregnancy or breastfeeding condition
* Mental retardation
* Dementia

Primary outcomes:
measure: Change from baseline in 10 meter maximum gate velocity
timeFrame: 8 weeks after injections
Secondary outcomes:
measure: Change from baseline in Spastic Paraplegia Rating Scale (SPRS),
timeFrame: 8 weeks after each procedure
measure: Change from baseline in Ashworth spasticity scale of adductors and triceps surae muscles
timeFrame: 8 weeks after each procedure
measure: Change from baseline in muscle strengh (Medical Research Council scale) concerning adductors and triceps surae muscles.
timeFrame: 8 weeks after each procedure
measure: Change from baseline in visual analogic scale of pain
timeFrame: 8 weeks after each procedure
measure: Change from baseline in brief pain inventory scale
timeFrame: 8 weeks after each procedure
measure: Change from baseline in modified fatigue impact scale
timeFrame: 8 weeks after each procedure
measure: Change from baseline in 10 meter comfortable walking velocity
timeFrame: 8 weeks after each procedure
Other outcomes:
Locations:
city: Campinas
country: Brazil
facility: Univeristy of Campinas Hospital
state: SP
Study officials:
affiliation: University of Campinas, Brazil
name: Marcondes c França Júnior, M.D, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: de Niet M, de Bot ST, van de Warrenburg BP, Weerdesteyn V, Geurts AC. Functional effects of botulinum toxin type-A treatment and subsequent stretching of spastic calf muscles: a study in patients with hereditary spastic paraplegia. J Rehabil Med. 2015 Feb;47(2):147-53. doi: 10.2340/16501977-1909.