Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
Condition: Hereditary Spastic Paraplegia
MeSH terms: Muscle Spasticity; Paraplegia; Spastic Paraplegia, Hereditary
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): Botulinum Toxin Injections; Placebo Injections
Intervention type(s): Other; Other
Intervention description(s): 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.; Each patient in the placebo group will receive sterile sodium chloride injections at adductors and triceps surae muscles bilaterally.
Intervention MeSH terms: Botulinum Toxins
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Spasticity; Botulinum Toxin; Hereditary Spastic Paraplegia