Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia (SPASTOX)
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|ClinicalTrials.gov Identifier: NCT02604186|
Recruitment Status : Completed
First Posted : November 13, 2015
Last Update Posted : November 7, 2017
|First Submitted Date ICMJE||November 9, 2015|
|First Posted Date ICMJE||November 13, 2015|
|Last Update Posted Date||November 7, 2017|
|Actual Study Start Date ICMJE||March 9, 2016|
|Actual Primary Completion Date||March 15, 2017 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Change from baseline in 10 meter maximum gate velocity [ Time Frame: 8 weeks after injections ]
The primary outcome measure will be change from baseline in 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.
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT02604186 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia|
|Official Title ICMJE||Botulinum Toxin in Patients With Hereditary Spastic Paraplegia: a Randomized, Double-blind, Placebo-controlled, Crossover Study|
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.
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.
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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Condition ICMJE||Hereditary Spastic Paraplegia|
|Publications *||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.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date||March 15, 2017|
|Actual Primary Completion Date||March 15, 2017 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years to 80 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Brazil|
|Removed Location Countries|
|NCT Number ICMJE||NCT02604186|
|Other Study ID Numbers ICMJE||CAAE: 48177315.9.1001.5404|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||
|Responsible Party||Marcondes Cavalcante França Júnior, University of Campinas, Brazil|
|Study Sponsor ICMJE||University of Campinas, Brazil|
|PRS Account||University of Campinas, Brazil|
|Verification Date||November 2017|
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