Clinical trial NCT01096082: Safety and Efficacy of Lithium Carbonate in Patients With Spinocerebellar Ataxia Type 3
Official title: Randomized Clinical Trial to Assess the Safety and Efficacy of Lithium Carbonate in Patients With Spinocerebellar Ataxia Type 3
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Spinocerebellar Ataxia Type 3
Machado Joseph Disease
Keywords: spinocerebellar ataxia
Treatment
Lithium carbonate
Lead sponsor: Hospital de Clinicas de Porto Alegre
Sponsor class: OTHER
First posted: 2010-03-30
Enrollment: 62
Sex: ALL
Minimum age (years): 16
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Design: Phase II-III, double-blind, parallel, placebo controlled randomized Clinical trial

Background: Spinocerebellar ataxia type 3 (SCA-3) is an autosomal dominant adult-onset neurodegenerative disorder for which there is no current treatment. Patients will invariably become dependent from others and unable to walk during the disease course.

Hypothesis: Lithium Carbonate is safe and effective in treating neurological symptoms and improving quality of life of patients with SCA3.

Outcomes:

Primary

* Phase 2 - To assess safety and tolerability of Lithium Carbonate in patients with SCA3 after 6 months of follow-up
* Phase 3 (if Phase II study shows safety of therapy) - To assess efficacy of Lithium Carbonate in patients with SCA3 through the Neurological Examination Score for SCA 3 (NESSCA) after 12 months of follow-up .

Secondary

1. - To assess efficacy on neurological function, ataxic, depressive and quality of life scores of Lithium Carbonate in patients with SCA3 through the Scale for the Assessment and Rating of Ataxia (SARA), 9-Hole Peg Board test, 8m walking time, PATA repetition rate, Click Test, SCA Functional Index (SCAFI), Composite Cerebellar Functional Score (CCFS), Beck Depression Inventory, Barthel Index and WHOQol after 6 and 12 months of follow-up.
2. - To assess the effect of Lithium Carbonate in peripheral levels and expression of treatment biomarkers (BDNF, NSE, HDAC, GSK-3Beta)

Study Duration: 12 months

* Final analysis of phase 2 (safety study) at 6 months with continuous monitoring until the end of phase 3 (efficacy study).
* Preliminary analysis of efficacy on ataxia scales at 6 months of study and final analysis of phase 3 at 12 months.

Obs: A futility analysis will be performed after 12 months of therapy if no statistically significant difference between groups were found. This analysis will define if the study will continue until 18 or 24 months of follow-up or will be ended at 12 months.

Location: Hospital de Clínicas de Porto Alegre

Subjects: 60 molecularly diagnosed SCA3 patients from the outpatient unit of the Medical Genetics Service of Hospital de Clínicas de Porto Alegre

Intervention: Lithium Carbonate tablets of 300mg. Starting dose will be 300mg/day with drug titration during 49 days or until achieving the defined target lithium serum level of 0.5 to 0.8 mEq/L


Eligibility criteria: Inclusion Criteria:

* Prior molecular diagnose of SCA3 with determined number of CAG expanded repeat.
* Not restricted to wheelchair.
* With disease duration between 2 and 10 years and more than 16 years old.

Exclusion Criteria:

* Signs of cardiopathy, elevated levels of creatinine, transaminases, bilirubins more than 1.5 times the normal upper limit at baseline.
* History of previous lithium carbonate significant adverse reaction, or drug abuse or alcoholism.
* Disturbance of thyroid function at baseline.
* Participation on another clinical trial less than 4 weeks before the study entrance.
* Current use of valproic acid, memantine, neuroleptics and anticoagulants
* If the individual (woman) did not agree in utilize a high effective contraceptive method during the study period and 3 months after the study-end.

Primary outcomes:
measure: Phase 2 - Safety and tolerability of Lithium Carbonate treatment in patients with SCA3
timeFrame: 6 months
measure: Phase 3 - Efficacy of Lithium Carbonate treatment in patients with SCA3
timeFrame: 12 months
Secondary outcomes:
measure: Efficacy of Lithium Carbonate in patients with SCA3 on neurological function, ataxic, depressive and quality of life scores
timeFrame: 6 and 12 months
measure: Effect of Lithium Carbonate treatment in peripheral levels and expression of treatment biomarkers
timeFrame: 3 and 6 months
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: Rio Grande do Sul
Study officials:
affiliation: Medical Genetics Service Hospital de Clinicas de Porto Alegre
name: Laura B Jardim, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Neurology Service Hospital de Clínicas de Porto Alegre
name: Jonas AM Saute, MD
role: STUDY_DIRECTOR
References:
citation: Watase K, Gatchel JR, Sun Y, Emamian E, Atkinson R, Richman R, Mizusawa H, Orr HT, Shaw C, Zoghbi HY. Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse model. PLoS Med. 2007 May;4(5):e182. doi: 10.1371/journal.pmed.0040182.
citation: Saute JA, Rieder CR, Castilhos RM, Monte TL, Schumacher-Schuh AF, Donis KC, D'Avila R, Souza GN, Russo AD, Furtado GV, Gheno TC, Souza DO, Saraiva-Pereira ML, Portela LV, Camey S, Torman VB, Jardim LB. Planning future clinical trials in Machado Joseph disease: Lessons from a phase 2 trial. J Neurol Sci. 2015 Nov 15;358(1-2):72-6. doi: 10.1016/j.jns.2015.08.019. Epub 2015 Aug 14.
citation: Saute JA, de Castilhos RM, Monte TL, Schumacher-Schuh AF, Donis KC, D'Avila R, Souza GN, Russo AD, Furtado GV, Gheno TC, de Souza DO, Portela LV, Saraiva-Pereira ML, Camey SA, Torman VB, de Mello Rieder CR, Jardim LB. A randomized, phase 2 clinical trial of lithium carbonate in Machado-Joseph disease. Mov Disord. 2014 Apr;29(4):568-73. doi: 10.1002/mds.25803. Epub 2014 Jan 7.