Dual Treatment With Lithium and Valproate in ALS.

Study Overview
=================
Brief Summary
-----------------
This is a pilot study in 40 subjects with definite ALS to evaluate the efficacy of valproate and lithium carbonate. After a random assignation of the dual treatment vs. placebo, a follow-up of 20 months will allow to know the clinical and functional evolution so as the status of biomarkers under each treatment.

Detailed Description
-----------------
Amyotrophic lateral sclerosis (ALS) is a rare but fatal condition of the motor neuron. Despite intense therapeutic research in recent years, riluzole remains the only drug with proven efficacy in patients with this disease. In 2008 an Italian clinical-basic study reported benefits with lithium carbonate in both the experimental model of ALS and in a small sample of patients. In the same year, two Chinese studies showed a synergistic neuroprotective effect of valproate administered with lithium in neuronal cultures and in G93A ALS transgenic models. A clinical trial with lithium carbonate and magnesium valproate,conducted from 2009 to 2012 in 18 patients with diagnostic criteria of ALS compared to a sample of 31 contemporary patients who did not receive the drug showed functionnal stability and an increase in antioxidant defenses in subjects under double treatment. Despite the low level of evidence from this open study, the combination of clinical and biological results as well as the significant increase in survival of treated subjects invites us to conduct a study yielding harsh results on the efficacy of dual treatment. To obtain harder data, the study will include 40 subjects with random assignation of the treatments (active vs. placebo) by electronic means. The development of the placebo tablets will be in charge of two pharmaceutical companies. Their delivery and purchase will be performed by a nursing team, the same team that will store and conserve the treatments. The preparation and packaging of the tablets for two months for 10 patients will be done regularly in a sterile environment. Two computer engineers will be in charge of the elaboration of the labels and the numerical draw of the treatments. The coordinator of the study will request the treatments in the nursing warehouse equipped with humidity and temperature control. Another person will be trained to make contacts, home deliveries, bottle changes and tablet counts. The appointments will be scheduled by the researchers every 2 months as well as biosecurity exams and magnetic resonance studies in each patient within a 20-month interval. This pilot study will allow the treatment efficacy to calculate the sample size required for the national and international multicenter clinical trial if relevant, to be promoted at the Mexican Academy of Neurology. It will also allow the study of the behavior of blood and MRI biomarkers ( SOD activity , DTI in cortico-spinal tract, and morphometric indexes).

Official Title
-----------------
A Randomized Clinical Trial, Double Blind, Placebo-controlled of Lithium and Valproate in Amyotrophic Lateral Sclerosis.

Conditions
-----------------
Amyotrophic Lateral Sclerosis, Amyotrophic Lateral Sclerosis, Sporadic

Intervention / Treatment
-----------------
* Combination Product: Active treatment with dual therapy
* Drug: Placebos


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: patients aged 40 to 70 years of both genders female patients who are either postmenopausal for at least 24 months or who are able to practice 2 methods of contraception. Clinical diagnosis of definite ALS supported by neurophysiological studies, according to El Escorial reviewed criteria and Awaji criteria. Sporadic ALS, a priori. Onset of weakness for 1 year ± 6 months Vital capacity of at least 60 % of the predicted value Other treatment (with riluzole or not) at fixed dosis 2 months before and during all the clinical trial. Patients who are willing to give informed consent Without gastrostomy Without jejunostomy Without traqueostomy Exclusion Criteria: Age less than 25 years** Patients with uncontrolled diabetes Patient with heart failure Patient with respiratory vital capacity < 60% Hepatic failure Dysthyroidism Do not give or sign informed consent Women in lactation, pregnancy or possibility of pregnancy Patients with significant sensory abnormalities and uncompensated medical illnesses Laboratory abnormalities consistent with clinically significant cardiovascular, respiratory, haematological, metabolic, hepatic and renal disease. Patients with gastrostomy With jejunostomy With nasogastric tube Tracheotomy and invasive ventilation Treatment with investigational drug within 3 months prior to screening Patients aged 26 to 39 years can be included at the discretion of medical researchers.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Twenty ALS patients under active treatment vs. twenty ALS patients under placebo treatment. 21 months follow-up whith clinimetry and biomarkers
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active treatment with dual therapy<br>This group is composed by 20 ALS subjects under 600mg valproate and 600 mg of litium carbonate per day, during 21 months. The tablets are given orally with meals. | Combination Product: Active treatment with dual therapy<br>* Blue pills ( 200 mg of magnesium valproate ) and white pills ( 300 mg of lithium carbonate) are administered orally with meals.<br>|
| Placebo Comparator: placebos<br>This group is composed by 20 ALS subjects under placebo. Blue tablets ( placebo of VPA) and white tablets (placebo of Li) are administered under the same conditions. | Drug: Placebos<br>* Administered orally under the same conditions<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in ALSFRS-R | To evaluate the effect of VPA+Li on progression of ALS by measuring functionnal changes from baseline in ALSFRS-R. | Every 2 months for 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in score in ALSAQ-5 | Changes from baseline in ALSAQ-5, a brief self-administered quality of life scale. | Baseline, Month 10, Month 20 | 
| Changes from baseline in FA (fractional anisotropy) | DTI biomarkers in corticospinal tract are measured in 6 regions bilaterally | Baseline and month18 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Amyotrophic lateral sclerosis, Dual therapy, Randomized controlled trial, ALSFRS-R