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Dual Treatment With Lithium and Valproate in ALS.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03204500
Recruitment Status : Active, not recruiting
First Posted : July 2, 2017
Last Update Posted : February 26, 2019
Information provided by (Responsible Party):
Marie Catherine Boll Woehrlen, El Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez

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.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Amyotrophic Lateral Sclerosis, Sporadic Combination Product: Active treatment with dual therapy Drug: Placebos Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Investigator)
Masking Description: This is a prospective randomized double-blind placebo-controlled trial. The randomization is made in blocks of 4 treatments (2 active and 2 placebo). Only the 4-digit numbers on the bottle label will identify the type of treatment.
Primary Purpose: Treatment
Official Title: A Randomized Clinical Trial, Double Blind, Placebo-controlled of Lithium and Valproate in Amyotrophic Lateral Sclerosis.
Actual Study Start Date : May 2016
Estimated Primary Completion Date : April 2019
Estimated Study Completion Date : July 2019

Arm Intervention/treatment
Experimental: Active treatment with dual therapy
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
Blue pills ( 200 mg of magnesium valproate ) and white pills ( 300 mg of lithium carbonate) are administered orally with meals.

Placebo Comparator: placebos
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
Administered orally under the same conditions

Primary Outcome Measures :
  1. Changes in ALSFRS-R [ Time Frame: Every 2 months for 20 months ]
    To evaluate the effect of VPA+Li on progression of ALS by measuring functionnal changes from baseline in ALSFRS-R.

Secondary Outcome Measures :
  1. Changes in score in ALSAQ-5 [ Time Frame: Baseline, Month 10, Month 20 ]
    Changes from baseline in ALSAQ-5, a brief self-administered quality of life scale.

  2. Changes from baseline in FA (fractional anisotropy) [ Time Frame: Baseline and month18 ]
    DTI biomarkers in corticospinal tract are measured in 6 regions bilaterally

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   40 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03204500

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Instituto Nacional de Neurologia Y Neurocirugia Mvs
Mexico City, Distrito Federal, Mexico, 14269
Sponsors and Collaborators
El Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez
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Principal Investigator: MARIE CATHERINE BOLL, MD,PhD. 525556063822
Machado Ximenes JC, Lima Verde EC, Naffah-Mazzacoratti MG, Barros Viana GS. Valproic Acid, a Drug with Multiple Molecular Targets Related to Its Potential Neuroprotective Action. Neuroscience & Medicine, 2012, 3, 107-123

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Responsible Party: Marie Catherine Boll Woehrlen, MD,PhD, El Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez Identifier: NCT03204500    
Other Study ID Numbers: CONACYT234154
First Posted: July 2, 2017    Key Record Dates
Last Update Posted: February 26, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Marie Catherine Boll Woehrlen, El Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez:
Amyotrophic lateral sclerosis
Dual therapy
Randomized controlled trial
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases