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Dual Treatment With Lithium and Valproate in ALS.

Primary Purpose

Amyotrophic Lateral Sclerosis, Amyotrophic Lateral Sclerosis, Sporadic

Status
Completed
Phase
Phase 2
Locations
Mexico
Study Type
Interventional
Intervention
Active treatment with dual therapy
Placebos
Sponsored by
El Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis focused on measuring Amyotrophic lateral sclerosis, Dual therapy, Randomized controlled trial, ALSFRS-R

Eligibility Criteria

40 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Instituto Nacional de Neurologia Y Neurocirugia Mvs

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Active treatment with dual therapy

placebos

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Changes in ALSFRS-R
To evaluate the effect of VPA+Li on progression of ALS by measuring functionnal changes from baseline in ALSFRS-R.

Secondary Outcome Measures

Changes in score in ALSAQ-5
Changes from baseline in ALSAQ-5, a brief self-administered quality of life scale.
Changes from baseline in FA (fractional anisotropy)
DTI biomarkers in corticospinal tract are measured in 6 regions bilaterally

Full Information

First Posted
June 28, 2017
Last Updated
August 6, 2020
Sponsor
El Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez
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1. Study Identification

Unique Protocol Identification Number
NCT03204500
Brief Title
Dual Treatment With Lithium and Valproate in ALS.
Official Title
A Randomized Clinical Trial, Double Blind, Placebo-controlled of Lithium and Valproate in Amyotrophic Lateral Sclerosis.
Study Type
Interventional

2. Study Status

Record Verification Date
February 2019
Overall Recruitment Status
Completed
Study Start Date
May 2016 (Actual)
Primary Completion Date
April 2019 (Actual)
Study Completion Date
August 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
El Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyotrophic Lateral Sclerosis, Amyotrophic Lateral Sclerosis, Sporadic
Keywords
Amyotrophic lateral sclerosis, Dual therapy, Randomized controlled trial, ALSFRS-R

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Twenty ALS patients under active treatment vs. twenty ALS patients under placebo treatment. 21 months follow-up whith clinimetry and biomarkers
Masking
ParticipantInvestigator
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.
Allocation
Randomized
Enrollment
43 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Active treatment with dual therapy
Arm Type
Experimental
Arm Description
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.
Arm Title
placebos
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Combination Product
Intervention Name(s)
Active treatment with dual therapy
Intervention Description
Blue pills ( 200 mg of magnesium valproate ) and white pills ( 300 mg of lithium carbonate) are administered orally with meals.
Intervention Type
Drug
Intervention Name(s)
Placebos
Intervention Description
Administered orally under the same conditions
Primary Outcome Measure Information:
Title
Changes in ALSFRS-R
Description
To evaluate the effect of VPA+Li on progression of ALS by measuring functionnal changes from baseline in ALSFRS-R.
Time Frame
Every 2 months for 20 months
Secondary Outcome Measure Information:
Title
Changes in score in ALSAQ-5
Description
Changes from baseline in ALSAQ-5, a brief self-administered quality of life scale.
Time Frame
Baseline, Month 10, Month 20
Title
Changes from baseline in FA (fractional anisotropy)
Description
DTI biomarkers in corticospinal tract are measured in 6 regions bilaterally
Time Frame
Baseline and month18

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
MARIE CATHERINE BOLL, MD,PhD.
Organizational Affiliation
525556063822
Official's Role
Principal Investigator
Facility Information:
Facility Name
Instituto Nacional de Neurologia Y Neurocirugia Mvs
City
Mexico City
State/Province
Distrito Federal
ZIP/Postal Code
14269
Country
Mexico

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
24667005
Citation
Boll MC, Bayliss L, Vargas-Canas S, Burgos J, Montes S, Penaloza-Solano G, Rios C, Alcaraz-Zubeldia M. Clinical and biological changes under treatment with lithium carbonate and valproic acid in sporadic amyotrophic lateral sclerosis. J Neurol Sci. 2014 May 15;340(1-2):103-8. doi: 10.1016/j.jns.2014.03.005. Epub 2014 Mar 11.
Results Reference
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PubMed Identifier
12716019
Citation
Boll MC, Alcaraz-Zubeldia M, Montes S, Murillo-Bonilla L, Rios C. Raised nitrate concentration and low SOD activity in the CSF of sporadic ALS patients. Neurochem Res. 2003 May;28(5):699-703. doi: 10.1023/a:1022853531855.
Results Reference
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PubMed Identifier
19932742
Citation
Caldero J, Brunet N, Tarabal O, Piedrafita L, Hereu M, Ayala V, Esquerda JE. Lithium prevents excitotoxic cell death of motoneurons in organotypic slice cultures of spinal cord. Neuroscience. 2010 Feb 17;165(4):1353-69. doi: 10.1016/j.neuroscience.2009.11.034. Epub 2009 Nov 22.
Results Reference
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10540002
Citation
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Results Reference
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PubMed Identifier
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Citation
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Results Reference
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PubMed Identifier
18640245
Citation
Feng HL, Leng Y, Ma CH, Zhang J, Ren M, Chuang DM. Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience. 2008 Aug 26;155(3):567-72. doi: 10.1016/j.neuroscience.2008.06.040. Epub 2008 Jun 21.
Results Reference
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PubMed Identifier
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Citation
Fornai F, Longone P, Cafaro L, Kastsiuchenka O, Ferrucci M, Manca ML, Lazzeri G, Spalloni A, Bellio N, Lenzi P, Modugno N, Siciliano G, Isidoro C, Murri L, Ruggieri S, Paparelli A. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2052-7. doi: 10.1073/pnas.0708022105. Epub 2008 Feb 4. Erratum In: Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16404-7.
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PubMed Identifier
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Citation
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PubMed Identifier
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Citation
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Dual Treatment With Lithium and Valproate in ALS.

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