Dual Treatment With Lithium and Valproate in ALS.

Amyotrophic Lateral Sclerosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03204500
• Other study ID #: CONACYT234154
• Status: Completed
• Phase: Phase 2
• Start date: May 2016
• Est. completion date: August 2019

Study information

• Verified date: February 2019
• Source: El Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: August 2019
• Est. primary completion date: April 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Amyotrophic Lateral Sclerosis, Sporadic
• Motor Neuron Disease
• Sclerosis

Intervention

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.

Drug:
• Placebos
Administered orally under the same conditions

Locations

Country	Name	City	State
Mexico	Instituto Nacional de Neurologia Y Neurocirugia Mvs	Mexico City	Distrito Federal

Sponsors (1)

Lead Sponsor	Collaborator
El Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez

Country where clinical trial is conducted

Mexico, 

References & Publications (12)

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. — View Citation

Boll MC, Bayliss L, Vargas-Cañas S, Burgos J, Montes S, Peñaloza-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. — View Citation

Calderó 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. — View Citation

Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999 Oct 31;169(1-2):13-21. — View Citation

Chen RW, Chuang DM. Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem. 1999 Mar 5;274(10):6039-42. — View 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. — View 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. — View Citation

Jenkinson C, Fitzpatrick R. Reduced item set for the amyotrophic lateral sclerosis assessment questionnaire: development and validation of the ALSAQ-5. J Neurol Neurosurg Psychiatry. 2001 Jan;70(1):70-3. — View Citation

Kimura F, Fujimura C, Ishida S, Nakajima H, Furutama D, Uehara H, Shinoda K, Sugino M, Hanafusa T. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology. 2006 Jan 24;66(2):265-7. — View Citation

Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM. Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci. 2008 Mar 5;28(10):2576-88. doi: 10.1523/JNEUROSCI.5467-07.2008. — View Citation

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 http://dx.doi.org/10.4236/nm.2012.31016

Yasuda S, Liang MH, Marinova Z, Yahyavi A, Chuang DM. The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry. 2009 Jan;14(1):51-9. Epub 2007 Oct 9. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Changes from baseline in FA (fractional anisotropy)	DTI biomarkers in corticospinal tract are measured in 6 regions bilaterally	Baseline and month18