Dual Treatment With Lithium and Valproate in ALS.

NCT03204500 | Completed Phase 2

• 1 other identifier: CONACYT234154
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

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.

Conditions

Amyotrophic Lateral Sclerosis; Amyotrophic Lateral Sclerosis, Sporadic

Keywords

Amyotrophic lateral sclerosis; Dual therapy; Randomized controlled trial; ALSFRS-R

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Changes in score in ALSAQ-5

  Baseline, Month 10, Month 20

• Changes from baseline in FA (fractional anisotropy)

  Baseline and month18

Study Arms (2)

Active treatment with dual therapy

EXPERIMENTAL

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

placebos

PLACEBO COMPARATOR

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

Interventions

Active treatment with dual therapy COMBINATION_PRODUCT

Blue pills ( 200 mg of magnesium valproate ) and white pills ( 300 mg of lithium carbonate) are administered orally with meals.

Active treatment with dual therapy

Placebos DRUG

Administered orally under the same conditions

placebos

Eligibility Criteria

• Age: 40 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• El Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez: lead

Study Sites (1)

Instituto Nacional de Neurologia Y Neurocirugia Mvs

Mexico City, Mexico City, 14269, Mexico

Location

Related Publications (12)

• 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.

  PMID: 24667005 BACKGROUND

• 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.

  PMID: 12716019 BACKGROUND

• 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.

  PMID: 19932742 BACKGROUND

• 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. doi: 10.1016/s0022-510x(99)00210-5.

  PMID: 10540002 BACKGROUND

• 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. doi: 10.1074/jbc.274.10.6039.

  PMID: 10037682 BACKGROUND

• 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.

  PMID: 18640245 BACKGROUND

• 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.

  PMID: 18250315 BACKGROUND

• 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. doi: 10.1212/01.wnl.0000194316.91908.8a.

  PMID: 16434671 BACKGROUND

• 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.

  PMID: 18322101 BACKGROUND

• 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

  BACKGROUND

• 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. doi: 10.1038/sj.mp.4002099. Epub 2007 Oct 9.

  PMID: 17925795 BACKGROUND

• 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. doi: 10.1136/jnnp.70.1.70.

  PMID: 11118250 BACKGROUND

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis; Amyotrophic lateral sclerosis 1

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• MARIE CATHERINE BOLL, MD,PhD.

  525556063822

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD,PhD

Model Details: Twenty ALS patients under active treatment vs. twenty ALS patients under placebo treatment. 21 months follow-up whith clinimetry and biomarkers

Study Record Dates

• First Submitted: June 28, 2017
• First Posted: July 2, 2017
• Study Start: May 1, 2016
• Primary Completion: April 1, 2019
• Study Completion: August 1, 2019
• Last Updated: August 10, 2020

Record last verified: 2019-02

Data Sharing

• IPD Sharing: Will not share

Locations

ME (1)