Tolerability and Efficacy of L-Serine in Patients With Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS) Clinical Trial

— ALS  

Official title:

Tolerability and Efficacy of L-Serine in Patients With Amyotrophic Lateral Sclerosis: A Phase IIa Study

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03580616
• Other study ID #: D18095
• Status: Terminated
• Phase: Phase 2
• Start date: October 24, 2018
• Est. completion date: December 20, 2022

Study information

• Verified date: August 2023
• Source: Dartmouth-Hitchcock Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the tolerability of L-Serine oral doses for ALS patients and assess preliminary indications of efficacy

Description:

All patients will receive the same dose of the study treatment over 6 months. For each participant the study will last approximately one year with follow up visits after the treatment period of 6 months is completed. The visits will include blood draws, vital sign checks, neurological and physical exams, pulmonary testing with forced vital capacity (FVC), and questionnaires.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 43
• Est. completion date: December 20, 2022
• Est. primary completion date: August 3, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of probable or definite ALS
• ALSFRS-R score >25 and FVC score = 60% predicted
• If currently taking Riluzole and/or Edaravone/Radicava must be on stable dose for 3 months prior to Baseline/Screening. If the dosing has not been stable for 3 months prior to Baseline/Screening or if stopped due to an adverse event, the waiting period off the medication will be 7 days. If not on either of these medications may start if desired either or both medications after enrollment into study.

Exclusion Criteria:

• Diagnosis of probable or definite ALS more than 3 years prior to study enrollment
• Diagnosis or previous history of ischemic stroke, brain tumor, uncontrolled diabetes, renal insufficiency, or severe hypertension.
• Diagnosis or previous history of comorbid progressive neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, Lewy Body disease, Pick's disease, Huntington's disease, Progressive Supranuclear palsy. ALS patients diagnosed with frontotemporal dementia will not be excluded from this study.
• Diagnosis or previous history of symptomatic peripheral neuropathy. Patients with findings of peripheral neuropathy on electrodiagnostic tests only but no clinical symptoms at the time of enrollment are eligible.
• Undergoing any chemotherapy or radiation therapy for any cancer
• Any medical condition likely to interfere with the conduct of the trial or survival of the patient during this study period
• Pregnant women or women who are breast feeding
• Has taken L-Serine supplement within 30 days prior to start of study drug

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Amyotrophic Lateral Sclerosis (ALS)
• Motor Neuron Disease
• Sclerosis

Intervention

Drug:
• L-Serine
L-Serine is a naturally occurring dietary amino acid. It is abundant in soy products, some edible seaweeds, sweet potatoes, eggs and meat.

Locations

Country	Name	City	State
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire

Sponsors (2)

Lead Sponsor	Collaborator
Elijah W. Stommel	Brain Chemistry Labs, Institute for Ethnomedicine

Country where clinical trial is conducted

United States, 

References & Publications (37)

Abe K, Itoyama Y, Sobue G, Tsuji S, Aoki M, Doyu M, Hamada C, Kondo K, Yoneoka T, Akimoto M, Yoshino H; Edaravone ALS Study Group. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec;15(7-8):610-7. doi: 10.3109/21678421.2014.959024. Epub 2014 Oct 6. — View Citation

Andrew AS, Caller TA, Tandan R, Duell EJ, Henegan PL, Field NC, Bradley WG, Stommel EW. Environmental and Occupational Exposures and Amyotrophic Lateral Sclerosis in New England. Neurodegener Dis. 2017;17(2-3):110-116. doi: 10.1159/000453359. Epub 2017 Jan 26. — View Citation

Banack SA, Murch SJ, Cox PA. Neurotoxic flying foxes as dietary items for the Chamorro people, Marianas Islands. J Ethnopharmacol. 2006 Jun 15;106(1):97-104. doi: 10.1016/j.jep.2005.12.032. Epub 2006 Feb 7. — View Citation

Braak H, Braak E. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging. 1995 May-Jun;16(3):271-8; discussion 278-84. doi: 10.1016/0197-4580(95)00021-6. — View Citation

Brannath W, Burger HU, Glimm E, Stallard N, Vandemeulebroecke M, Wassmer G. Comments on the draft guidance on "adaptive design clinical trials for drugs and biologics" of the U.S. Food and Drug Administration. J Biopharm Stat. 2010 Nov;20(6):1125-31. doi: 10.1080/10543406.2010.514453. — View Citation

Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec;1(5):293-9. doi: 10.1080/146608200300079536. No abstract available. — View Citation

Caller TA, Andrews A, Field NC, Henegan PL, Stommel EW. The Epidemiology of Amyotrophic Lateral Sclerosis in New Hampshire, USA, 2004-2007. Neurodegener Dis. 2015;15(4):202-6. doi: 10.1159/000374117. Epub 2015 Apr 16. — View Citation

Canu N, Ciotti MT, Pollegioni L. Serine racemase: a key player in apoptosis and necrosis. Front Synaptic Neurosci. 2014 Apr 21;6:9. doi: 10.3389/fnsyn.2014.00009. eCollection 2014. — 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. doi: 10.1016/s0022-510x(99)00210-5. — View Citation

Cox PA, Banack SA, Murch SJ. Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13380-3. doi: 10.1073/pnas.2235808100. — View Citation

Cox PA, Davis DA, Mash DC, Metcalf JS, Banack SA. Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain. Proc Biol Sci. 2016 Jan 27;283(1823):20152397. doi: 10.1098/rspb.2015.2397. — View Citation

de Koning TJ. Treatment with amino acids in serine deficiency disorders. J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):347-51. doi: 10.1007/s10545-006-0269-0. — View Citation

Desai JR, Bowen EA, Danielson MM, Allam RR, Cantor MN. Creation and implementation of a historical controls database from randomized clinical trials. J Am Med Inform Assoc. 2013 Jun;20(e1):e162-8. doi: 10.1136/amiajnl-2012-001257. Epub 2013 Feb 28. — View Citation

Dunlop RA, Cox PA, Banack SA, Rodgers KJ. The non-protein amino acid BMAA is misincorporated into human proteins in place of L-serine causing protein misfolding and aggregation. PLoS One. 2013 Sep 25;8(9):e75376. doi: 10.1371/journal.pone.0075376. eCollection 2013. — View Citation

Dunlop RA, Powell J, Guillemin GJ, Cox PA. Mechanisms of L-Serine Neuroprotection in vitro Include ER Proteostasis Regulation. Neurotox Res. 2018 Jan;33(1):123-132. doi: 10.1007/s12640-017-9829-3. Epub 2017 Nov 2. — View Citation

Dunlop RA, Powell JT, Metcalf JS, Guillemin GJ, Cox PA. L-Serine-Mediated Neuroprotection Includes the Upregulation of the ER Stress Chaperone Protein Disulfide Isomerase (PDI). Neurotox Res. 2018 Jan;33(1):113-122. doi: 10.1007/s12640-017-9817-7. Epub 2017 Oct 3. — View Citation

Fiandaca MS, Kapogiannis D, Mapstone M, Boxer A, Eitan E, Schwartz JB, Abner EL, Petersen RC, Federoff HJ, Miller BL, Goetzl EJ. Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study. Alzheimers Dement. 2015 Jun;11(6):600-7.e1. doi: 10.1016/j.jalz.2014.06.008. Epub 2014 Aug 15. — View Citation

Garofalo K, Penno A, Schmidt BP, Lee HJ, Frosch MP, von Eckardstein A, Brown RH, Hornemann T, Eichler FS. Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest. 2011 Dec;121(12):4735-45. doi: 10.1172/JCI57549. — View Citation

Goetzl EJ, Boxer A, Schwartz JB, Abner EL, Petersen RC, Miller BL, Kapogiannis D. Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology. 2015 Jul 7;85(1):40-7. doi: 10.1212/WNL.0000000000001702. Epub 2015 Jun 10. — View Citation

Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R. How common are the "common" neurologic disorders? Neurology. 2007 Jan 30;68(5):326-37. doi: 10.1212/01.wnl.0000252807.38124.a3. — View Citation

Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, Pradat PF, Camu W, Meininger V, Dupre N, Rouleau GA. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008 May;40(5):572-4. doi: 10.1038/ng.132. Epub 2008 Mar 30. — View Citation

Kaufmann P, Levy G, Thompson JL, Delbene ML, Battista V, Gordon PH, Rowland LP, Levin B, Mitsumoto H. The ALSFRSr predicts survival time in an ALS clinic population. Neurology. 2005 Jan 11;64(1):38-43. doi: 10.1212/01.WNL.0000148648.38313.64. — View Citation

Levine TD, Miller RG, Bradley WG, Moore DH, Saperstein DS, Flynn LE, Katz JS, Forshew DA, Metcalf JS, Banack SA, Cox PA. Phase I clinical trial of safety of L-serine for ALS patients. Amyotroph Lateral Scler Frontotemporal Degener. 2017 Feb;18(1-2):107-111. doi: 10.1080/21678421.2016.1221971. Epub 2016 Sep 2. — View Citation

Logroscino G, Traynor BJ, Hardiman O, Chio A, Mitchell D, Swingler RJ, Millul A, Benn E, Beghi E; EURALS. Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry. 2010 Apr;81(4):385-90. doi: 10.1136/jnnp.2009.183525. Epub 2009 Aug 25. — View Citation

Mehta P, Kaye W, Bryan L, Larson T, Copeland T, Wu J, Muravov O, Horton K. Prevalence of Amyotrophic Lateral Sclerosis - United States, 2012-2013. MMWR Surveill Summ. 2016 Aug 5;65(8):1-12. doi: 10.15585/mmwr.ss6508a1. — View Citation

Metcalf JS, Dunlop RA, Powell JT, Banack SA, Cox PA. L-Serine: a Naturally-Occurring Amino Acid with Therapeutic Potential. Neurotox Res. 2018 Jan;33(1):213-221. doi: 10.1007/s12640-017-9814-x. Epub 2017 Sep 19. — View Citation

Metcalf JS, Lobner D, Banack SA, Cox GA, Nunn PB, Wyatt PB, Cox PA. Analysis of BMAA enantiomers in cycads, cyanobacteria, and mammals: in vivo formation and toxicity of D-BMAA. Amino Acids. 2017 Aug;49(8):1427-1439. doi: 10.1007/s00726-017-2445-y. Epub 2017 Jun 15. — View Citation

Murch SJ, Cox PA, Banack SA. A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12228-31. doi: 10.1073/pnas.0404926101. Epub 2004 Aug 4. — View Citation

Phukan J, Elamin M, Bede P, Jordan N, Gallagher L, Byrne S, Lynch C, Pender N, Hardiman O. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry. 2012 Jan;83(1):102-8. doi: 10.1136/jnnp-2011-300188. Epub 2011 Aug 11. — View Citation

Polman CH, Reingold SC, Barkhof F, Calabresi PA, Clanet M, Cohen JA, Cutter GR, Freedman MS, Kappos L, Lublin FD, McFarland HF, Metz LM, Miller AE, Montalban X, O'Connor PW, Panitch H, Richert JR, Petkau J, Schwid SR, Sormani MP, Thompson AJ, Weinshenker BG, Wolinsky JS. Ethics of placebo-controlled clinical trials in multiple sclerosis: a reassessment. Neurology. 2008 Mar 25;70(13 Pt 2):1134-40. doi: 10.1212/01.wnl.0000306410.84794.4d. — View Citation

Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Schulz PE. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology. 2005 Aug 23;65(4):586-90. doi: 10.1212/01.wnl.0000172911.39167.b6. — View Citation

Splawinski J, Kuzniar J. Clinical trials: active control vs placebo--what is ethical? Sci Eng Ethics. 2004 Jan;10(1):73-9. doi: 10.1007/s11948-004-0065-x. — View Citation

Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-arm clinical trials with multiple outcomes. Stat Med. 1995 Feb 28;14(4):357-79. doi: 10.1002/sim.4780140404. — View Citation

Thompson AG, Gray E, Heman-Ackah SM, Mager I, Talbot K, Andaloussi SE, Wood MJ, Turner MR. Extracellular vesicles in neurodegenerative disease - pathogenesis to biomarkers. Nat Rev Neurol. 2016 Jun;12(6):346-57. doi: 10.1038/nrneurol.2016.68. Epub 2016 May 13. — View Citation

Viele K, Berry S, Neuenschwander B, Amzal B, Chen F, Enas N, Hobbs B, Ibrahim JG, Kinnersley N, Lindborg S, Micallef S, Roychoudhury S, Thompson L. Use of historical control data for assessing treatment effects in clinical trials. Pharm Stat. 2014 Jan-Feb;13(1):41-54. doi: 10.1002/pst.1589. Epub 2013 Aug 5. — View Citation

Wheaton MW, Salamone AR, Mosnik DM, McDonald RO, Appel SH, Schmolck HI, Ringholz GM, Schulz PE. Cognitive impairment in familial ALS. Neurology. 2007 Oct 2;69(14):1411-7. doi: 10.1212/01.wnl.0000277422.11236.2c. — View Citation

Winston CN, Goetzl EJ, Akers JC, Carter BS, Rockenstein EM, Galasko D, Masliah E, Rissman RA. Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile. Alzheimers Dement (Amst). 2016 May 7;3:63-72. doi: 10.1016/j.dadm.2016.04.001. eCollection 2016. — View Citation

* Note: There are 37 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose tolerability based on subject reporting	Dose tolerability is based on subject interviews and diary assessment evaluating the presence or absence of adverse events	6 months
Secondary	Efficacy based on ALS Functional Rating Scale - Revised (ALSFRS-R)	Change in ALSFRS-R questionnaire scale. The ALSFRS-R provides a physician-generated estimate of the patient's degree of functional impairment, which can be evaluated serially to objectively assess any response to treatment or progression of disease. The ALSFRS includes ten questions that ask the physician to rate his/her impression of the patients level of functional impairment in performing one of ten common tasks, e.g. climbing stairs. Each task is rated on a five-point scale from 0 = can't do, to 4 = normal ability. Individual item scores are summed to produce a reported score of between 0=worst and 40=best.	Baseline, 1 year
Secondary	Efficacy based on neurological exam	Change in neurological exams with testing of muscle flexion and extension (scale: 0 to 5 with 0 being the most impaired) reflexes (scale: absent to brisk with absent being the most impaired), and sensation (scale: normal to abnormal), cranial nerves (scale: normal to abnormal on ocular movement, yes to no on Ptosis, normal to atrophy on tongue, and normal to abnormal on tongue movement).	Baseline, 6 months
Secondary	Efficacy based on pulmonary forced vital capacity	Change in % predicted in forced vital capacity	Baseline, 6 months