Trial of Oxaloacetate in ALS

Brief Title

Trial of Oxaloacetate in ALS

Official Title

Trial of Oxaloacetate in ALS

Brief Summary

      The purpose of this study is to determine the safety and the maximal tolerated dose of
      Oxaloacetate (OAA) in patients with Amyotrophic Lateral Sclerosis (ALS).
    

Detailed Description

      Overview This is a safety and dose finding study looking at Oxaloacetate (OAA) in patients
      with Amyotrophic Lateral Sclerosis (ALS). This study will aim to determine the maximal dose
      that a person can tolerate. We will also learn how OAA affects mitochondria in subjects with
      ALS. This is a 28 day study in which we will attempt to enroll approximately 24 participants.
      Participants will know that they are on OAA.

      Specific Aims (Hypothesis and Objectives)

      The overall goal of this proposal is to determine if reducing mitochondrial stress is a
      viable treatment strategy for ALS. This study will determine the maximal tolerated dose of
      OAA and whether OAA improves biomarkers of mitochondrial stress. ALS is a progressive fatal
      neurodegenerative disorder caused by loss of motor neurons in the brain and spinal cord.
      Despite multiple clinical trials and advances in understanding of the pathogenesis of ALS,
      riluzole and edaravone, the only Food and Drug Administration (FDA) approved ALS drugs, the
      former only extends life by a few months, and the latter possibly slows down functional
      decline. Hence there is a clear need for new treatments for ALS.

      While the exact underlying cause of this motor neuron degeneration remains uncertain,
      candidate mechanisms include glutamate excitotoxicity, free radical-mediated oxidative
      cytotoxicity, neuroinflammation, mitochondrial dysfunction, autoimmune processes, protein
      aggregation, and cytoskeletal abnormalities. Mitochondrial dysfunction in particular may play
      a critical role in ALS neurodegeneration, an observation supported by both human and animal
      model studies. The characteristic pathological ALS finding of cytoplasmic inclusions (Bunina
      bodies) in motor neuron cell bodies may represent mitochondria-containing autophagic
      vacuoles. Functional studies of ALS mitochondria were also reported: calcium levels in motor
      neuron synaptic terminals of ALS subjects were found to be elevated despite increased numbers
      of local mitochondria, suggesting a defect of mitochondrial calcium sequestration; increased
      complex I activity was seen with familial ALS; and reduced cytochrome oxidase activity was
      shown in sporadic ALS patients. In mutant SOD mouse model, evidence of mitochondrial
      dysfunction appears before motor neuron degeneration. Similar observations have been noted in
      human sporadic ALS tissue. In humans with pathogenic mutations in TARDBP and C9ORF72,
      mitochondrial functionality is abnormal in peripheral fibroblasts. The dexpramipexole trial
      in ALS, while negative, is based on the mitochondrial ALS pathogenesis theory. We performed
      an open label study of rasagiline in ALS and demonstrated target engagement of several blood
      mitochondrial biomarkers. We completed an 80 patient randomized controlled trial of
      rasagiline in ALS and again we measured mitochondrial biomarkers.

      Rationale: Human and animal studies suggest targeting mitochondrial dysfunction may be an
      important approach to slow disease progression in ALS. Mitochondrial dysfunction can be seen
      in both in vitro and in vivo experimental ALS models, may explain the characteristic Bunina
      bodies, a key ALS pathological hallmark, and mitochondrial abnormalities are found in patient
      autopsies. In cell models of mitochondrial dysfunction, OAA has been shown to be
      cytoprotective. In addition, there is evidence that OAA, in preclinical studies in Alzheimer
      disease, reduces neuroinflammation, another possible ALS pathological pathway. A phase 2
      trial of OAA in in Alzheimer Disease is currently being conducted at KUMC but at a lower dose
      than is proposed in this ALS study. We are interested in OAA as a potential therapeutic agent
      in ALS as it crosses the blood brain barrier, accesses motor neurons, activates mitochondrial
      bioenergetics, increases respiratory capacity, and increases glycolysis capacity. Preliminary
      data of OAA in an ALS mouse model at KUMC increased muscle strength compared to untreated
      animals.

      Hypothesis: OAA will be neuroprotective in ALS by reducing mitochondrial stress. This trial
      will determine whether OAA is tolerable and whether it engages mitochondrial targets in ALS
      patients. The result of this trial will lead to a larger phase II trial to further assess
      safety and to begin to study efficacy in slowing the disease process. This short 28 day study
      is too brief to study efficacy.

      Specific Aim 1: To determine safety and the maximal tolerated dose of OAA in patients with
      ALS. To achieve this aim we will conduct a prospective 3 + 3 dose escalating clinical trial
      in up to 24 clinically definite, probable, or laboratory supported probable ALS patients.

      Sub-aim 1: We will determine the pharmacokinetic profile of OAA in ALS patients. We will
      evaluate OAA drug levels in a pre-dose sample, 1 hour and 4 hours after dosing.

      Specific Aim 2: To determine OAA target engagement. We will evaluate a panel of mitochondrial
      biomarkers, platelet TDP-43 levels and MR spectroscopy of brain glutathione, at baseline then
      at the end of treatment and compare biomarker levels to dose, to evaluate possible
      dose-response relationship in our biomarkers.

      Future Aim: Our goal is to use the results from this study to conduct a larger prospective
      placebo controlled trial to determine if OAA is well tolerated and slows disease progression
      in ALS using the maximal tolerated dose that will be determined during this current study

      .
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Dose limiting toxicities (DLT)

Secondary Outcome

 Pharmacokinetic testing

Condition

ALS

Intervention

Oxaloacetic Acid

Study Arms / Comparison Groups

 Oxaloacetate
Description:  3+3 dose escalating trial starting with 500mg twice daily orally and ending with 2500mg twice daily.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

24

Start Date

January 2020

Completion Date

February 2021

Primary Completion Date

January 2021

Eligibility Criteria

        Inclusion Criteria:

          -  A clinical diagnosis by a study investigator of laboratory-supported probable,
             probable, or definite ALS, according to the modified El Escorial criteria[1]

          -  Vital capacity (VC) greater or equal to 50% of predicted

          -  Diagnosis with ALS within 3 years prior to enrollment

          -  If patients are taking riluzole for ALS, they must be on a stable dose for at least
             thirty days prior to the baseline visit

          -  Women of childbearing age must use protection against pregnancy.

        Exclusion Criteria:

          -  Requirement for tracheotomy ventilation or non-invasive ventilation for > 23 hours per
             day

          -  Diagnosis of other neurodegenerative diseases (e.g., Parkinson disease, Alzheimer
             disease)

          -  Clinically significant history of unstable medical illness (e.g., unstable angina,
             advanced cancer) over the last 30 days

          -  Current pregnancy or lactation

          -  Limited mental capacity such that the patient cannot provide written informed consent
             or comply with evaluation procedures

          -  Receipt of any investigational drug within the past 30 days from enrollment
      

Gender

All

Ages

21 Years - 80 Years

Accepts Healthy Volunteers

No

Contacts

Omar Jawdat, MD, 913-588-5095, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04204889

Organization ID

TOALS

Secondary IDs

8009

Responsible Party

Sponsor-Investigator

Study Sponsor

Omar Jawdat

Collaborators

 Clinical Research in ALS and Related Disorders for Therapeutic Development

Study Sponsor

Omar Jawdat, MD, Principal Investigator, University of Kansas Medical Center


Verification Date

December 2019