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Parkinson DiseasePhase 1NCT04273932

Effects of Lithium Therapy on Blood-based Therapeutic Targets in Parkinson's Disease.

A Phase 1 study testing Lithium in people with Parkinson Disease, run by State University of New York at Buffalo at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This study aims to determine if one of three low doses of lithium therapy for 6 months can engage one or more blood-based therapeutic targets implicated in Parkinson's disease (PD) pathophysiology. Read more about this study

Who is it for?
Ages 45 to 80 years
Conditions the study is for
Parkinson Disease
What is being tested?
Lithium
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
19 participants
Where
1 siteUnited States
Study dates
17 Oct 2019to 12 Aug 2023
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 45 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult
  1. Diagnosed with PD according to the UK Brain Bank Criteria.
  2. 45-80yo.
  3. Clinical Dementia Rating Scale score of 0 or 0.5.
  4. Stable PD medications for previous 30 days and no current need for changes in the opinion of the PI.
  5. No formed visual hallucinations or delusions for previous year.
  6. Never taken prescription or over-the-counter lithium.
  7. Stable or no diuretics for past 4 weeks and no need for changes for at least 6 months, in the PI's opinion.
  8. Stable doses of antidepressants, antihypertensives and non-steroidal anti-inflammatory medications (NSAIDs) for previous 60 days and no current need to adjust such medications.
  9. No history of cardiac arrhythmias besides atrial fibrillation that is rate controlled.
  10. No unstable cardiac, medical or psychiatric condition in the opinion of the PI.
  11. No current use of illicit drugs or current alcohol abuse in the opinion of the PI.
  12. No history of hypothyroidism, not receiving thyroid replacement therapy and normal thyroid stimulating hormone (TSH) level at screening visit.
  13. Estimated renal glomerular filtration rate ≥50 at screening visit.
  14. No history of receiving or planning to receive nilotinib or a glucagon-like peptide-1 agonist medication such as exenatide.
  15. No use of tobacco products for the previous year.
  16. No deep brain stimulation (DBS) or possible need for DBS for at least 1-year in the opinion of the PI.
  17. Women with child bearing potential will need a negative pregnancy test and not be nursing an infant at screening. Women with child bearing potential will need to report using barrier method or hormonal contraception.
  18. Not enrolled in another clinical trial.
  19. Willing and able to sign informed consent and follow study procedures.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • University at Buffalo

    Williamsville, New York, 14221

Other trials in United States

About this study

This study aims to determine if one of three low doses of lithium therapy for 6 months can engage one or more blood-based therapeutic targets implicated in Parkinson's disease (PD) pathophysiology. Results of this study will help to determine if lithium therapy is worthwhile to further investigate as a potential disease-modifying therapy in PD, the optimal dose to study and the optimal PD subgroup most likely to benefit from lithium therapy.

Read the detailed description

Lithium belongs to a class of kinase-targeting therapies, including the diabetes medication exenatide and the cancer medication nilotinib, that have demonstrated promise as disease-modifying therapies for Parkinson's disease (PD). Exenatide was recently shown to engage protein kinase B (Akt) and provide significant symptomatic and possible disease-modifying benefit in PD in a phase 2 randomized controlled trial (RCT). Nilotinib engages c-Abelson kinase (c-Abl) and its disease-modifying effects are currently being investigated in two, phase 2 PD RCTs. Lithium targets Akt, glycogen synthase kinase-3 beta (GSK-3B, a downstream target of Akt) and cyclin-dependent kinase 5 (cdk5, a downstream target of c-Abl) in manners that recapitulate those of exenatide and nilotinib. Also, lithium inhibits inositol monophosphate leading to enhanced autophagy and reduced intracellular levels of alpha-synuclein (a-synuclein), which is believed to be a primary mediator of the progressive neurodegeneration in PD. In addition to a-synuclein, genome-wide association studies (GWAS) have implicated oligomeric tau in the pathogenesis of PD. Pathological mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of a late-onset parkinsonism that is clinically indistinguishable from sporadic PD and very similar pathologically. Pathological LRRK2 mutations affect the activities of Akt, GSK-3B and cdk5 to greatly increase the formation of phosphorylated tau (p-tau) - the precursor to tau oligomer formation - and decrease the activity of the transcriptional cofactor B-catenin - which mediates the transcription of neuronal survival genes implicated in PD such as nuclear receptor related 1 (Nurr1). Through its ability to inhibit GSK-3B, lithium can enhance B-catenin-mediated activity and Nurr1 expression. Lithium was also effective in several PD animal models. Finally, both clinical trial and epidemiologic data suggest that lithium exposures of even <1mg a day may provide significant disease-modifying effects in neurodegenerative diseases including PD.

The investigators propose to assess the effects of 3 lithium dosages for 6 months on the above targets measured in blood in a randomized, parallel design, proof of concept clinical trial among 18 PD patients. In addition, 2 PD patients will serve as controls and not receive lithium therapy.

Being tested
Lithium
Keywords
Lithium, Alpha-synuclein
Medical subject headings
Parkinson Disease, Parkinson Disease 4, Autosomal Dominant Lewy Body

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LithiumDrug

    Lithium aspartate of lithium carbonate will be administered by mouth.

Study groups in NCT04273932
Study groupRoleWhat they receive
Lithium aspartate 15mg a dayExperimental15mg of elemental lithium administered every morning by mouth.
Receives: Drug: Lithium
Lithium aspartate 45mg a dayExperimental20mg every morning and 25mg every evening of elemental lithium administered by mouth.
Receives: Drug: Lithium
Lithium carbonateExperimentalThe dose will be titrated based on weekly blood tests to achieve a target serum level of 0.40-0.50mmol/L, which represents an elemental lithium dose of about 85-170mg a day.
Receives: Drug: Lithium
No lithium treatmentNo interventionControl arm

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Plasma alpha-synuclein assessed by ultra-sensitive, immunomagnetic reduction assay (MagQu, LLC, Surprise, AZ).

    Measured: Change from baseline to 24 weeks

  2. Peripheral blood mononuclear cell (PBMC) Nurr1 mRNA levels by real-time polymerase chain reaction.

    Measured: Change from baseline to 24 weeks

  3. PBMC phosphorylated (p) and total (t) levels of pSerine9 and t-glycogen synthase kinase-3B

    Measured: Change from baseline to 24 weeks

  4. Plasma brain-derived neurotrophic factor (BDNF).

    Measured: Change from baseline to 24 weeks

  5. PBMC pThreonine308 and t-protein kinase B (Akt).

    Measured: Change from baseline to 24 weeks

Secondary outcomes (9)

  1. Trough, steady-state plasma lithium levels by ICP/MS

    Measured: Change from baseline to 24 weeks

  2. Patient tolerability

    Assessed by patient reported adverse events.

    Measured: Up to 24 weeks

  3. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part III (Motor Examination) and question 1.11 (Constipation Problems) in the "on" state

    Score range 0-132 with higher values indicating more severe symptoms.

    Measured: Change from baseline to weeks 12 and 24.

  4. Parkinson's Anxiety Scale

    Score range 0-48 with higher values indicating more severe symptoms.

    Measured: Change from baseline to weeks 12 and 24.

  5. Geriatric Depression Scale-15

    Score range 0-15 with higher values indicating more severe symptoms.

    Measured: Change from baseline to weeks 12 and 24.

  6. Fatigue Severity Scale

    Score range 9-56 with higher values indicating more severe symptoms.

    Measured: Change from baseline to weeks 12 and 24.

  7. Insomnia Severity Index

    Score range 0-28 with higher values indicating more severe symptoms.

    Measured: Change from baseline to weeks 12 and 24.

  8. Parkinson's Disease Questionnaire-8

    Score range 0-32 with higher values indicating more severe symptoms.

    Measured: Change from baseline to weeks 12 and 24.

  9. Montreal Cognitive Assessment (MoCA)

    Score range 0-30 with higher values indicating more severe symptoms.

    Measured: Change from screening to week 24

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Feb 2020
  2. Study start17 Oct 2019
  3. Primary completion15 Jun 2023
  4. Study completion12 Aug 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Randomized, parallel group, open-label trial
Masking
None (open label)
Enrolment
19 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04273932
Sponsor's protocol ID
STUDY00003688
Status last verified
Aug 2023
First submitted
31 Oct 2019
Last updated
15 Aug 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Guttuso T Jr, Shepherd R, Frick L, Feltri ML, Frerichs V, Ramanathan M, Zivadinov R, Bergsland N. Lithium's effects on therapeutic targets and MRI biomarkers in Parkinson's disease: A pilot clinical trial. IBRO Neurosci Rep. 2023 May 7;14:429-434. doi: 10.1016/j.ibneur.2023.05.001. eCollection 2023 Jun.

    PubMed 37215748

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Lithium in people with Parkinson Disease, run by State University of New York at Buffalo at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 15 Aug 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Plasma alpha-synuclein assessed by ultra-sensitive, immunomagnetic reduction assay (MagQu, LLC, Surprise, AZ). (time frame: Change from baseline to 24 weeks). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04273932, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Aug 2023.

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