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Parkinson DiseasePhase 4NCT05855577

Motor Function Efficacy of Pharmacological Treatments Targeting Energy Metabolism, in Parkinson's Patients

A Phase 4 study testing Terazosin in people with Parkinson Disease and Gait Analysis, run by I.R.C.C.S. Fondazione Santa Lucia.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

Consistent evidence suggests that mitochondrial dysfunction plays a crucial role in Parkinson¿s disease pathogenesis. Inhibition of complex I of the mitochondrial electron transport chain is sufficient to reproduce biochemical and pathological features of Parkinson¿s Disease in animal models (PD). Read more about this study

Who is it for?
Ages 40 years and older
What is being tested?
Terazosin
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
50 participants
Where
No sites listed yet
Study dates
Dec 2023to May 2026
Phase
Phase 4
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 40 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patient with rigid-acinetic bilateral PD form
  • At least 5 years of disease history
  • H\&Y between 2-3.5
  • Stable drug therapy response without any change performed in the 3 months before the study.
  • MMSE>24/30 (Mini-Mental State Examination)
  • No severe gastrointestinal pathologies.

Who cannot join

  • Systemic illness
  • Presence of cardiac pacemaker
  • Presence of deep brain stimulation
  • Presence of severe dysautonomia with marked hypotension
  • Obsessive-Compulsive Disorder (OCD)
  • Major depression
Show all 13Show fewer
  • Dementia
  • History or active neoplasia
  • Pregnancy
  • Lack of autonomy in walking;
  • Malabsorption and gastrointestinal disorders;
  • Gluten intolerance
  • Ipotiroidism

Trial locations and contacts

No sites are listed yet.

Antonella Peppe, MD contact

+39 3493746450 ext. 0651501764

a.peppe@hsantalucia.it

Giusy Martella, DR contact

+39 3293112506

martellag@gmail.com

About this study

Official title: -Clinical Efficacy of Pharmacological Treatments Targeting Energy Metabolism, Evaluated by Gait Analysis, on Motor Function in Parkinson's Disease Patients

Consistent evidence suggests that mitochondrial dysfunction plays a crucial role in Parkinson¿s disease pathogenesis.

Inhibition of complex I of the mitochondrial electron transport chain is sufficient to reproduce biochemical and pathological features of Parkinson¿s Disease in animal models (PD). Alterations of mitochondrial energy metabolism may intervene in PD pathogenesis by inducing inflammation, generation of reactive oxygen species (ROS), and neurodegeneration. The Nuclear factor erythroid 2-related factor 2 (Nrf2) is a regulator both of mitochondrial function and biogenesis, and of cellular resistance to oxidative stress, and may represent a novel target of PD disease-modifying therapies.

The aims of the present study are to validate indicators of energy metabolism as biomarkers in PD patients and to evaluate the efficacy of drugs and natural food supplements acting on the Nrf2 pathway in improving motor impairment and Gait in PD patients.

Read the detailed description

Bradykinesia, causing impairment of gait and an associated significant risk of falls, is among the most debilitating core features of Parkinson¿s disease (PD), a movement disorder characterized by the degeneration of Substantia nigra dopaminergic neurons. The pacemaking action potential firing activity of nigral neurons requires high energy consumption and is coupled to large cytosolic calcium oscillations, which influence mitochondrial respiration, energy metabolism, and reactive oxygen species (ROS) production. Mitochondrial dysfunction, on the other hand, can drive dysregulation of calcium homeostasis, especially in dopaminergic neurons, and is recognized as a key component in PD progression. Notably, both calcium-binding and increased ROS production, resulting from inefficiencies in the mitochondrial electron transport chain, can trigger alpha-synuclein aggregation, thus contributing to neuronal loss and disease progression in PD. The Nuclear factor erythroid 2- related factor 2 (Nrf2) is a regulator of mitochondrial function and biogenesis, and cellular resistance to oxidative stress. Bioactive compounds activating the Nrf2 signaling pathway ameliorate Parkinsonian phenotypes in experimental models, suggesting the Nrf2 pathway potential novel therapeutic target in PD.

Bradykinesia, causing impairment of gait and an associated significant risk of falls, is among the most debilitating core features of PD. PD gait is characterized by shuffling steps accompanied by a stooped posture. In advanced PD, other complications may arise such as disturbances in speech, gait, posture, and balance, as well as hypomimia, impaired decision-making, alertness, and regulation of emotions.

The increased energy demand associated with bradykinesia is coupled with the impairment of energy metabolism in Parkinsonians, negatively affecting walking, gait, and postural stability, suggesting that the modulation of mitochondrial energy metabolism may ameliorate gait and postural stability in Parkinsonians. Cardinal symptoms of PD: Tremors, Rigidity, Bradykinesia, and postural instability, all elements that lead in almost all patients to a walking disorder. In fact, walking in Parkinson's disease is present since in the early stages of the disease, the step is reduced in length and speed, the swinging phase of the step (swing) is reduced, while the support (Stance) single and double is increased in duration. Progression as well as the severity of disease over time, leads to a significant increase in the risk of falls, inducing a reduction in autonomy in daily living activity. As mentioned Gait is influenced in a principal way. Bipedal walking, in humans, is well orchestrated, consistent with the intrinsic "kinetic melody". This "melody" in subjects with PD is altered appears clear that the analysis of the gait represents a key element for establishing functional recovery therapies aimed at restoring motor skills. Therefore, it seems sensible to hypothesize that energy metabolism parameters may represent reliable biomarkers in PD and that the Nrf2 pathway may be a new therapeutic target for the recovery of motor function in PD patients. Not only that, but the identification of reliable biomarkers that are easy to measure over time can aid in the diagnosis, and possible prognosis, and improve management.

In support of this view, PD pathogenesis is known to involve the loss of the homeostatic functions controlling mitochondrial energy metabolism. The transcription factor Nrf2 is a master controller of these functions. Notably, Nrf2 activity is compromised during aging and in neurodegenerative diseases.

The investigators hypothesize that energy metabolism parameters may represent reliable biomarkers in PD and that the Nrf2 pathway may be a novel therapeutic target for the rescue of motor function in Parkinsonians.

The identification of reliable biomarkers, easy to measure over time, is fundamental to facilitating diagnosis, prognosis, and better management of PD patients. The proposed study on PD patients will provide information immediately transferable to the clinical practice. Additionally, the clinical trial planned in the present project will provide substantial information regarding the effectiveness of different pharmacological approaches targeting the Nrf2 pathway in ameliorating gait and balance in Parkinsonians, thus reducing the substantial social and economic burden of PD to society, patients, and caregivers. Many drugs and natural food supplements acting on the Nrf2 pathway are available; therefore, the transfer to the clinical practice of the results of the present project is expected to be rapid.

Being tested
Terazosin
Keywords
parkinson's disease, gait Analysis, mitocondrial, therapy
Medical subject headings
Parkinson Disease, Directly Observed Therapy, Metabolic Diseases

What participants receive

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

  • TerazosinDrug

    Also called Lisosan-g

    Treatment of Terazosine vs placebo and Lisosan-G vs placebo in cross-over double-blind, double-dummy

Study groups in NCT05855577
Study groupRoleWhat they receive
TerazosineExperimentalPharmacological Treatment of Pakinson's disease patients using Terazosin 2 mg
Receives: Drug: Terazosin
placebo TPlacebo comparatorPharmacological Treatment of Parkinson's disease patients using Placebo
Receives: Drug: Terazosin
Lisosan-G (Nutritional Supplement)ExperimentalTreatment of Parkinson's disease patients using Lisosan-G
Receives: Drug: Terazosin
Lisosan_G PlaceboPlacebo comparatorTreatment of Parkinson's disease patients using Lisosan-G
Receives: Drug: Terazosin

What is being measured

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

  1. Clinical evaluation, Gait Analysis and Metabolic variables efficacy of therapy

    MD UPDRs : Four Parts: II questionary by Parkinsonian or care-given, III-IV: Motor Part and Complication by neurologist , Each item rate from 0: no sign to 4: max sign PDQ39 questionary performed by Parkinsonian each item rate from 0: never, to 5:always. Gait Analysis following spatio-temporal parameters will be taken in to account: Right and Left Step Length, Stride time% Stance Swing , Double support t, Mean Velocity, Cadence, Stepwidth, and t for turning task:• Number of steps to complete the lap,• Lap time, Metabolomic Variables: Steady State oxygen uptake (VO2, mlkg-1min-1) and carbon dioxide production (VCO2), heart rate (HR), Walking energy cost per unit of time-WECt8Jkg-1min-1),Metabolic human blood variabes : G6PD mU/109 erytrocytes, CAT, GPx, NQO1,HO-1,SOD: U/mg protein, GSH mmol GSH/l, MDA mmol/MDA/l,NrF2 gene expression

    Measured: 2year

Secondary outcomes (1)

  1. The efficacy and molecular mechanisms of Nrf2 pathway modulation in PD rodent models

    Animal models allow an in-depth analysis, in strictly controlled experimental conditions, of several biological parameters, both at the peripheral level and in the brain, in relation to the expression of a motor phenotype. First, protein levels and mRNA expression of markers of energy metabolism will be measured both in the blood and in relevant brain areas of a group of PD and control rodents..

    Electrophysiological recordings and intracellular calcium measurements from striatum and substantia nigra neurons in acute slices of PD and control rodents will allow an analysis of the correlation between the biomarker profile, the neuronal function, and the parkinsonian motor behavior. In a second phase, we will test the efficacy of in vivo treatments with different modulators of the Nrf2 pathway in rescuing the PD model¿s motor behavior, energy metabolism biomarkers, and both striatal and substantia nigra neuron physiology.

    See metabolic human blood variables

    Measured: 2 years

Timeline

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

  1. First posted11 May 2023
  2. Study startDec 2023 (estimated)
  3. Primary completionMay 2026 (estimated)
  4. Study completionMay 2026 (estimated)

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 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Model description
25 M-PD (H\&Y\< 2.5) and 25 S-PD (H\&Y \> 2.5) patients with idiopathic PD will be enrolled sequentially in the randomized double-blind, double-dummy study.
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
50 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05855577
Sponsor's protocol ID
RF-2021-12374979
Status last verified
May 2023
First submitted
28 Feb 2023
Last updated
22 Sep 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Amato R, Rossino MG, Cammalleri M, Timperio AM, Fanelli G, Dal Monte M, Pucci L, Casini G. The Potential of Lisosan G as a Possible Treatment for Glaucoma. Front Pharmacol. 2021 Jul 28;12:719951. doi: 10.3389/fphar.2021.719951. eCollection 2021.

    PubMed 34393798

  • Barichella M, Cereda E, Pinelli G, Iorio L, Caroli D, Masiero I, Ferri V, Cassani E, Bolliri C, Caronni S, Maggio M, Ortelli P, Ferrazzoli D, Maras A, Riboldazzi G, Frazzitta G, Pezzoli G. Muscle-targeted nutritional support for rehabilitation in patients with parkinsonian syndrome. Neurology. 2019 Jul 30;93(5):e485-e496. doi: 10.1212/WNL.0000000000007858. Epub 2019 Jul 5.

    PubMed 31278117

  • Belluscio V, Iosa M, Vannozzi G, Paravati S, Peppe A. Auditory Cue Based on the Golden Ratio Can Improve Gait Patterns in People with Parkinson's Disease. Sensors (Basel). 2021 Jan 29;21(3):911. doi: 10.3390/s21030911.

    PubMed 33573043

  • Bonsi P, Ponterio G, Vanni V, Tassone A, Sciamanna G, Migliarini S, Martella G, Meringolo M, Dehay B, Doudnikoff E, Zachariou V, Goodchild RE, Mercuri NB, D'Amelio M, Pasqualetti M, Bezard E, Pisani A. RGS9-2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models. EMBO Mol Med. 2019 Jan;11(1):e9283. doi: 10.15252/emmm.201809283.

    PubMed 30552094

  • Christiansen CL, Schenkman ML, McFann K, Wolfe P, Kohrt WM. Walking economy in people with Parkinson's disease. Mov Disord. 2009 Jul 30;24(10):1481-7. doi: 10.1002/mds.22621.

    PubMed 19441128

  • Cuadrado A. Brain-Protective Mechanisms of Transcription Factor NRF2: Toward a Common Strategy for Neurodegenerative Diseases. Annu Rev Pharmacol Toxicol. 2022 Jan 6;62:255-277. doi: 10.1146/annurev-pharmtox-052220-103416. Epub 2021 Oct 12.

    PubMed 34637322

  • Giordano N, Iemolo A, Mancini M, Cacace F, De Risi M, Latagliata EC, Ghiglieri V, Bellenchi GC, Puglisi-Allegra S, Calabresi P, Picconi B, De Leonibus E. Motor learning and metaplasticity in striatal neurons: relevance for Parkinson's disease. Brain. 2018 Feb 1;141(2):505-520. doi: 10.1093/brain/awx351.

    PubMed 29281030

  • Gruetter R, Tkac I. Field mapping without reference scan using asymmetric echo-planar techniques. Magn Reson Med. 2000 Feb;43(2):319-23. doi: 10.1002/(sici)1522-2594(200002)43:23.0.co;2-1.

    PubMed 10680699

  • Guatteo E, Yee A, McKearney J, Cucchiaroni ML, Armogida M, Berretta N, Mercuri NB, Lipski J. Dual effects of L-DOPA on nigral dopaminergic neurons. Exp Neurol. 2013 Sep;247:582-94. doi: 10.1016/j.expneurol.2013.02.009. Epub 2013 Feb 26.

    PubMed 23481547

  • Guatteo E, Rizzo FR, Federici M, Cordella A, Ledonne A, Latini L, Nobili A, Viscomi MT, Biamonte F, Landrock KK, Martini A, Aversa D, Schepisi C, D'Amelio M, Berretta N, Mercuri NB. Functional alterations of the dopaminergic and glutamatergic systems in spontaneous alpha-synuclein overexpressing rats. Exp Neurol. 2017 Jan;287(Pt 1):21-33. doi: 10.1016/j.expneurol.2016.10.009. Epub 2016 Oct 20.

    PubMed 27771352

  • Heger LM, Wise RM, Hees JT, Harbauer AB, Burbulla LF. Mitochondrial Phenotypes in Parkinson's Diseases-A Focus on Human iPSC-Derived Dopaminergic Neurons. Cells. 2021 Dec 7;10(12):3436. doi: 10.3390/cells10123436.

    PubMed 34943944

  • Imbriani P, Tassone A, Meringolo M, Ponterio G, Madeo G, Pisani A, Bonsi P, Martella G. Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson's Disease. Int J Mol Sci. 2019 Jul 11;20(14):3407. doi: 10.3390/ijms20143407.

    PubMed 31336695

  • Imbriani P, D'Angelo V, Platania P, Di Lazzaro G, Scalise S, Salimei C, El Atiallah I, Colona VL, Mercuri NB, Bonsi P, Pisani A, Schirinzi T, Martella G. Ischemic injury precipitates neuronal vulnerability in Parkinson's disease: Insights from PINK1 mouse model study and clinical retrospective data. Parkinsonism Relat Disord. 2020 May;74:57-63. doi: 10.1016/j.parkreldis.2020.04.004. Epub 2020 Apr 20.

    PubMed 32335490

  • Iosa M, Morone G, Fusco A, Marchetti F, Caltagirone C, Paolucci S, Peppe A. Loss of fractal gait harmony in Parkinson's Disease. Clin Neurophysiol. 2016 Feb;127(2):1540-1546. doi: 10.1016/j.clinph.2015.11.016. Epub 2015 Dec 2.

    PubMed 26679417

  • Jeng B, Cederberg KLJ, Lai B, Sasaki JE, Bamman MM, Motl RW. Oxygen cost of over-ground walking in persons with mild-to-moderate Parkinson's disease. Gait Posture. 2020 Oct;82:1-5. doi: 10.1016/j.gaitpost.2020.08.108. Epub 2020 Aug 11.

    PubMed 32836026

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Terazosin in people with Parkinson Disease and Gait Analysis, run by I.R.C.C.S. Fondazione Santa Lucia.

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

Who may be eligible to take part?

The sponsor lists 6 inclusion and 13 exclusion criteria. 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: status not confirmed, as of the sponsor's last update on 22 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

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

Are results available for this study?

Results are not available in the source record.

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

Contact Antonella Peppe, MD (+39 3493746450 ext. 0651501764, a.peppe@hsantalucia.it), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Clinical evaluation, Gait Analysis and Metabolic variables efficacy of therapy (time frame: 2year). 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 NCT05855577, which also lists 36 linked publications.

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 22 Sep 2023.

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