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To Assess the Efficacy and Safety of Ceftriaxone in Patients With Mild to Moderate Parkinson's Disease Dementia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03413384
Recruitment Status : Recruiting
First Posted : January 29, 2018
Last Update Posted : February 19, 2019
Sponsor:
Information provided by (Responsible Party):
BrainX Corporation

Brief Summary:
This is a randomized, double blinded, placebo-controlled Phase II study to investigate the efficacy and safety of ceftriaxone in patients with mild to moderate Parkinson's disease dementia (PDD).This study will enroll approximately 106 patients to have up to 84 evaluable subjects, and conduct in Chung Shan Medical University Hospital, National Taiwan University Hospital,Taichung Veterans General Hospital, Kaohsiung Medical University Hospital and Tungs' Taichung MetroHarbor Hospital.

Condition or disease Intervention/treatment Phase
Parkinson's Disease Dementia Drug: Ceftriaxone Other: Placebo Phase 2

Detailed Description:

Parkinson's disease (PD) is a common neurodegenerative disorder that can cause significant disability and decrease quality of life. It is a chronic and progressive disease which means the symptoms become worse over time.

Parkinson's disease dementia (PDD) is a decline in thinking and reasoning that develops in many people living with PD at least a year after diagnosis. An estimated 50 to 80 percent of patients with PD eventually experience dementia as the disease progresses. Key risk factors or correlation consistently associated with PDD are older age, more severe parkinsonism (particularly rigidity, postural instability and gait disturbance), male gender, certain psychiatric symptoms (depression, psychosis) and mild cognitive impairment. PDD has a unique clinical profile and neuropathology, commonly reported symptoms include changes in memory, concentration and judgment; trouble interpreting visual information; muffled speech; visual hallucinations; delusions, especially paranoid ideas; depression, irritability and anxiety; and sleep disturbances, including excessive daytime drowsiness and rapid eye movement sleep disorder.

The investigational product (IP) is 1 g of ceftriaxone powder manufactured by Sandoz Company reconstituted with 1% lidocaine as diluent before use. Ceftriaxone is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intramuscular or intravenous administration. Ceftriaxone is the drug substance of Rocephin first approved by FDA in 1984 as a cephalosporin antibiotic, and is clinically widely used and currently off patent.

The current main treatment goal of PDD focuses on the improvement of disease symptoms. However, the irreversible deterioration of cognitive and motor functions is the most challenge issue for therapeutic agent development. Ceftriaxone was found to have functions in reducing glutamatergic hyperactivity and excitotoxicity and may exhibit neuro-protective functions as the mechanism in PDD treatment. The therapeutic effects of ceftriaxone on the animal model of PDD showed ceftriaxone works on 1) preventing cognitive and motor deficits, 2) inhibiting dopaminergic degeneration and restoring neuronal density and activity in the striatum and SNc, 3) inhibiting cell loss and restoring neuronal density and activity in the hippocampus , 4) increasing neurogenesis in the substantia nigra and hippocampus dentate gyrus, 5) increasing glutamate transporter expression in the striatum and hippocampus , and 6) decreasing neuronal hyperactivity in the subthalamic nucleus (STN). The effects observed in the animal model of PDD have suggested ceftriaxone as a potential promising medical treatment for PDD patients to improve the cognitive and motor function defects. For such reasons, the investigators plan to conduct this phase II trial of ceftriaxone to determine the potential efficacy and obtain safety profiles in PDD patients.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 106 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double Blinded, Placebo-controlled Phase II Study to Assess the Efficacy and Safety of Ceftriaxone in Patients With Mild to Moderate Parkinson's Disease Dementia
Actual Study Start Date : February 15, 2019
Estimated Primary Completion Date : July 31, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Ceftriaxone
  1. Name: Ceftriaxone
  2. Dosage form: crystalline powder for intramuscular injection
  3. Dose(s): 1 g
  4. Dosing schedule: 1 g ceftriaxone with around 2.0 ml of lidocaine solvent per day for Day 1, 3, and 5 per cycle on a 2 weekly cycle
Drug: Ceftriaxone
1 g ceftriaxone per day for Day 1, 3, and 5 per cycle on a 2 weekly cycle
Other Name: Ceftriaxone Sandoz powder for IV Injection

Placebo Comparator: Placebo
same amount volume of placebo will be given on Day 1, Day 3, and Day 5 per cycle on a 2 weekly cycle
Other: Placebo
Placebo per day for Day 1, 3, and 5 per cycle on a 2 weekly cycle




Primary Outcome Measures :
  1. Compare the treatment difference in mean net change in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) score with time course [ Time Frame: from baseline to week 17 and 33 visits ]
    ADAS-Cog is a validated instrument to assess dementia covering memory, orientation, language, praxis and consisting of 11 items. The total possible scores range from 70 (severe impairment) to 0 (no impairment).


Secondary Outcome Measures :
  1. Changes in Unified Parkinson's Disease Rating Scale (UPDRS) score [ Time Frame: from baseline to week 17 and 33 visits ]
    The UPDRS system is a composite scale intended for rating patients with PD. Scores are rated as 0-4 (0-1 for some Part IV), representing 0=normal and 1 or 4=maximal deficit, symptoms, or impairment.

  2. Changes in Judgment of Line Orientation score [ Time Frame: from baseline to week 17 and 33 visits ]
    The Judgment of Line Orientation (JLO) test is a widely used measure of visuospatial judgment. A score of 17 or less is considered a sign of severe deficit.

  3. Changes in Mini-Mental State Examination (MMSE) score [ Time Frame: from baseline at week 17 and 33 visits ]
    The MMSE is a brief, quantitative measure of cognitive status in adults. The instrument examines orientation, registration, attention, calculation, recall, visuo-spatial abilities and language. The maximum score is 30, with higher scores indicating better cognitive function.

  4. Changes in Clinical Dementia Rating (CDR) Scale score [ Time Frame: from baseline to week 17 and 33 visits ]
    The CDR Scale is a 5-point scale used to characterize 6 domains of cognitive and functional performance applicable to related dementias: memory, orientation, judgment & problem solving, community affairs, home & hobbies, and personal care. This score is useful for characterizing and tracking a patient's level of impairment/dementia with 0=normal, 0.5 =very mild dementia, 1=mild dementia, 2=moderate dementia, 3=severe dementia.

  5. Changes in Color Trail Test score [ Time Frame: from baseline to week 17 and 33 visits ]
    Color Trail Test provides quantitative and qualitative information by two trials. The length of time to complete each trial is recorded, along with qualitative features of performance indicative of brain dysfunction, such as near-misses, prompts, number sequence errors, and color sequence errors.

  6. Changes in MRI image for atrophy rate of brain [ Time Frame: from baseline to week 17 and 33 visits ]
    Multimodal MRI examinations will be performed on a 3T MRI scanner with a standard 8-channel head coil. Region of interest in the brain will be evaluated for functional changes including atrophy rate from baseline data.

  7. Changes in MRI image for dopaminergic projection from substantia nigra to striatum [ Time Frame: from baseline to week 17 and 33 visits ]
    Multimodal MRI examinations will be performed on a 3T MRI scanner with a standard 8-channel head coil. Region of interest in the brain will be evaluated for functional changes including dopaminergic projection from baseline data.

  8. Changes in Tc-99m TRODAT SPECT image [ Time Frame: from baseline to week 17 and 33 visits ]
    SPECT assessment will use Tc-99m, a radio tracer with high selectivity and specificity for the striatum dopamine transporter (DAT) density evaluation. DAT density change from baseline will be calculated from region of interest drawn in the striatum by independent readers.


Other Outcome Measures:
  1. Net change of biomarker α-synuclein data [ Time Frame: from baseline to week 17 and 33 visits ]
    Patients' plasma samples will be collected to analyze α-synuclen by immunomagnetic reduction (IMR) assay kit developed by Magqu Company.

  2. Net change of biomarker Aβ42 data [ Time Frame: from baseline to week 17 and 33 visits ]
    Patients' plasma samples will be collected to analyze α-synuclen by immunomagnetic reduction (IMR) assay kit developed by Magqu Company.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   50 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients are male or female, age 50-80 years, inclusive.
  2. Diagnosis of idiopathic Parkinson's disease (PD) within less than 10 years duration based on the UK Parkinson's Disease Society Brain Bank Criteria and with a modified Hoehn and Yahr Stage of I to III.
  3. Patients have been receiving stable dose of medications equivalent up to 800 mg/day of levodopa for Parkinson's disease at least 2 weeks prior to screening and patients are considered as being optimally treated at screening and no known further adjustments of current medication needed to improve the subject's status of PD during the study period by the judgment of the Investigator based on the subject's history, previous treatments, and the clinical presentation.
  4. Diagnosis of PDD based on Movement Disorder Society (MDS) Task Force criteria as the following items:

    1. A diagnosis of PD based on UK Parkinson's Disease Society Brain Bank Criteria
    2. PD development prior to the onset of dementia based on patient/caregiver history or records
    3. Cognitive deficiency severe enough to impair daily life based on patient/caregiver interview or pill questionnaire
    4. Impairment of at least 2 of the following domains: attention, executive function, visuo-constructive ability, memory Besides, patients' Mini-Mental State Examination (MMSE) should be in the range of 18-25 (inclusive) or CDR scale in the range of 0.5-2 and are currently not taking any treatment for dementia.
  5. Patients who are eligible and able to participate in the study must be judged by the investigator to evaluate the competency of providing informed consent for this dementia related study (the decision making is based on MacArthur Competence Assessment concept) and should be able to understand the language in which the tests require so and must be able to perform all the assessments.
  6. All male and female patients with child-bearing potential (between puberty and 2 years after menopause) should use at least any one of the appropriate contraception methods shown below, for during and at least 4 weeks after ceftriaxone treatment.

    1. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception).
    2. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
    3. Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject
    4. Combination of any two of the following listed methods: (d.1+d.2 or d.1+d.3, or d.2+d.3):

    d.1 Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.

    d.2 Placement of an intrauterine device (IUD) or intrauterine system (IUS). d.3 Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

Exclusion Criteria:

  1. Any indication of forms of Parkinsonism other than idiopathic PD.
  2. Diagnosis of possible PDD.
  3. Diagnosis of dementia with Lewy Bodies.
  4. Mental/physical/social condition which could preclude performing efficacy or safety assessments.
  5. Medical history of brain or other clinically significant neurological/psychiatric disorders or injuries other than PD or PDD.
  6. The patients have received neurosurgical intervention related to PD (e.g. deep brain stimulation (DBS), thalamotomy etc.) or are scheduled to do so during the trial period.
  7. The patients have history of allergic response to levodopa, ceftriaxone, cephalosporin class of drugs or ursodiol or lidocaine.
  8. Malignant neoplastic disease, either currently active or in remission for less than 1 year.
  9. Clinically significant and unstable gastrointestinal, renal, endocrine, pulmonary, or cardiovascular disease, including not well controlled hypertension, asthma, chronic obstructive pulmonary disease, and diabetes, hyperbilirubinemia, impaired vitamin K synthesis or low vitamin K stores that would hinder or interfere participation to the study in the opinion of the Investigator.
  10. Patients with a history of hepatobiliary and /or pancreatic disease or abdominal ultrasound examination imaging shows biliary system disease during screening.
  11. The patients are currently experiencing unpredictable or intractable or troublesome dyskinesia or fluctuations in their symptoms.
  12. Patients with the following medications that could put patients at risk, interfere with study evaluations, or prevent meeting the requirements of the study should be excluded :

    1. Anticholinergic medication or amantadine currently or within 4 weeks prior to the screening visit.
    2. Cocaine, opioids, ethanol (binge drinking or heavy alcohol defined by SAMHSA and NIAAA) currently or within 4 weeks prior to the screening visit; nicotine dependence, amphetamines, cannabinoids abuse history or taking currently or within 3 months prior to the screening visit.
    3. Acetylcholinesterase inhibitors or memantine currently or within 4 weeks prior to the screening visit.
    4. Ceftriaxone or cephalosporin or penicillin or β-lactam currently or within 4 weeks prior to the screening visit.
    5. Neuroleptic for treatment of psychotic symptoms (e.g., hallucinations) related to their anti-Parkinson medication within 4 weeks prior to the screening visit.
    6. Antipsychotics currently or within 4 weeks prior to the screening visit.
    7. A drug that has severe hepatotoxic or renal toxic within 4 weeks prior to the screening visit.
    8. Warfarin, cyclosporin, vancomycin, amsacrine, aminoglycosides, fluconazole, chloramphenicol currently or within 4 weeks prior to the screening visit.
  13. Currently participating in another clinical trial or who participated in a previous clinical trial and received any investigational product treatment within 4 weeks prior to the screening visit.
  14. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer from such.
  15. Patients who are not able to take MRI and TRODAT SPECT examination.
  16. Patients who are pregnant or breast feeding.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03413384


Contacts
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Contact: Director +886-7-322-0521 hcw@100cc.cc
Contact: Jui-Chi Hsu +886-7-322-0521 xrq@100cc.cc

Locations
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Taiwan
Kaohsiung Medical University Hospital Recruiting
Kaohsiung, Taiwan, 807
Contact: Ching-Kua Liu, M.D.    +886-7-3121101 ext 6761    ckliu@kmu.edu.tw   
Principal Investigator: Ching-Kua Liu, M.D.         
Chung Shan Medical University Hospital Recruiting
Taichung, Taiwan, 402
Contact: An-Chih Chen, M.D.    +886-4-24739595 ext 34834    cshy1135@csh.org.tw   
Principal Investigator: An-Chih Chen, M.D.         
Taichung Veterans General Hospital Not yet recruiting
Taichung, Taiwan, 407
Contact: Ming-Hong Chang, M.D.    +886-4-23741302    cmh50@ms10.hinet.net   
Principal Investigator: Ming-Hong Chang, M.D.         
Tungs' Taichung MetroHarbor Hospital Recruiting
Taichung, Taiwan, 435
Contact: Hung-Yi Hsu, M.D.    +886-4-26581919 ext 4517    hungyihsu@gmail.com   
Principal Investigator: Hung-Yi Hsu, M.D.         
National Taiwan University Hospital Recruiting
Taipei, Taiwan, 100
Contact: Chun-Hwei Tai, M.D.    +886-2-23123456 ext 65343    chtai1502@ntu.edu.tw   
Principal Investigator: Chun-Hwei Tai, M.D.         
Sponsors and Collaborators
BrainX Corporation

Publications:
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Responsible Party: BrainX Corporation
ClinicalTrials.gov Identifier: NCT03413384    
Other Study ID Numbers: BRICEFA20170414
First Posted: January 29, 2018    Key Record Dates
Last Update Posted: February 19, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by BrainX Corporation:
Parkinson's Disease
Parkinson's Disease Dementia
Additional relevant MeSH terms:
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Parkinson Disease
Dementia
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Ceftriaxone
Anti-Bacterial Agents
Anti-Infective Agents