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Efficacy and Safety of Tocotrienols in CADASIL

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04658823
Recruitment Status : Active, not recruiting
First Posted : December 9, 2020
Last Update Posted : March 24, 2022
Sponsor:
Information provided by (Responsible Party):
Hovid Berhad

Brief Summary:
CADASIL is a paradigmatic cerebral small vessel disease responsible for white-matter lesions, accumulation of lacunes, microbleeds and cerebral atrophy. The disease is responsible for stroke and cognitive decline associated with motor disability. The number of incident lacunes, and amount of cerebral atrophy were recently found to have a strong relationship to cognitive decline and disability progression over 3 years in a large sample of patients. Palm tocotrienols has previously shown evidence of therapeutic effect in attenuating the progression of WMH related to sporadic cerebral small vessel disease in a randomized controlled clinical trial. We hypothesize that palm tocotrienols complex (HOV-12020) can reduce the clinical progression in CADASIL.

Condition or disease Intervention/treatment Phase
Cadasil Drug: HOV-12020 (Palm tocotrienols complex) Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double blinded
Primary Purpose: Treatment
Official Title: A Randomized Placebo-controlled Double-blind Pilot / Phase II Study to Assess the Efficacy and Safety of HOV-12020 in Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)
Actual Study Start Date : December 21, 2020
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2023


Arm Intervention/treatment
Experimental: HOV-12020
Palm tocotrienols complex Oral softgel capsule (containing 285mg mixed tocotrienols and tocopherol)
Drug: HOV-12020 (Palm tocotrienols complex)
Oral Softgel capsule containing mixed tocotrienols and tocopherol with enhanced absorption delivery system; 1 capsule twice daily
Other Names:
  • HOV-12020
  • Palm Vitamin E
  • Tocotrienols
  • Tocovid Suprabio

Placebo Comparator: PLACEBO
Placebo Oral Softgel capsule (each capsule containing vitamin E stripped soybean oil)
Drug: Placebo
Oral Softgel capsule containing soybean oil; 1 capsule twice daily




Primary Outcome Measures :
  1. Incidence of manifestations related to clinical worsening [ Time Frame: 24 months ]

    Occurrence one failure event within 24 months after Baseline. A failure event is considered when at least one of the following manifestations is detected during the study period:

    • incident stroke
    • increase of disability corresponding to an increase in the mRS score of at least 1 point to result in a score of 2 or greater
    • cognitive decline corresponding to a reduction of at least 4 points of the VADAS-Cog score


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: 24 months ]
    Number of serious AEs, type of severe AEs, Total number of AEs


Other Outcome Measures:
  1. Change of cognitive performance on CDR [ Time Frame: 24 months ]
    Individual variation of different cognitive measures obtained using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB); score 0 to 18

  2. Change of cognitive performances on MDRS [ Time Frame: 24 months ]
    Individual variation of different cognitive measures obtained using the Mattis Dementia Rating Scale (MDRS); score 0 to 144

  3. Change of cognitive performances on sub-subscale of MDRS [ Time Frame: 24 months ]
    Individual variation of different cognitive measures obtained using the initiation/perseveration subscale of the MDRS (MDRS-I/P); score 0 to 37

  4. Change of cognitive performances on TMT [ Time Frame: 24 months ]
    Individual variation of different cognitive measures obtained using the Trail Making Test Part A and B time

  5. Changes of gait and balance performances on SPPB [ Time Frame: 24 months ]
    Between group difference on individual changes of the Short Physical Performance Battery (SPPB) score; score 0 (worst) to 12 (best)

  6. Effects on Quality of life using SF3-6 [ Time Frame: 24 months ]
    Between group differences in patient reported outcomes as assessed by the Short Form-36 (SF-36), score 0 to 100

  7. Effects on Quality of life, using DAD [ Time Frame: 24 months ]
    Between group differences in patient reported outcomes as assessed by the Disability Assessment for Dementia (DAD) scores; score 0 to 100



Information from the National Library of Medicine

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Ages Eligible for Study:   45 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female
  2. Participants aged 45 to 75 years inclusive, at the time of signing of informed consent
  3. Confirmed Diagnosis of CADASIL, defined by either:

    • A Typical mutation in the NOTCH3 gene responsible for an odd number of cystein residue OR
    • A positive skin biopsy showing typical granular osmiophilic material (GOM) in the vascular wall of small vessels with electron microscopy
  4. Presence of at least one prevalent lacune on the MRI identified on 3DT1 or FLAIR images.
  5. Presence of Confluent white matter hyperintensities (WMH) on T2-weighted or FLAIR MR images (Fazekas grade 2-3).
  6. MMSE score ≥15
  7. mRS at 0 - 3
  8. A woman of child bearing potential (WOCBP) is eligible to participate if she is not pregnant, not breastfeeding, and agrees to follow contraceptive guidance (as described in Appendix 5) provided by the study clinician during the treatment period and for 28 days after the last dose of the study treatment.
  9. Capable of giving signed informed consent and have a patient representative willing to co-sign informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

  1. Clinical stroke with persisting neurological deficit within 6 months prior to Screening.
  2. Any other neurodegenerative disorder, such as Parkinson's disease, Alzheimer's disease, or Huntington's disease.
  3. Current significant hematological, cardiac, pulmonary, metabolic, neurologic or psychiatric disorders, uncontrolled seizures, untreated hypertension, disorders increasing risk of bleeding (Hemophilia), or any other significant active medical condition which in the Investigator's opinion would impact participation in this study.
  4. History of myocardial infarction within 3 months prior to Screening, or current active angina pectoris, or symptomatic heart failure.
  5. History of cancer, within the past 5 years. Patients with basal cell carcinoma, squamous cell carcinoma, and Stage 1 prostate cancer can be included in the study.
  6. An episode of major depression within the last 6 months prior to Screening (clinically stable minor depression is not exclusionary).
  7. History of attempted suicide within 6 months prior to Screening or a positive response to items 4 or 5 of Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening and Baseline.
  8. History of drug or alcohol abuse or dependence.
  9. Contra-indications to MRI: presence of a pacemaker, severe claustrophobia, cochlear implants, ferromagnetic devices or clips, intracranial vascular clips, insulin pumps, metallic implants.
  10. Pregnancy or breastfeeding women.
  11. History of human immunodeficiency virus (HIV), hepatitis B or C.
  12. History of allergy or severe intolerance to Vitamin E (tocopherols / tocotrienols).
  13. Presence at Screening of alanine aminotransferase (ALT), aspartate aminotransferase (AST), amylase, or lipase 2x above the upper limit of normal (ULN) of laboratory reference range, total bilirubin 1.5x ULN, any other clinically significant laboratory abnormality.
  14. Presence at Screening of Creatinine clearance <60 (estimated by Cockcroft-Gault equation).
  15. Cognitive enhancers such as donepezil, are allowed only if stable dosage within 3 months prior to Screening.
  16. Use of tocotrienol supplementation within 3 months prior to Screening or any current use of Vitamin E other than study drug (all other vitamin supplements are allowed, if stable dosage within 3 months prior to screening).
  17. Participation in a clinical trial with investigational product (IP) within 30 days prior to Screening. Patients participating in observational studies with no IP, will be allowed to participate in this study
  18. Indication for anti-coagulant therapy
  19. Patients with known sensitivity to polyoxyl castor oil or risk of allergy to soybean and peanuts.

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): NCT04658823


Locations
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France
Hôpital Lariboisière APHP
Paris, France, 75010
Sponsors and Collaborators
Hovid Berhad
Investigators
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Principal Investigator: Pr Hugues Chabriat Hôpital Lariboisière APHP
Study Director: David Ho Hovid Berhad
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Responsible Party: Hovid Berhad
ClinicalTrials.gov Identifier: NCT04658823    
Other Study ID Numbers: T3-CAD-01
First Posted: December 9, 2020    Key Record Dates
Last Update Posted: March 24, 2022
Last Verified: March 2022
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 Hovid Berhad:
CADASIL
Tocotrienols
Vitamin E
Vascular
Stroke
Dementia
Cerebral Small Vessel Disease
Cognitive disorder
Neurovascular disease
Hereditary multi-infarct
Cerebrovascular disease
Additional relevant MeSH terms:
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CADASIL
Dementia, Multi-Infarct
Cerebral Infarction
Brain Infarction
Brain Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Cerebral Small Vessel Diseases
Dementia, Vascular
Cerebral Arterial Diseases
Intracranial Arterial Diseases
Stroke
Dementia
Vascular Diseases
Cardiovascular Diseases
Genetic Diseases, Inborn
Infarction
Ischemia
Pathologic Processes
Necrosis
Neurocognitive Disorders
Mental Disorders
Vitamin E
Tocopherols
Tocotrienols
Tocovid
Vitamins
Micronutrients