CERebrolysin in CADASIL (CERICA)

A Randomized, Double-blind, Single-centre, Two-period Cross-over, Placebo-controlled Trial on Safety and Efficacy in Patients with Genetically Proven CADASIL

The objective of this trial is the global risk-benefit assessment of Cerebrolysin as compared to Placebo in patients with genetically proven CADASIL. In addition, a traditional approach will be taken based on an evaluation of the separate risk and benefit domains in comparison with placebo.

Study Overview

• Status: Active, not recruiting
• Conditions: Cadasil
• Intervention / Treatment: Drug: Cerebrolysin; Drug: 0.9 % NaCl

Detailed Description

Safety data area collected throughout the study (adverse events, vital signs and laboratory tests) and thereafter in case of ongoing serious adverse events (SAEs) at study endpoint.

Optional secondary parameters include analyses of biomarkers (samples of blood, hair, urine, and saliva).

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Praha, Czechia, 150 06
    • Motol University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients of ≥18 years of age, all genders
2. Diagnosis of CADASIL based on clinical symptoms, MRI, and genetic analysis
3. MoCA >11
4. Adequate visual, auditory, and language skills (no language interpreter required) to follow study procedures
5. Patient is not of childbearing potential (i.e. women are post-menopausal for two years, surgically sterile, or using adequate method of contraception)
6. Patient participates voluntarily and gave written informed consent

Exclusion Criteria:

1. Any significant neurological disease/conditions other than CADASIL

2. Focal lesions that may be responsible for the cognitive status of the patient (e.g.

   infectious disease, space-occupying lesion, normal pressure hydrocephalus)

3. Any other diseases/conditions that may affect compliance with the protocol, such as:

   1. severe psychiatric disorders within the last three months
   2. delusional symptoms
   3. history of schizophrenia, schizoaffective disorder, bipolar affective disorder
   4. major depressive disorder newly identified within eight weeks before screening
   5. history of alcohol or substance abuse or dependence within the past two years
4. Any circumstances that -in the investigator's opinion- may result in the patient's non-compliance with study procedures, e.g. fragile or thin veins that prevent many i.v. infusions

5. Any other disease/conditions that may affect the safety assessment, such as:

   1. history of systemic cancer within the past two years
   2. history of myocardial infarction in the past year or unstable or severe cardiovascular disease (including uncontrolled hypertension and/or history of unstable hypertension not compensated by antihypertensive therapy)
   3. any clinically significant laboratory abnormalities at screening
   4. uncontrolled insulin-requiring diabetes or non-insulin dependent diabetes mellitus (HbA1c >87 mmol/mol)
6. Use of concomitant medication with neuroprotective/neurotrophic/nootropic effects (e.g. ginkgo biloba, erythropoietin, citicoline, amantadine, piracetam)

7. Any condition that would represent a contraindication for Cerebrolysin administration:

   1. hypersensitivity to one of the components of the drug
   2. epilepsy
   3. severe renal impairment (estimated Glomerular Filtration Rate [eGFR] <30 ml/min/1.73 m2 as assessed at local laboratory within one month before screening)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Study group 1; Cerebrolysin - Placebo	Drug: Cerebrolysin; 40 ml Cerebrolysin and 60 ml 0.9% NaCl per day for 4 days every month for 1 year; Other Names: Renacenz; Drug: 0.9 % NaCl; 100 ml 0.9% NaCl per day for 4 days every month for 1 year; Other Names: Sodium Chloride
Other: Study group 2; Placebo - Cerebrolysin	Drug: Cerebrolysin; 40 ml Cerebrolysin and 60 ml 0.9% NaCl per day for 4 days every month for 1 year; Other Names: Renacenz; Drug: 0.9 % NaCl; 100 ml 0.9% NaCl per day for 4 days every month for 1 year; Other Names: Sodium Chloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cognitive battery (ROCF: Copy, immediate recall)	- Rey-Osterrieth Complex Figure Test (ROCF): Copy, immediate recall	Baseline, Month 6, Month 12, Month 21, Month 27
Change in cognitive battery (Digit Symbol Coding, subscale of WAIS-PSI)	- Digit Symbol Coding (subscale of WAIS-PSI)	Baseline, Month 6, Month 12, Month 21, Month 27
Change in cognitive battery (Digit Span: Digit backward (subscale of WAIS-WMI)	- Digit Span: Digit backward (subscale of WAIS-WMI)	Baseline, Month 6, Month 12, Month 21, Month 27
Change in cognitive battery (Trail Making Test, Part B)	- Trail Making Test (Part B)	Baseline, Month 6, Month 12, Month 21, Month 27
Change in cognitive battery (ROCF: Delayed recall)	- Rey-Osterrieth Complex Figure Test (ROCF): Delayed recall	Baseline, Month 6, Month 12, Month 21, Month 27
Change in cognitive battery (MoCA)	- Montreal Cognitive Assessment (MoCA)	Baseline, Month 6, Month 12, Month 21, Month 27
Change in cognitive battery (RAVLT)	- Rey Auditory Verbal Learning Test (AVLT)	Baseline, Month 6, Month 12, Month 21, Month 27
Change in cognitive battery (Stroop Color and Word Test - Prague Version)	- Stroop Color and Word Test - Prague Version (word/dots interference)	Baseline, Month 6, Month 12, Month 21, Month 27
Change in mood (Beck Depression Inventory-II)	- Beck Depression Inventory-II (BDI-II)	Baseline, Month 6, Month 12, Month 21, Month 27
Change in imaging (White matter lesion volume)	- White matter lesion volume (MRI)	Baseline, Month 12, Month 27

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cognitive battery, secondary outcome (Trail Making Test, Part A)	- Trail Making Test (Part A)	Baseline, Month 6, Month 12, Month 21, Month 27
Change in cognitive battery, secondary outcome (Symbol Search, subscale of WAIS-PSI)	- Symbol Search (subscale of WAIS-PSI)	Baseline, Month 6, Month 12, Month 21, Month 27
Change in cognitive battery, secondary outcome (Digit Span: Digit forward, subscale of WAIS-WMI)	- Digit Span: Digit forward (subscale of WAIS-WMI)	Baseline, Month 6, Month 12, Month 21, Month 27
Change in imaging, secondary outcome (Index of general cortical thinning)	- Index of general cortical thinning (MRI)	Baseline, Month 12, Month 27
Change in imaging, secondary outcome (Post-stroke lacune volume)	- Post-stroke lacune volume (MRI)	Baseline, Month 12, Month 27
Change in cognitive battery, secondary outcome (Spatial Pattern Separation Task)	- Spatial Pattern Separation Task	Baseline, Month 6, Month 12, Month 21, Month 27
Change in cognitive battery, secondary outcome (Navigation Test Suite)	- Navigation Test Suite	Baseline, Month 6, Month 12, Month 21, Month 27
Change in cognitive battery, secondary outcome (Stroop Color and Word Test - Prague Version)	- Stroop Color and Word Test - Prague Version (color-word/dots interference)	Baseline, Month 6, Month 12, Month 21, Month 27
Change in mood, secondary outcome (Beck Anxiety Inventory)	- Beck Anxiety Inventory	Baseline, Month 6, Month 12, Month 21, Month 27
Change in neurological deficits, secondary outcome (NIH stroke scale)	- NIH stroke scale (NIHSS)	Baseline, Month 6, Month 12, Month 21, Month 27
Change in biomarker analysis, secondary outcome (Neurofilament light chain)	- Neurofilament light chain (NFL)	Baseline, Month 12, Month 27

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Experimental (to be defined after study endpoint): Change in Serotonin level (hair, mean)	- mean over several weeks	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Oxytocin level (hair, mean)	- mean over several weeks	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Cortisol level (hair, mean)	- mean over several weeks	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Serotonin level (hair, greyish level)	- hair color (greyish level)	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Oxytocin level (hair, greyish level)	- hair color (greyish level)	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Cortisol level (hair, greyish level)	- hair color (greyish level)	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Serotonin level (saliva, day value)	- value of this time at this day	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Oxytocin level (saliva, day value)	- value of this time at this day	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Cortisol level (saliva, day value)	- value of this time at this day	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Serotonin level (saliva, epigenetic age)	- epigenetic age	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Oxytocin level (saliva, epigenetic age)	- epigenetic age	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Cortisol level (saliva, epigenetic age)	- epigenetic age	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Serotonin level (blood pellet, epigenetic age)	- epigenetic age	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Oxytocin level (blood pellet, epigenetic age)	- epigenetic age	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Cortisol level (blood pellet, epigenetic age)	- epigenetic age	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Serotonin level (blood pellet, omega-3 fatty acids)	- omega-3 fatty acids	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Oxytocin level (blood pellet, omega-3 fatty acids)	- omega-3 fatty acids	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Cortisol level (blood pellet, omega-3 fatty acids)	- omega-3 fatty acids	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Serotonin level (blood plasma)	- somascan	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Oxytocin level (blood plasma)	- somascan	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Cortisol level (blood plasma)	- somascan	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Serotonin level (urine, alpha klotho)	- alpha klotho	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Oxytocin level (urine, alpha klotho)	- alpha klotho	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Cortisol level (urine, alpha klotho)	- alpha klotho	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Serotonin level (urine, epigenetic markers)	- epigenetic markers	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Oxytocin level (urine, epigenetic markers)	- epigenetic markers	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in Cortisol level (urine, epigenetic markers)	- epigenetic markers	Baseline, Month 12, Month 27
Experimental (to be defined after study endpoint): Change in capillary permeability (Ktrans) in grey and white matter	Capillary permeability (Ktrans) in grey and white matter (MRI)	Baseline, Month 12, Month 27

Collaborators and Investigators

• Sponsor: Ever Neuro Pharma GmbH
• Collaborators: XClinical GmbH; idv Datenanalyse & Versuchsplanung
• Investigators: Principal Investigator: Aleš Tomek, MUDr., Ph.D., Motol University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2023
• Primary Completion (Estimated): March 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: February 14, 2023
• First Submitted That Met QC Criteria: February 23, 2023
• First Posted (Actual): March 6, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 24, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Mental Disorders; Pathologic Processes; Genetic Diseases, Inborn; Neurocognitive Disorders; Brain Infarction; Brain Ischemia; Infarction; Necrosis; Dementia; Ischemia; Intracranial Arterial Diseases; Stroke; Cerebral Arterial Diseases; Cerebral Infarction; Cerebral Small Vessel Diseases; Dementia, Vascular; CADASIL; Dementia, Multi-Infarct; Physiological Effects of Drugs; Protective Agents; Neuroprotective Agents; Nootropic Agents; Cerebrolysin
• Other Study ID Numbers: EVER-CZ-0421; 2022-002394-29 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No