Phase I/II Safety and Tolerability Study of striatal administration of BV-101 in adult subjects with Early Manifest Huntington's Disease (HD)
- Conditions
- Huntington's diseaseMedDRA version: 20.0Level: PTClassification code 10070668Term: Huntington's diseaseSystem Organ Class: 10010331 - Congenital, familial and genetic disordersTherapeutic area: Diseases [C] - Nervous System Diseases [C10]
- Registration Number
- EUCTR2021-003052-16-FR
- Lead Sponsor
- Brainvectis
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 18
1. Male or Female subjects between ages 18 and 65 years (both inclusive) at time of consenting, able to provide Informed Consent and able to understand and comply with all study procedures.
2. Documented genetic confirmation of pathological CAG expansion in the huntingtin gene =40.
3. Early manifest HD as defined by a UHDRS total functional capacity (TFC) score of 9 to 13 and a diagnostic classification level (DCL) of 4, or a DCL of 3 if present with cognitive impairment and clear evidence of disease progression.
4. Striatal MRI volumes per hemisphere compatible with the local delivery of IMP: Putamen = 2.3 cm3 (per side); Caudate = 1.7 cm3 on Screening MRI.
5. All HD concomitant medications stable for at least 30 days prior to screening at the investigator’s discretion.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 17
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 1
1. Prior or ongoing medical condition, physical findings, ECG findings, or laboratory abnormality that, in the investigator’s opinion, would impact subject’s safety and compliance with the study procedures.
2. Metastatic neoplasms within the five years prior to screening.
3. Presence of clinically relevant immunologic, hematologic, hepatic, cardiac, or renal disease at the time of screening as per investigator’s clinical judgment.
4. History of or current active psychosis, confusional state, or violent behavior per the investigator’s judgement.
5. Cognitive impairment preventing the ability to understand and sign the informed consent as per the investigator’s judgement.
6. Current untreated and unstable depressive disorder or a serious mood disorder requiring hospitalization.
7. History of prior suicide attempt or imminent risk of self-harm based on investigator’s judgment or with a yes” answer on item 4 or 5 on the Columbia Suicide Severity Rating Scale (CSSRS).
8. Suspected or known history of alcohol and/or substance disorder within 12 months of screening as per the judgement of the investigator.
9. History of non-compliance with prescribed medications for HD management.
10. Patients with history of confirmed stroke, known intracranial neoplasms, vascular malformations, or intracranial hemorrhage.
11. Subjects not deemed suitable for the surgical procedure as per the Neurosurgeon’s judgment.
12. Positive for hepatitis C virus (HCV) or hepatitis B surface antigen (HBsAg) at screening
13. Coagulopathy, use of antiplatelet or anticoagulant therapy or inability to temporarily stop any antithrombotic medication
14. Any infection or vaccination within 14 days prior to screening and within 14 days prior to the scheduled surgical IP dosing day.
15. Any history of gene therapy, cell transplantation or any other experimental brain surgery.
16.Any RNA or DNA targeted HD specific investigational agents such as antisense oligonucleotides within 6 months prior to screening.
17. Use of statins within 5 half-lives of baseline visit. If the subject is on a statin, he/she may transition to an alternative cholesterol lowering treatment, and baseline visit can occur after a duration of at least 5 half-lives after discontinuation of statin.
18. Contraindication to MRI such as claustrophobia, severe movement disorders or inability to lay flat that, in the investigator's judgment, precludes the subject's safe participation in and completion of the study. Subjects with a history of working with metal (using grinders, etc.) should have a safety check for residual metal fragments in their eyes to avoid damage from the magnetic fields.
19. Implanted devices such as stimulators, spinal rods, cardiac pacemaker that would interfere with MRI interpretation.
20. Subjects unable to tolerate or unwilling to undergo multiple lumbar punctures.
21. Participation in any clinical trial of an approved or non-approved investigational drug or intervention within 12 weeks or 5 half-lives whichever is longer prior to treatment.
22. Female subjects who are pregnant or breastfeeding or who may plan to become pregnant within 12 months of the expected/scheduled day of dosing.
23. Female subjects of childbearing potential unwilling to agree to contraception guidance detailed in section 9.4.2 for at least 12 months after the study intervention
24. Male subjects unwilling to agree to contraception guidance detailed in Section 9.4.2 for at least 6 months after the study interventi
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: Assess the safety and tolerability of a one-time, bilateral administration of BV-101 into the caudate nucleus and putamen<br><br>Select the dose of BV-101 to be utilized in the Expansion Part <br>;Secondary Objective: Assess key biomarkers and preliminary efficacy;Primary end point(s): Incidence of Dose Limiting Toxicities (DLTs), Treatment Emergent Adverse Events (TEAEs), and Serious Adverse Events (SAEs) through Week 52 ;Timepoint(s) of evaluation of this end point: All visits (details in Clinical Protocol)
- Secondary Outcome Measures
Name Time Method Timepoint(s) of evaluation of this end point: Several visits (details in Clinical Protocol);Secondary end point(s): • Magnitude and variability of change from baseline in anatomical and volumetric measures of brain regions impacted by HD as assessed by MRI<br>• Change from baseline in the cUHDRS<br>• Change from baseline in blood and CSF mHTT, NfL and 24OH cholesterol <br>• Change from baseline in MRS metabolic profile <br>• Change from baseline in PET FDG striatal profile <br>