Huntington Disease MedDRA version: 27.1 Level: PT Classification code 10070668 Term: Huntington's disease System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: rAAV5-miHTT
Product Code: AMT-130
Pharmaceutical Form: Solution for infusion
Current Sponsor code: AMT-130
Other descriptive name: ADENO-ASSOCIATED VIRUS SEROTYPE 5 ENCODING A MICRORNA T
Sponsors
uniQure biopharma B.V.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Able and willing to provide written informed consent prior to the study and any study related procedure. 2. Male and female participants 25 to 65 years of age. 3. Cohorts 1 & 2: Early manifest HD as defined by a UHDRS TFC score of 9 to 13 and EITHER - a. a DCL of 4 OR - b. a DCL of 3 with either a positive (“Yes”) response to UHDRS Question 80 (multidimensional manifest diagnosis on motor, cognitive, behavioral, functional) or DSM5 2criteria for cognitive disorder (American Psychiatric Association, 2013; MDS Task Force criteria). Cohort 3: Early manifest HD as defined by a UHDRS TFC score of =11 and EITHER a. a DCL of 4 OR b. a DCL of 3 with either a positive (“Yes”) response to UHDRS Question 80 (multidimensional manifest diagnosis on motor, cognitive, behavioral, functional) or DSM5 criteria for cognitive disorder (Movement Disorder Society Task Force criteria) 4. HTT gene expansion testing with the presence of =40 CAG repeats (confirmed by genetic testing at central laboratory). 5. Striatal MRI volume requirements per hemisphere: • Putamen =2.5 cm3 (per side) • Caudate =2.0 cm3 (per side) 6. All HD concomitant medications (addressing motor, behavioral and cognitive symptoms) must be stable for 3 months prior to Screening with no change in clinical symptoms requiring change in medication prior to anticipated administration procedure. 7. Able and willing to comply with all procedures and the study visit schedule as outlined in the protocol. 8. All female participants of childbearing potential (FOCP) must have a negative serum pregnancy test at Screening (and Visit 1A, as appropriate), a negative pregnancy urine dipstick at Baseline and not be breastfeeding. All FOCPs and sexually mature males must be compliant with a highly effective birth control method as outlined in Section 4.5 of the protocol. 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 15 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: 1. Evidence of suicide risk, defined as: • Suicide attempt within 1 year prior to Screening (Visit 1/1A). • Suicidal ideation as defined by a positive response to question 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation Section within 60 days prior to Screening (Visit 1/1A) • Significant risk of suicide as judged by the Investigator 2. Receipt of an experimental agent within 60 days or 5 half-lives prior to Screening or anytime over the duration of this study. 3. Participation in an investigational trial or investigational paradigm (e.g. exercise/physical activity, cognitive therapy, brain stimulation) within 60 days prior to Screening or any time over the duration of this study. 4. Presence of an implanted deep brain stimulation device, ventriculoperitoneal or other CSF shunt, or other implanted catheter. 5. Any history of gene therapy, RNA or DNA targeted HD specific investigational agents, such as antisense oligonucleotides (ASOs), cell transplantation, or any other experimental brain surgery. 6. Any contraindication to 3.0 Tesla MRI as per local guidelines. 7. Brain and spinal pathology that may interfere with the surgical delivery of AMT-130 or represents a significant neurologic comorbid disorder. 8. Any contraindication to lumbar puncture as per local guidelines. 9. Malignancy within 5 years of screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. 10. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study. 11. Current or recurrent disease (including pre-existing cardiovascular or pulmonary conditions), infection, or other significant concurrent medical condition or medications that could confound clinical and laboratory evaluations or could affect a participant’s safety or their ability to undergo the neurosurgical procedure (10+ hour surgical procedure) or comply with the procedures and study visit schedule. 12. Known or suspected intolerance or hypersensitivity to the investigational product(s), closely related compounds, or any of the stated ingredients. 13. Any known allergy to gadoteridol (ProHance®). 14. Screening laboratory values (as measured by the central laboratory): • Alanine aminotransferase (ALT) >2 × upper limit of normal (ULN) • Aspartate aminotransferase (AST) >2 × ULN • Total bilirubin >2 × ULN • Alkaline phosphatase (ALP) >2 × ULN • Creatinine >1.5 × ULN • Platelet count 1.2 x ULN • Partial thromboplastin time (PTT) >1.2 x ULN Additional Exclusion Criteria for Participants in Cohort 3 1. Known immunocompromised status including participants who have undergone organ transplantation or who test positive at Screening for human immunodeficiency virus (HIV); or who are at risk of pathogen reactivation if immunosuppressed, including participants who test positive at Screening for hepatitis C virus antibody (anti-HCV) or hepatitis B surface antigen (HBsAg); or who have history of active tuberculosis or a positive tuberculosis blood test during Screening. For participants with an indeterminate tuberculosis blood test result or positive tuberculosis test result, repeat testing is recommended. 2. Known allergy, sensitivity, or other contraindication to immunosuppression regimens in this protocol. 3. Any participant with an active infection (e.g., coronavirus disease 2019 [C
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult participants with early manifest HD;Secondary Objective: Determine the duration of persistence of AMT-130 in the brain;Primary end point(s): • Type and incidence of AEs. • Change from baseline in vital signs, electrocardiogram (ECG) parameters, physical examinations, and neurological examinations. • Change from baseline in clinical chemistry and hematology safety laboratory tests. • Change from baseline in routine urinalysis and CSF analysis. • Change over time in AAV5 vector shedding. • Change over time in antibodies against AAV5, cytokines, and ELISpot, astroglial activation glial fibrillary acidic protein [GFAP] and microglial activation (YKL-40). • Prospective assessment of suicidality via the Columbia-Suicide Severity Rating Scale (C-SSRS). • Change from baseline to Day 14 and Month 1 in the Montreal Cognitive Assessment (MoCA) • Change from baseline in edema, inflammation, volume loss, and structural changes as measured by the following MRI pulse sequences: T1, T2, and diffusion MRI (dMRI). ;Timepoint(s) of evaluation of this end point: • AEs - measured throughout • Vital signs, chemistry panel, urinalysis, CSF analysis, neurological and physical exams - screening, baseline, Day 7, Day 14, Month 1, 3, 6, 9, 12, 15, 18, 24, 30, 36, 48, 60. (rescreening if applicable). • Vector shedding - baseline, Day 7, 14, Month 1, 3, 6, 9, 12, 15, 18, 24, 30, 36, 48, 60. • AAV5 and ELISpot - baseline, Day 7, 14, Month 1, 3, 6, 9, 12, 15, 18, 24, 30, 36, 48, 60. •Cytokines, GFAP, YKL-40- baseline, Day 7, 14, Month 1, 3, 6, 9, 12 • C-SSRS - screening, rescreening (if applicable), baseline, Day 14, Month 1, 3, 6, 9, 12, 15, 18, 24, 30,36, 42, 48, 54, 60. • MoCA - baseline, Day 14, Month 1, 3 • Imaging - screening, rescreening (if applicable) baseline, Day 0, Day 14, Month 1, 3, 6, 9, 12, 15, 18, 24, 30, 36, 48, 60. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Change over time in levels of AMT-130-derived vector DNA and miRNA expression in the CSF in Cohorts 1 and 2 through approval of CT-AMT-130-02 Protocol Amendment 6.0 Version 7.0. • Change over time in levels of only AMT-130 derived vector DNA in Cohorts 1 and 2 post-approval and throughout the trial in Cohort 3.;Timepoint(s) of evaluation of this end point: Baseline, then post treatment at month 1, 3 , 6 , 9, 12, 15, 18 , 24, 30, 36, 48 and 60. | — |
Countries
Germany, Poland, United Kingdom
Contacts
Public ContactRegulatory Affairs
uniQure biopharma B.V.
Outcome results
None listed