Safety and Proof-of-Concept (POC) Study With AMT-130 in Adults With Early Manifest Huntington's Disease

Huntington's Disease Clinical Trial

Official title:

A Phase I/II, Randomized, Double-Blind, Sham Control Study to Explore Safety, Tolerability, and Efficacy Signals of Multiple Doses of Striatally-Administered rAAV5-miHTT Total Huntingtin Gene (HTT) Lowering Therapy (AMT-130) in Early Manifest Huntington's Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04120493
• Other study ID #: CT-AMT-130-01
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: September 6, 2019
• Est. completion date: June 2029

Study information

• Verified date: April 2024
• Source: UniQure Biopharma B.V.
• Contact: Diane Lopez, MS
• Phone: 781-777-3697
• Email: amt130_clinical_trials[@]uniqure.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is the first study of AMT-130 in patients with early manifest HD and is designed to establish safety and proof-of-concept (PoC). CT-AMT-130-01 is a Phase I/II, randomized, multicenter, multiple dose, double-blind, imitation surgery, first-in-human (FIH) study.

Cohort 3 participants will receive either high or low dose (1:1 randomization). Participants enrolled in Cohort 3 will also receive an immunosuppression regimen consisting of dexamethasone, sirolimus, and rituximab.

Description:

AMT-130 is an investigational, single administration gene therapy intended to modify the disease course for HD. Preclinical studies have shown that AMT-130 lowers huntingtin protein and is associated with decreased progression of Huntington's Disease signs in animal models.

Cohort 1 & 2 consists of a blinded 12-month Core Study Period to evaluate the safety and potential impact of AMT-130 on disease progression and an unblinded 4-year Long-Term Period with periodic follow-up visits to evaluate the safety of AMT-130 and disease progression in treated individuals. Cohort 2 Sham participants who do not cross over to receive AMT-130 treatment will have the opportunity to participate in the Optional Extended Follow-Up Period and will be followed for an additional 2 years.

Following completion of the 12-month blinded post treatment follow-up period (Cohorts 1 & 2 only), once the crossover has been activated after review of data by the DSMB, subjects randomized to the imitation (sham) procedure who continue to meet inclusion/exclusion criteria will be allowed to crossover to receive AMT-130 treatment.

Cohort 3 participants will receive either high or low dose AMT-130. Following completion of the Month 36 visit, they will be unblinded to their treatment arm. Cohort 3 will further evaluate the safety and exploratory efficacy data of low or high dose AMT-130. Cohort 3 participants will also receive pre and post-operative immunosuppressant therapies composed of dexamethasone, sirolimus, and rituximab.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: June 2029
• Est. primary completion date: April 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 25 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Able and willing to provide written informed consent prior to the study and study-related procedure

2. Participants 25 to 65 years of age of both sexes

3a. Cohort 1 & 2: Early manifest HD as defined by a UHDRS total functional capacity (TFC) score of 9 to 13 and EITHER a diagnostic confidence level (DCL) of 4 OR a DCL of 3 if the subject either meets the definition of multidimensional manifest HD (UHDRS question 80) or has cognitive symptoms

3b. Cohort 3: Early manifest HD as defined by a UHDRS TFC score of = 11 and EITHER a DCL of 4 or 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

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.

Exclusion Criteria:

1. Evidence of suicide risk

2. Receipt of an experimental agent within 60 days or five half-lives prior to Screening or anytime over the duration of this study.

3. Participation in an investigational trial or investigational paradigm (such as exercise/physical activity, cognitive therapy, brain stimulation) within 60 days prior to Screening or anytime 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 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): a. Alanine aminotransferase (ALT) >2 × upper limit of normal (ULN) b. Aspartate aminotransferase (AST) >2 × ULN c. Total bilirubin >2 × ULN d. Alkaline phosphatase (ALP) >2 × ULN e. Creatinine >1.5 × ULN f. Platelet count <100,000/mm3g.Prothrombin time (PT) >1.2 × ULN h. Partial thromboplastin time (PTT) >1.2 × ULN

15. 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), hepatitis C virus ribonucleic acid (HCV RNA), 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.

16. Known allergy, sensitivity, or other contraindication to medications in the immunosuppression regimen in this protocol.

17. Any participant with an active infection (e.g., coronavirus disease 2019 [COVID-19]) at Screening or at the time of treatment that requires medical intervention. Participants may rescreen, or if screened eligible and an open surgical slot is available, may receive treatment after recovery.

Related Conditions & MeSH terms

• Huntington Disease
• Huntington's Disease

Intervention

Genetic:
• intra-striatal rAAV5-miHTT
One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain

Other:
• Imitation (sham) surgery
Simulated surgical procedure with skin incisions only; no intrastriatal injections and no burr holes through the skull

Locations

Country	Name	City	State
United States	University of Michigan Department of Neurology	Ann Arbor	Michigan
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Rush University Medical Center	Chicago	Illinois
United States	Ohio State University	Columbus	Ohio
United States	CenExel Rocky Mountain Clinical Research	Englewood	Colorado
United States	University of Florida College of Medicine	Gainesville	Florida
United States	The University of Texas	Houston	Texas
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Virginia Commonwealth University VCU School of Medicine, Department of Neurology	Richmond	Virginia
United States	University of California, San Francisco	San Francisco	California
United States	University of Washington Medical Center	Seattle	Washington
United States	University of Arizona (Surgical Site Only)	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
UniQure Biopharma B.V.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	CSF Mutant Protein (fM)	Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment.	Collected for duration of study through month 60
Other	CSF/Serum Neurofilament Light Chain (pg/mL)	Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment.	Collected for duration of study through month 60
Other	Unified Huntington Disease Rating Scale (UHDRS)	The UHDRS will assess changes from baseline in summary scores of domains of motor function, cognitive function, behavioral function, and functional abilities.	Collected for duration of study through month 60
Other	Quantitative Motor (Q-Motor) Testing	Q-Motor testing will measure disease progression and responsiveness to AMT-130 treatment.	Collected for duration of study through month 60
Other	Magnetic Resonance Imaging (MRI)	MRI assessments will include whole brain volume, striatal region volumes, white matter volume, gray matter volume, ventricular volume, cortical thickness, and diffusion MRI measures.	Collected for duration of study through month 60
Other	Neuro-QoL Measures	The Neuro-QoL is a brief, reliable, valid, standardized set of patient reported, Health Related Quality of Life (HRQoL) measures for people living with neurological conditions.	Collected for duration of study through month 60
Other	HDQLIFE Measures	The HDQLIFE is a measurement system that was designed to provide a brief, reliable and valid assessment of HRQoL in HD and consists of NeuroQoL measures that have been validated in the HD population and several new HD specific measures.	Collected for duration of study through month 60
Primary	Number and type of Adverse Events (AE)	Safety will be assessed by adverse events (AEs) related to clinical safety laboratory tests, vital signs, electrocardiograms (ECGs), neurological and physical examinations, rAAV5 vector shedding, immunogenicity response, suicidality risk [Columbia-Suicide Severity Rating Scale [C-SSRS)], changes in global cognitive functioning [Montreal Cognitive Assessment Scale (MoCA)] and MRI measures of edema, inflammation, volume loss and structural changes.	12 months (Cohorts 1 & 2) and 12 months (Cohort 3)
Secondary	Duration of persistence of AMT-130 in the brain	Change over time in levels of AMT-130-derived Vector DNA Expression in the Cerebrospinal Fluid (CSF)	Collected for duration of study through month 60