RECRUITING

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

Conditions

Huntington's Disease Gene therapy AAV (adeno-associated virus)serotype 5 AAV (adeno-associated virus)serotype 5 Viral vector miHTT muHTT Huntington's Disease (HD)

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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 1/2, multicenter, first-in-human (FIH) study. The first three cohorts of the study have completed enrollment, including the randomized, double-blind, sham-controlled cohorts. Cohort 4 is open-label. Cohort 4 participants will receive high dose AMT-130.

Official Title

A Phase 1/2, Randomized, Double-Blind, Sham Control and Open-Label 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

Quick Facts

Study Start:2019-09-06

Study Completion:2029-12

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT04120493

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:25 Years to 65 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
* Able and willing to provide written informed consent prior to the study and study-related procedure * Participants 25 to 65 years of age of both sexes * Cohorts 1, 2, \& 3: 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 * 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). * HTT gene expansion testing with the presence of ≥40 CAG repeats * Striatal MRI volume requirements per hemisphere: * Cohorts 1, 2, \& 3: Putamen ≥2.5 cm\^3 (per side); Caudate ≥2.0 cm\^3 (per side) * Cohort 4: Putamen \<2.5 cm\^3 (on either side); Caudate \<2.0 cm\^3 (on either side) * 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 * Able and willing to comply with all procedures and the study visit schedule as outlined in the protocol * 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.	* Evidence of suicide risk * Receipt of an experimental agent within 60 days or five half-lives prior to Screening or anytime over the duration of this study. * 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. * Presence of an implanted deep brain stimulation device, ventriculoperitoneal or other CSF shunt, or other implanted catheter * 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. * Any contraindication to 3.0 Tesla MRI as per local guidelines * Brain and spinal pathology that may interfere with the surgical delivery of AMT-130 or represents a significant neurologic comorbid disorder * Any contraindication to lumbar puncture as per local guidelines * 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 * Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study * 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 * Known or suspected intolerance or hypersensitivity to the investigational product(s), closely-related compounds, or any of the stated ingredients * Any known allergy to gadoteridol (ProHance) * 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 * Known allergy, sensitivity, or other contraindication to medications in the immunosuppression regimen in this protocol. * 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. * Cohort 4 ONLY: Inability to establish a safe trajectory to administer AMT-130 to the target structures, as assessed by neuroimaging.

Inclusion Criteria

Exclusion Criteria

* Able and willing to provide written informed consent prior to the study and study-related procedure
* Participants 25 to 65 years of age of both sexes
* Cohorts 1, 2, \& 3: 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
* 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).
* HTT gene expansion testing with the presence of ≥40 CAG repeats
* Striatal MRI volume requirements per hemisphere:
* Cohorts 1, 2, \& 3: Putamen ≥2.5 cm\^3 (per side); Caudate ≥2.0 cm\^3 (per side)
* Cohort 4: Putamen \<2.5 cm\^3 (on either side); Caudate \<2.0 cm\^3 (on either side)
* 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
* Able and willing to comply with all procedures and the study visit schedule as outlined in the protocol
* 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.

* Evidence of suicide risk
* Receipt of an experimental agent within 60 days or five half-lives prior to Screening or anytime over the duration of this study.
* 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.
* Presence of an implanted deep brain stimulation device, ventriculoperitoneal or other CSF shunt, or other implanted catheter
* 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.
* Any contraindication to 3.0 Tesla MRI as per local guidelines
* Brain and spinal pathology that may interfere with the surgical delivery of AMT-130 or represents a significant neurologic comorbid disorder
* Any contraindication to lumbar puncture as per local guidelines
* 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
* Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study
* 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
* Known or suspected intolerance or hypersensitivity to the investigational product(s), closely-related compounds, or any of the stated ingredients
* Any known allergy to gadoteridol (ProHance)
* 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
* Known allergy, sensitivity, or other contraindication to medications in the immunosuppression regimen in this protocol.
* 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.
* Cohort 4 ONLY: Inability to establish a safe trajectory to administer AMT-130 to the target structures, as assessed by neuroimaging.

Contacts and Locations

Study Contact

uniQure

CONTACT

1-866-520-1257

medinfo@uniqure.com

Principal Investigator

David H. Margolin, MD, PhD

STUDY_DIRECTOR

uniQure, Inc.

Study Locations (Sites)

University of Alabama at Birmingham

Birmingham, Alabama, 35294-0111

United States

University of Arizona (Surgical Site Only)

Tucson, Arizona, 85724

United States

University of California, San Francisco

San Francisco, California, 94158

United States

CenExel Rocky Mountain Clinical Research

Englewood, Colorado, 80113

United States

University of Florida College of Medicine

Gainesville, Florida, 32610

United States

Rush University Medical Center

Chicago, Illinois, 60612

United States

Johns Hopkins University

Baltimore, Maryland, 21287

United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215

United States

University of Michigan Department of Neurology

Ann Arbor, Michigan, 48105

United States

Ohio State University

Columbus, Ohio, 43210

United States

Vanderbilt University Medical Center

Nashville, Tennessee, 37232

United States

The University of Texas

Houston, Texas, 77030

United States

Virginia Commonwealth University VCU School of Medicine, Department of Neurology

Richmond, Virginia, 23298

United States

University of Washington Medical Center

Seattle, Washington, 98195

United States

Collaborators and Investigators

Sponsor: UniQure Biopharma B.V.

David H. Margolin, MD, PhD, STUDY_DIRECTOR, uniQure, Inc.

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2019-09-06

Study Completion Date2029-12

Study Record Updates

Study Start Date2019-09-06

Study Completion Date2029-12

Terms related to this study

Keywords Provided by Researchers

Gene therapy
AAV (adeno-associated virus)
serotype 5 AAV (adeno-associated virus)
serotype 5
Viral vector
miHTT
muHTT
Huntington's Disease (HD)

Additional Relevant MeSH Terms

Huntington's Disease