A Study to Investigate the Efficacy, Safety and Tolerability of Votoplam in Participants With Huntington's Disease (INVEST-HD)

May 25, 2026 updated by: Novartis Pharmaceuticals

A Randomized, Placebo-controlled, Double-blind Phase 3 Study to Evaluate the Efficacy, Safety and Tolerability of Votoplam in Participants With Huntington's Disease

The purpose is to assess safety and tolerability of votoplam and to determine whether votoplam slows disease progression in patients with early symptomatic Huntington's disease (HD) compared to the control arm.

HTT227 - current compound code (former code is PTC518 from PTC Therapeutics), HTT227 is Novartis code under Novartis sponsorship.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This study will have a variable double-blind treatment duration of up to 36 months. As part of the study design, not every participant will complete 36 months of treatment.

The study consists of 3 periods:

  • Screening Period: A period of up to 42-days to assess participants eligibility
  • Double-blind Treatment Period: This period will have variable individual treatment duration, up to 36 months. The double-blind treatment period concludes when ≥50% patients complete Month 36. The maximum treatment duration for an individual participant is 36 months.
  • Safety Follow-up Period: A period consisting of one safety follow-up visit, conducted on site or by phone call, for all participants not continuing treatment in the separate open-label extension study or discontinuing early. The visit/phone call will take place 30 days after End of Study (EOS)

Study Type

Interventional

Enrollment (Estimated)

770

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Novartis Pharmaceuticals
  • Phone Number: +41613241111

Study Locations

  • Canada
    • Ontario
      • North York, Ontario, Canada, M2K1E1
        • Recruiting
        • North York General Hospital
        • Contact:
        • Principal Investigator:
          • Ragini Srinivasan, MD
    • Quebec
      • Montreal, Quebec, Canada, H2W 1T8
      • Montreal, Quebec, Canada, H3A 2B4
        • Recruiting
        • CUSM Montreal Neurological Institute
        • Principal Investigator:
          • Anne-Louise Lafontaine
        • Contact:
  • United Kingdom
      • London, United Kingdom, NW1 2BU
        • Recruiting
        • Novartis Investigative Site
      • Southampton, United Kingdom, SO16 6YD
        • Recruiting
        • Novartis Investigative Site
  • United States
    • Colorado
      • Englewood, Colorado, United States, 80113
        • Recruiting
        • CenExcel Rocky Mtn Clin Research
        • Principal Investigator:
          • Meagen Salinas
        • Contact:
    • District of Columbia
      • Washington D.C., District of Columbia, United States, 20007
        • Recruiting
        • Georgetown University
        • Principal Investigator:
          • Karen Anderson
        • Contact:
    • New York
      • Albany, New York, United States, 12208
        • Recruiting
        • Albany Medical College
        • Contact:
        • Principal Investigator:
          • Era Kaur Hanspal
      • Buffalo, New York, United States, 14202
        • Recruiting
        • UBMD Neurology
        • Contact:
        • Principal Investigator:
          • Kelly Andrzejewski
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19107
    • Texas
      • Georgetown, Texas, United States, 78628
        • Recruiting
        • TX Movement Disorder Spec PLLC
        • Principal Investigator:
          • Michael Soileau
        • Contact:
      • Houston, Texas, United States, 77030
        • Recruiting
        • U of TX Health Science Ct
        • Principal Investigator:
          • Erin Furr Stimming
        • Contact:
    • Washington
      • Seattle, Washington, United States, 98195
        • Recruiting
        • University of Washington Medical Center
        • Principal Investigator:
          • Suman Jayadev
        • Contact:

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.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Signed informed consents must be obtained prior to participation in the study
  • Ambulatory male or female participants between 21 to 70 years of age, inclusive, on the day of Informed Consent signature
  • Genetically confirmed HD diagnosis with a cytosine-adenine-guanine (CAG) repeat length of 40 or above. Participants must have prior genetic confirmation and known CAG repeat length obtained prior to screening.

  • Meets all of the following criteria:

    • UHDRS IS score ≥90
    • UHDRS TFC score = 13
    • UHDRS TMS score = 7-25, inclusive
    • CAP100 ≥ 70 Calculation: CAP = Age at study entry × (CAG length - 30) / 6.49

Exclusion Criteria:

  • History of gene therapy or cell transplantation or any other experimental brain surgery for the treatment of HD

  • Serologic evidence for active viral hepatitis as indicated by:

    • positive anti-HBc IgM
    • positive anti-HBc IgG confirmed by positive HBsAg and/or HBV DNA
    • positive HCV ab test confirmed by positive HCV RNA
    • Immunodeficiency diseases, including a positive human immunodeficiency virus (HIV) test result

  • History or current diagnosis of ECG or cardiac abnormalities indicating significant risk of safety for participants such as:

    • Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second- or third-degree AV block without a pacemaker
    • History of familial long QT syndrome or known family history of Torsade de Pointes

  • Women of childbearing potential, defined as all women physiologically capable of becoming pregnant from menarche until becoming post-menopausal, unless they have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral salpingectomy at least six weeks before taking study treatment. In the case of oophorectomy alone, the reproductive status of the woman needs to have been confirmed by follow-up hormone level assessment.

    o WOCBP are excluded unless they are using highly effective methods of contraception (failure rate < 1% per year) while taking study treatment and for 8 months after stopping study treatment.

  • Pregnant or nursing (breastfeeding) women

Other protocol defined inclusion/exclusion criteria may apply

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Votoplam
Votoplam (blinded) taken orally, randomized in a 3:2 ratio (Votoplam: Placebo)
Drug: Votoplam (blinded)
Votoplam (blinded) active treatment
Other Names:
  • HTT227
Placebo Comparator: Placebo
Placebo (blinded) taken orally, randomized in a 3:2 ratio (Votoplam: Placebo)
Drug: Placebo
Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from Baseline in cUHDRS score
Time Frame: Baseline, Month 36

The Composite Unified Huntingtons Disease Ratings Scale (cUHDRS) is an improved composite measure to assess multi-domain clinical progression in HD. The cUHDRS is a combined weighted score of measures of motor function (TMS), cognition (SDMT and SWRT) and overall functional capacity (TFC):

cUHDRS = [(TFC-10.4)/1.9 - (TMS-29.7)/14.9 + (SDMT-28.4)/11.3 + (SWRT - 66.1)/20.1] + 10.

In conjunction with one another, these measures provide a comprehensive, sensitive and specific tool for monitoring disease progression, with lower scores indicating more severe disease. cUHDRS score range from -8 to 25.
Baseline, Month 36

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from Baseline in UHDRS-TFC
Time Frame: Baseline, Month 36
The UHDRS-Total Functional Capacity (TFC) focuses on the Investigator's assessment of the participant's capacity to perform a range of activities including occupation, finances, self-care, domestic chores and activities of daily living. The responses are derived from interview with the participant and/or companion, if applicable. Scores range from 0 to 13, with higher scores representing better functioning.
Baseline, Month 36
Change from Baseline in UHDRS-IS
Time Frame: Baseline, Month 36
The UHDRS-Independence Scale (IS) measures a patient's overall level of functional independence in activities of daily living. It provides a single score ranging from 10 (total dependence/bedbound) to 100 (no special care needed) in intervals of 10, with higher scores indicating better functioning. Scores can also be assigned in increments of 5 for intermediate levels of function.
Baseline, Month 36
The time to decline in TFC score by at least one or IS score by at least 10
Time Frame: Baseline to end of treatment up to 36 months

The UHDRS-Total Functional Capacity (TFC) focuses on the Investigator's assessment of the participant's capacity to perform a range of activities including occupation, finances, self-care, domestic chores and activities of daily living. The responses are derived from interview with the participant and/or companion, if applicable. Scores range from 0 to 13, with higher scores representing better functioning.

The UHDRS-Independence Scale (IS) measures a patient's overall level of functional independence in activities of daily living. It provides a single score ranging from 10 (total dependence/bedbound) to 100 (no special care needed) in intervals of 10, with higher scores indicating better functioning. Scores can also be assigned in increments of 5 for intermediate levels of function.
Baseline to end of treatment up to 36 months
Change from Baseline in UHDRS-TMS
Time Frame: Baseline, Month 36
The UHDRS-Total Motor Score (TMS) is the cumulative sum of the individual motor ratings obtained during the administration of the motor assessment portion of the UHDRS. It includes items related to eye movements, speech, limb movements (including hand taps and pronation-supination), dystonia, chorea, and gait/balance. Scores range from 0 to 124, with higher scores indicating greater motor impairment.
Baseline, Month 36
Change from Baseline in SDMT
Time Frame: Baseline, Month 36
The Symbol Digit Modality Test (SDMT) is used to assess attention, working memory, psychomotor speed and visual perceptual processing. Participants are presented with a translation key of specific numbers paired with unique abstract symbols. Below the translation key is an array of symbols paired with empty spaces, the participant's task is to match the number for each symbol as quickly as possible in a given time frame. Scores are based on number of correctly paired items and range from 0 to 110, with higher scores representing better performance.
Baseline, Month 36
Change from Baseline in SWRT
Time Frame: Baseline, Month 36
The Stroop Word Reading Test (SWRT) is a measure of processing and psychomotor speed. Participants are presented with a list or words (color names) printed in black ink and asked to read aloud as many words as possible within a set timeframe. Scores are based on the number of words read correctly and range from 0 to 60, with higher scores representing better performance.
Baseline, Month 36
Percent change from Baseline in blood mHTT protein
Time Frame: Baseline to steady state and up to 36 months in blood mHTT protein

The mutant huntington protein (mHTT) which is detectable both in blood and cerebrospinal fluid (CSF), represents a reliable biomarker for HD due to its direct involvement in disease pathology.

Blood mHTT is a direct product of the pathogenic HTT gene mutation and represents a proximal marker of Huntington's disease (HD) biology.
Baseline to steady state and up to 36 months in blood mHTT protein
Change from Baseline in serum NfL
Time Frame: Baseline, Month 36
Serum Neurofilament light chain NfL is a component of the neuronal cytoskeleton, released into CSF and blood after neuro-axonal damage, serving as a marker of neurodegeneration and disease progression in HD.
Baseline, Month 36
Incidence and severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and TEAEs leading to participant withdrawal
Time Frame: Baseline to up to 36 months
Number of participants with AEs and SAEs, including notable findings on physical examination, changes in vital signs, laboratory parameters, ECG, etc.
Baseline to up to 36 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Novartis Pharmaceuticals

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 Major Dates

Study Start (Actual)

March 24, 2026

Primary Completion (Estimated)

April 2, 2030

Study Completion (Estimated)

April 30, 2030

Study Registration Dates

First Submitted

January 7, 2026

First Submitted That Met QC Criteria

January 7, 2026

First Posted (Actual)

January 8, 2026

Study Record Updates

Last Update Posted (Actual)

May 27, 2026

Last Update Submitted That Met QC Criteria

May 25, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CHTT227A12301

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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