PRidopidine Outcome On Function in Huntington Disease (PROOF-HD)


PROOF-HD is a Phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of pridopidine in patients with early stage of Huntington disease.

Pridopidine is a small molecule developed by Prilenia for the treatment of neurodegenerative disorders such as HD. Pridopidine binds and activates the Sigma-1 receptor (S1R), a protein that is expressed at high levels within the brain. The S1R regulates key cellular pathways, commonly impaired in neurodegeneration.1

Pridopidine, by activation of the S1R, demonstrates beneficial effects in numerous cellular and animal models of HD. For example, pridopidine rescues neurons from mutant Huntingtin (mHTT) induced cell death, in HD patient-derived induced Pluripotent Stem Cells (iPSCs) and in mouse HD neurons.2 Furthermore, HD mice treated with pridopidine show improvement in multiple behavioral and motor functions.6,7

A PET imaging study in humans demonstrated that at 45 mg twice daily (BID) (the dose to be tested in this study), pridopidine occupies ~90% of the S1Rs in the brain. This is very important as it provides support for the appropriate dose to be tested in the clinical trial.

Importantly, extensive prior clinical data with pridopidine demonstrate that this drug has a favorable safety profile and is well tolerated.

The purpose of this study is to evaluate the effect of pridopidine 45 mg twice daily (BID) on functional capacity, as well as on motor and behavioral features in participants with early-stage HD.

In a recently completed clinical study in HD (PRIDE-HD), participants receiving pridopidine dose of 45 mg twice daily, showed maintenance of functional capacity compared to patients receiving placebo, at 52 weeks. This was measured by the Unified Huntington Disease Rating Scale (UHDRS)-Total Functional Capacity (TFC).11

The UHDRS-TFC scale is an accepted tool used by clinicians to assess HD disease stage and the level of patient’s functionality. The scale is driven by tasks that have high relevance to HD patients and families and assesses the patient’s ability to work, to manage finances, to manage a home, to manage oneself, and to live independently at home. TFC is most sensitive to evaluate functionality in early HD patients.


Eligible participants should meet the following criteria, in addition to other criteria:

• Male or female, 25 years of age and older, capable of giving informed consent.
• Have a diagnosis of HD based on clinical features.
• Have confirmed presence of CAG repeats of 36 or greater in the huntingtin gene.
• Must have adult-onset HD with onset of signs and symptoms at, or later than 18 years of age
• Must be willing and able to comply with the study instructions.

There are additional eligibility requirements that the site Principal Investigator (PI) can explain to you.


The study will consist of a screening period, a double-blind treatment period (Main study) and an Open-label extension (OLE).


After signing informed consent, participants will undergo screening assessments to determine eligibility.

Treatment Period

The screening period will be followed by a double blind treatment period that will last between 65 to 78 weeks (Main study).

Open-Label Extension (OLE)

Eligible participants who complete the Main study will have the option to enroll into an OLE period and receive pridopidine (no patients will receive placebo during the OLE).


Proactive mitigation measures to ensure participant’s safety and study integrity during COVID-19 pandemic (or any Public Health Emergency) are included in this study. Virtual visits are incorporated into the protocol to ensure the participants safety and minimize the risk of missing data. In addition, in-clinic visits may be converted into virtual visits, if needed.


PROOF-HD is being conducted by Prilenia Neurotherapeutics (“Sponsor”) in partnership with the Huntington Study Group (HSG). PROOF-HD will take place in North America and Europe.

View active study locations

North America

If you are interested in participating in PROOF-HD in North America, please contact the HSG to find a site nearest to you. Study center personnel will determine your eligibility to participate in the PROOF-HD study.

Call Toll-Free (North America): 800-487-7671


If you are interested in participating in PROOF-HD in Europe, please contact the HSG’s European partner. Study center personnel will determine your eligibility to participate in the PROOF-HD study.

Get European Site Contact Information


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2 Chelsy Eddings, Nicolas Arbez, Sergey Akimov, Michal Geva, Michael Hayden Ross C, Eddings CR, Arbez N, Akimov S, Geva M, Hayden MR, et al. Pridopidine Protects Neurons from Mutant-Huntingtin Toxicity via the Sigma-1 Receptor. Neurobiol Dis. 2017;

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7 Kusko R, Dreymann J, Ross J, Cha Y, Escalante-Chong R, Garcia-Miralles M, et al. Large-scale transcriptomic analysis reveals that pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse. Mol Neurodegener. 2018;13(1):1–15.

8 Ryskamp D, Wu J, Geva M, Kusko R, Grossman I, Hayden M, et al. The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease. Neurobiol Dis [Internet]. 2017 Jan [cited 2019 Mar 12];97(Pt A):46–59. Available from:

9 Geva M, Kusko R, Soares H, Fowler KD, Birnberg T, Barash S, et al. Pridopidine activates neuroprotective pathways impaired in Huntington Disease. Hum Mol Genet [Internet]. 2016 [cited 2019 Mar 12];25(18):3975–87. Available from:

10 Smith-dijak AI, Nassrallah W, Zhang L, Geva M, Hayden M, Raymond L. Impairment and Restoration of Homeostatic Plasticity in Cultured Cortical Neurons from a Mouse Model of Huntington Disease.

11 Reilmann R, McGarry A, Mendis N, Schubert R, Skitt Z, Slawek J, et al. Safety and efficacy of pridopidine in patients with Huntington’s disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study. Lancet Neurol. 2018;18(2):165–76.