Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD)

a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study

European Huntington's Disease Network, Huntington Study Group investigators

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington's disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability. Methods: PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington's disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington's Disease Rating Scale total motor score [UHDRS-TMS] ≥25 points), and reduced independence (UHDRS independence score ≤90%). Patients were randomly assigned (1:1:1:1:1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67·5, 90, or 112·5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials.gov (NCT02006472). Findings: Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67·5 mg (n=82), 90 mg (n=81), or 112·5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67·5 mg group, 81 in the 90 mg group, and 81 in the 112·5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n=4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112·5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug. Interpretation: Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies. Funding: Teva Pharmaceutical Industries.

Original languageEnglish
Pages (from-to)165-176
Number of pages12
JournalThe Lancet Neurology
Volume18
Issue number2
DOIs
Publication statusPublished - Feb 1 2019

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Huntington Disease
Placebos
Safety
Aspiration Pneumonia
Sleep Initiation and Maintenance Disorders
Diarrhea
Nasopharyngitis
Suicidal Ideation
Placebo Effect
pridopidine
Austria
Cytosine
Russia
Drug Industry
Guanine
Dizziness
Adenine
Poland
Denmark
Random Allocation

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD) : a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study. / European Huntington's Disease Network; Huntington Study Group investigators.

In: The Lancet Neurology, Vol. 18, No. 2, 01.02.2019, p. 165-176.

Research output: Contribution to journalArticle

European Huntington's Disease Network ; Huntington Study Group investigators. / Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD) : a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study. In: The Lancet Neurology. 2019 ; Vol. 18, No. 2. pp. 165-176.
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title = "Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study",
abstract = "Background: Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington's disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability. Methods: PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington's disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington's Disease Rating Scale total motor score [UHDRS-TMS] ≥25 points), and reduced independence (UHDRS independence score ≤90{\%}). Patients were randomly assigned (1:1:1:1:1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67·5, 90, or 112·5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials.gov (NCT02006472). Findings: Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67·5 mg (n=82), 90 mg (n=81), or 112·5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67·5 mg group, 81 in the 90 mg group, and 81 in the 112·5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n=4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112·5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug. Interpretation: Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies. Funding: Teva Pharmaceutical Industries.",
author = "{European Huntington's Disease Network} and {Huntington Study Group investigators} and Ralf Reilmann and Andrew McGarry and Grachev, {Igor D.} and Savola, {Juha Matti} and Beth Borowsky and Eli Eyal and Nicholas Gross and Douglas Langbehn and Robin Schubert and Wickenberg, {Anna Teige} and Spyros Papapetropoulos and Michael Hayden and Ferdinando Squitieri and Karl Kieburtz and Landwehrmeyer, {G. Bernhard} and Pinky Agarwal and Anderson, {Karen E.} and Aziz, {Nasir A.} and Azulay, {Jean Phillippe} and Bachoud-Levi, {Anne C.} and Roger Barker and Agnieszka Bebak and Markus Beuth and Kevin Biglan and Stephanie Blin and Stefan Bohlen and Raphael Bonelli and Sue Caldwell and Fabienne Calvas and Jonielyn Carlos and Simona Castagliuolo and Terrence Chong and Phyllis Chua and Allison Coleman and Jody Corey-Bloom and Rebecca Cousins and David Craufurd and Jill Davison and Eric Decorte and {De Michele}, Giuseppe and Laura Dornhege and Andrew Feigin and Stephanie Gallehawk and Pascale Gauteul and Carey Gonzales and Jane Griffith and Alexander Gustov and Romoli, {Anna M.} and Paola Soliveri and Sandro Sorbi",
year = "2019",
month = "2",
day = "1",
doi = "10.1016/S1474-4422(18)30391-0",
language = "English",
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pages = "165--176",
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TY - JOUR

T1 - Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD)

T2 - a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study

AU - European Huntington's Disease Network

AU - Huntington Study Group investigators

AU - Reilmann, Ralf

AU - McGarry, Andrew

AU - Grachev, Igor D.

AU - Savola, Juha Matti

AU - Borowsky, Beth

AU - Eyal, Eli

AU - Gross, Nicholas

AU - Langbehn, Douglas

AU - Schubert, Robin

AU - Wickenberg, Anna Teige

AU - Papapetropoulos, Spyros

AU - Hayden, Michael

AU - Squitieri, Ferdinando

AU - Kieburtz, Karl

AU - Landwehrmeyer, G. Bernhard

AU - Agarwal, Pinky

AU - Anderson, Karen E.

AU - Aziz, Nasir A.

AU - Azulay, Jean Phillippe

AU - Bachoud-Levi, Anne C.

AU - Barker, Roger

AU - Bebak, Agnieszka

AU - Beuth, Markus

AU - Biglan, Kevin

AU - Blin, Stephanie

AU - Bohlen, Stefan

AU - Bonelli, Raphael

AU - Caldwell, Sue

AU - Calvas, Fabienne

AU - Carlos, Jonielyn

AU - Castagliuolo, Simona

AU - Chong, Terrence

AU - Chua, Phyllis

AU - Coleman, Allison

AU - Corey-Bloom, Jody

AU - Cousins, Rebecca

AU - Craufurd, David

AU - Davison, Jill

AU - Decorte, Eric

AU - De Michele, Giuseppe

AU - Dornhege, Laura

AU - Feigin, Andrew

AU - Gallehawk, Stephanie

AU - Gauteul, Pascale

AU - Gonzales, Carey

AU - Griffith, Jane

AU - Gustov, Alexander

AU - Romoli, Anna M.

AU - Soliveri, Paola

AU - Sorbi, Sandro

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Background: Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington's disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability. Methods: PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington's disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington's Disease Rating Scale total motor score [UHDRS-TMS] ≥25 points), and reduced independence (UHDRS independence score ≤90%). Patients were randomly assigned (1:1:1:1:1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67·5, 90, or 112·5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials.gov (NCT02006472). Findings: Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67·5 mg (n=82), 90 mg (n=81), or 112·5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67·5 mg group, 81 in the 90 mg group, and 81 in the 112·5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n=4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112·5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug. Interpretation: Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies. Funding: Teva Pharmaceutical Industries.

AB - Background: Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington's disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability. Methods: PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington's disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington's Disease Rating Scale total motor score [UHDRS-TMS] ≥25 points), and reduced independence (UHDRS independence score ≤90%). Patients were randomly assigned (1:1:1:1:1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67·5, 90, or 112·5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials.gov (NCT02006472). Findings: Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67·5 mg (n=82), 90 mg (n=81), or 112·5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67·5 mg group, 81 in the 90 mg group, and 81 in the 112·5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n=4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112·5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug. Interpretation: Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies. Funding: Teva Pharmaceutical Industries.

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JO - The Lancet Neurology

JF - The Lancet Neurology

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