Huntington's Disease
Conditions
Keywords
Huntington's Disease, Pridopidine, Pride-HD
Brief summary
This is a multicenter, multinational, randomized, parallel-group, double-blind, placebo-controlled, dose range finding study to compare the efficacy and safety of different doses of pridopidine versus placebo in the treatment of motor impairment in Huntington's Disease (HD).
Detailed description
Originally, the study was designed to assess the effect of pridopidine on motor function at 26 weeks. Due to the recognition that the primary target of pridopidine is the Sigma-1 receptor, the trial was extended from 26 to 52 weeks to evaluate the effect of pridopidine on Total Functional Capacity (TFC). A minimum of 52 weeks are needed for the placebo group to decline and allow a window to assess an effect on TFC (a prespecified endpoint). Approximately 20% of patients completed 26 weeks of the study before IRB approvals for this extension, and did not continue into the 2nd treatment period up to 52 weeks.
Interventions
DRUGPridopidine
22.5 mg and 45 mg capsules
OTHERPlacebo
Capsules matching drug
Sponsors
European Huntington's Disease Network
Huntington Study Group
Prilenia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of HD based on the presence of \>/= 36 CAG repeats * Male or female age ≥21 years, with an onset of HD after 18 years' old. * Females of childbearing potential must be compliant in using adequate birth control throughout the duration of the study * Body weight ≥50 kg * Sum of \>= 25 points on the UHDRS-TMS and UHDRS Independence Score \<=90% * Able and willing to provide written informed consent prior to any study related procedure. * Willing to provide a blood sample for genetic analyses * Willing and able to take oral medication and able to comply with the study specific procedures. * Ambulatory, being able to travel to the study center, and judged by the investigator as likely to be able to continue to travel for the duration of the study. * Availability and willingness of a caregiver, informant or family member to accompany the patient to the clinic at study, and the suitability of the caregiver should be judged by the Investigator. * Other criteria apply, please contact the investigator for more information.
Exclusion criteria
* Patients with clinically significant heart disease at the screening visit * Treatment with tetrabenazine within 6 weeks of study screening * Patients with a history of epilepsy or of seizures within the last 5 years * Have other serious medical illnesses in the opinion of the investigator may put the patient at risk when participating in the study or may influence the results of the study or affect the patient's ability to take part in the study * Patients receiving medications (within the last 6 weeks prior to screening) that have been proven to prolong QT interval or who may require such medications during the course of the study such as but not limited to non allowed anti psychotic medications, tricyclic antidepressants and/or Class I antiarrhythmics * Other criteria apply, please contact the investigator for more information
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) at Week 26 | 26 weeks | TMS was defined as the sum of all UHDRS motor domains ratings. The motor section of the UHDRS assesses motor features of Huntington's Disease (HD) with standardized ratings of oculo-motor function, dysarthria, chorea, dystonia, gait, and postural stability. Each of 15 assessments is rated on a scale of 0 (normal) to 4 (marked impairment) for a TMS range of 0-124. Negative change from baseline values indicate improvement. |
Secondary
| Measure | Time frame |
|---|---|
| Number of Patients With Adverse Events | 52 weeks |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Functional Capacity (TFC) at Week 52 | 52 weeks | The TFC is one subscale of the Unified Huntington's Disease Rating Scale (UHDRS), comprising 5 functional domains associated with disability (occupation, finances, domestic chores, activities of daily living, and care level), with scores on each item ranging from 0 to either 2 or 3. The TFC total score is the sum of the 5 TFC items and can range from 0 to 13, with greater scores indicating higher functioning. Negative change from baseline indicates worsening. |
Countries
Australia, Austria, Canada, Denmark, France, Germany, Italy, Netherlands, Poland, Russia, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 492 patients were screened; of these, 408 were randomized. The main reason for not randomizing patients was noncompliance with the eligibility criteria.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Pridopidine matching placebo (hard capsules)
Patients received a starting dose of placebo matching pridopidine 22.5 mg or matching placebo and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52. | 82 |
| Pridopidine 45 mg BID Pridopidine given as hard capsules, twice daily
Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52. | 81 |
| Pridopidine 67.5 mg BID Pridopidine given as hard capsules, twice daily
Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52. | 82 |
| Pridopidine 90 mg BID Pridopidine given as hard capsules, twice daily
Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52. | 81 |
| Pridopidine 112.5 mg BID Pridopidine given as hard capsules, twice daily
Patients received a starting dose of pridopidine 22.5 mg and were during the first 4 weeks of treatment titrated to their randomized dose level. The randomized dose level was then to be maintained for the remainder of the treatment period through Week 52. | 82 |
| Total | 408 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Period 1 (Through Week 26) | Adverse Event | 5 | 6 | 11 | 11 | 14 |
| Period 1 (Through Week 26) | Lack of Efficacy | 0 | 0 | 1 | 0 | 0 |
| Period 1 (Through Week 26) | Noncompliance | 2 | 1 | 1 | 0 | 0 |
| Period 1 (Through Week 26) | Other | 1 | 5 | 0 | 2 | 3 |
| Period 1 (Through Week 26) | Protocol Violation | 1 | 1 | 1 | 1 | 0 |
| Period 1 (Through Week 26) | Withdrawal by Subject | 3 | 9 | 3 | 0 | 3 |
| Period 2 (Through Week 52) | Adverse Event | 1 | 4 | 5 | 1 | 1 |
| Period 2 (Through Week 52) | Lack of Efficacy | 1 | 0 | 0 | 1 | 1 |
| Period 2 (Through Week 52) | Noncompliance | 1 | 0 | 0 | 0 | 0 |
| Period 2 (Through Week 52) | Not treated | 0 | 0 | 2 | 0 | 0 |
| Period 2 (Through Week 52) | Other | 0 | 1 | 0 | 1 | 0 |
| Period 2 (Through Week 52) | Sponsor decision | 0 | 0 | 1 | 0 | 0 |
| Period 2 (Through Week 52) | Withdrawal by Subject | 2 | 1 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Pridopidine 45 mg BID | Total | Pridopidine 112.5 mg BID | Placebo | Pridopidine 90 mg BID | Pridopidine 67.5 mg BID |
|---|---|---|---|---|---|---|
| Age, Continuous | 51.9 years STANDARD_DEVIATION 11.75 | 50.4 years STANDARD_DEVIATION 11.85 | 47.5 years STANDARD_DEVIATION 11.4 | 50.3 years STANDARD_DEVIATION 11.34 | 51.3 years STANDARD_DEVIATION 12.69 | 51.0 years STANDARD_DEVIATION 11.83 |
| CYP2D6 genotype Extensive metaboliser | 70 Participants | 355 Participants | 69 Participants | 72 Participants | 74 Participants | 70 Participants |
| CYP2D6 genotype Intermediate metaboliser | 5 Participants | 35 Participants | 9 Participants | 8 Participants | 5 Participants | 8 Participants |
| CYP2D6 genotype Poor metaboliser | 5 Participants | 16 Participants | 4 Participants | 1 Participants | 2 Participants | 4 Participants |
| CYP2D6 genotype Ultra-rapid metaboliser | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Number of Cytosine-Adenosine-Guanine (CAG) Repeats | 44.1 Number of CAG repeats STANDARD_DEVIATION 4.12 | 44.7 Number of CAG repeats STANDARD_DEVIATION 4.18 | 45.3 Number of CAG repeats STANDARD_DEVIATION 3.66 | 44.4 Number of CAG repeats STANDARD_DEVIATION 3.23 | 44.5 Number of CAG repeats STANDARD_DEVIATION 4.9 | 45.0 Number of CAG repeats STANDARD_DEVIATION 4.73 |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Missing | 5 Participants | 25 Participants | 5 Participants | 8 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 75 Participants | 378 Participants | 77 Participants | 73 Participants | 75 Participants | 78 Participants |
| Sex: Female, Male Female | 40 Participants | 203 Participants | 39 Participants | 40 Participants | 43 Participants | 41 Participants |
| Sex: Female, Male Male | 41 Participants | 205 Participants | 43 Participants | 42 Participants | 38 Participants | 41 Participants |
| Use of neuroleptics No | 50 Participants | 251 Participants | 50 Participants | 51 Participants | 50 Participants | 50 Participants |
| Use of neuroleptics Yes | 31 Participants | 157 Participants | 32 Participants | 31 Participants | 31 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 82 | 0 / 81 | 0 / 82 | 1 / 81 | 1 / 82 |
| other Total, other adverse events | 45 / 82 | 49 / 81 | 63 / 82 | 57 / 81 | 53 / 82 |
| serious Total, serious adverse events | 0 / 82 | 8 / 81 | 9 / 82 | 9 / 81 | 9 / 82 |
Outcome results
Primary
Change From Baseline in Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) at Week 26
TMS was defined as the sum of all UHDRS motor domains ratings. The motor section of the UHDRS assesses motor features of Huntington's Disease (HD) with standardized ratings of oculo-motor function, dysarthria, chorea, dystonia, gait, and postural stability. Each of 15 assessments is rated on a scale of 0 (normal) to 4 (marked impairment) for a TMS range of 0-124. Negative change from baseline values indicate improvement.
Time frame: 26 weeks
Population: Full analysis set (FAS) i.e. patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) at Week 26 | -4.79 score on a scale | Standard Error 0.99 |
| Pridopidine 45 mg BID | Change From Baseline in Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) at Week 26 | -3.37 score on a scale | Standard Error 1.05 |
| Pridopidine 67.5 mg BID | Change From Baseline in Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) at Week 26 | -3.09 score on a scale | Standard Error 1.02 |
| Pridopidine 90 mg BID | Change From Baseline in Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) at Week 26 | -4.13 score on a scale | Standard Error 1 |
| Pridopidine 112.5 mg BID | Change From Baseline in Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) at Week 26 | -2.74 score on a scale | Standard Error 1.01 |
p-value: 0.320295% CI: [-1.39, 4.23]Mixed Models Analysis
p-value: 0.226695% CI: [-1.06, 4.46]Mixed Models Analysis
p-value: 0.634895% CI: [-2.07, 3.39]Mixed Models Analysis
p-value: 0.144795% CI: [-0.71, 4.8]Mixed Models Analysis
Secondary
Number of Patients With Adverse Events
Time frame: 52 weeks
Population: Safety Analysis set, i.e. patients who received at least one dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Patients With Adverse Events | 62 Participants |
| Pridopidine 45 mg BID | Number of Patients With Adverse Events | 63 Participants |
| Pridopidine 67.5 mg BID | Number of Patients With Adverse Events | 69 Participants |
| Pridopidine 90 mg BID | Number of Patients With Adverse Events | 71 Participants |
| Pridopidine 112.5 mg BID | Number of Patients With Adverse Events | 67 Participants |
Post Hoc
Change From Baseline in Quantitative Motor (Q-motor) Measurements, Pro-Sup-Inter-Tap-interval-MN-Hand, Early HD
Q-motor assessments were based on the application of force transducers and 3-dimensional position sensors. The reported parameter is the Pro-Sup-Inter-Tap-interval-MN-Hand, measured in seconds. Positive change from baseline indicates worsening.
Time frame: 26 and 52 weeks
Population: FAS i.e. pts receiving \>=1 dose of study drug and with \>=1 post-BL efficacy assessment; pts with early HD defined by BL TFC score ≥7.~The study tested 4 pridopidine doses on TMS for 26 w. Due to a new understanding on pridopidine's mechanism of action (S1R agonist), the study was extended to 52w to assess TFC in all HD. A post-hoc analysis for the 45 mg bid dose was performed for TFC in early HD, and the dose was chosen for Phase 3.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Quantitative Motor (Q-motor) Measurements, Pro-Sup-Inter-Tap-interval-MN-Hand, Early HD | Change from baseline to Week 26 | 0.0247 seconds | Standard Error 0.0118 |
| Placebo | Change From Baseline in Quantitative Motor (Q-motor) Measurements, Pro-Sup-Inter-Tap-interval-MN-Hand, Early HD | Change from baseline to Week 52 | 0.0447 seconds | Standard Error 0.0142 |
| Pridopidine 45 mg BID | Change From Baseline in Quantitative Motor (Q-motor) Measurements, Pro-Sup-Inter-Tap-interval-MN-Hand, Early HD | Change from baseline to Week 26 | -0.0096 seconds | Standard Error 0.011 |
| Pridopidine 45 mg BID | Change From Baseline in Quantitative Motor (Q-motor) Measurements, Pro-Sup-Inter-Tap-interval-MN-Hand, Early HD | Change from baseline to Week 52 | 0.0003 seconds | Standard Error 0.015 |
Comparison: At Week 26p-value: 0.034695% CI: [-0.0658, -0.0026]Mixed Models Analysis
Comparison: At Week 52p-value: 0.030595% CI: [-0.0847, -0.0042]Mixed Models Analysis
Other Pre-specified
Change From Baseline in Total Functional Capacity (TFC) at Week 52
The TFC is one subscale of the Unified Huntington's Disease Rating Scale (UHDRS), comprising 5 functional domains associated with disability (occupation, finances, domestic chores, activities of daily living, and care level), with scores on each item ranging from 0 to either 2 or 3. The TFC total score is the sum of the 5 TFC items and can range from 0 to 13, with greater scores indicating higher functioning. Negative change from baseline indicates worsening.
Time frame: 52 weeks
Population: Full analysis set (FAS) i.e. patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Total Functional Capacity (TFC) at Week 52 | -0.83 score on a scale | Standard Error 0.2 |
| Pridopidine 45 mg BID | Change From Baseline in Total Functional Capacity (TFC) at Week 52 | 0.04 score on a scale | Standard Error 0.22 |
| Pridopidine 67.5 mg BID | Change From Baseline in Total Functional Capacity (TFC) at Week 52 | -0.72 score on a scale | Standard Error 0.21 |
| Pridopidine 90 mg BID | Change From Baseline in Total Functional Capacity (TFC) at Week 52 | -0.65 score on a scale | Standard Error 0.2 |
| Pridopidine 112.5 mg BID | Change From Baseline in Total Functional Capacity (TFC) at Week 52 | -0.59 score on a scale | Standard Error 0.22 |
p-value: 0.003295% CI: [0.29, 1.45]Mixed Models Analysis
p-value: 0.704295% CI: [-0.46, 0.68]Mixed Models Analysis
p-value: 0.509995% CI: [-0.37, 0.75]Mixed Models Analysis
p-value: 0.406195% CI: [-0.33, 0.82]Mixed Models Analysis
Post Hoc
Change in Total Functional Capacity (TFC) From Baseline in Patients With Early HD (Defined as Patients With TFC>=7)
The TFC is one subscale of the Unified Huntington's Disease Rating Scale (UHDRS), comprising 5 functional domains associated with disability (occupation, finances, domestic chores, activities of daily living, and care level), with scores on each item ranging from 0 to either 2 or 3. The TFC total score is the sum of the 5 TFC items and can range from 0 to 13, with greater scores indicating higher functioning. Negative change from baseline indicates worsening.
Time frame: 52 weeks
Population: FAS i.e. pts receiving ≥1 dose of study drug and with ≥1 post-BL efficacy assessment; pts with early HD defined by BL TFC score ≥7.~The study tested 4 pridopidine doses on TMS for 26 w. Due to a new understanding on pridopidine's mechanism of action (S1R agonist), the study was extended to 52w to assess TFC in all HD. A post-hoc analysis for the 45 mg bid dose was performed for TFC in early HD, and the dose was chosen for Phase 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Total Functional Capacity (TFC) From Baseline in Patients With Early HD (Defined as Patients With TFC>=7) | -1.17 score on a scale | Standard Error 0.22 |
| Pridopidine 45 mg BID | Change in Total Functional Capacity (TFC) From Baseline in Patients With Early HD (Defined as Patients With TFC>=7) | -0.01 score on a scale | Standard Error 0.23 |
p-value: 0.000395% CI: [0.54, 1.78]Mixed Models Analysis
Post Hoc
Total Functional Capacity Responder Rate in Early HD
The TFC is one subscale of the Unified Huntington's Disease Rating Scale (UHDRS), comprising 5 functional domains associated with disability (occupation, finances, domestic chores, activities of daily living, and care level), with scores on each item ranging from 0 to either 2 or 3. The TFC total score is the sum of the 5 TFC items and can range from 0 to 13, with greater scores indicating higher functioning. Responder was defined as a TFC change to Week 52 of TFC\>=0.
Time frame: 52 weeks
Population: FAS i.e. pts receiving ≥1 dose of study drug and with ≥1 post-BL efficacy assessment; pts with early HD defined by BL TFC score ≥7 who completed 52 weeks.~The study tested 4 pridopidine doses on TMS for 26 w. Due to a new understanding on pridopidine's mechanism of action (S1R agonist), the study was extended to 52w to assess TFC in all HD. A post-hoc analysis for the 45 mg bid dose was performed for TFC in early HD, and the dose was chosen for Phase 3.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Total Functional Capacity Responder Rate in Early HD | 20 Participants |
| Pridopidine 45 mg BID | Total Functional Capacity Responder Rate in Early HD | 30 Participants |
p-value: 0.003Chi-squared