Primary Objective: The primary objective of this study is to evaluate safety and tolerability of pridopidine in patients with HD.Secondary Objectives: The secondary objectives of the study are to assess the effects of long-term, open-label dosing…
ID
Source
Brief title
Condition
- Neurological disorders congenital
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this study is to evaluate safety and tolerability of
pridopidine in patients with HD.
Safety endpoints:
Safety measures will include the following:
* adverse events (AEs)
* vital signs assessments
* concomitant medication usage
* physical examination findings
* clinical laboratory evaluations (hematology, clinical chemistry, and
urinalysis)
* Electrocardiography (ECG) findings
* Suicidality [using the Columbia-Suicide Severity Rating Scale (C-SSRS)] and
Problem Behaviors Assessment-Short form (PBA-s)
Tolerability endpoints:
* Proportion of subjects (%) who prematurely discontinued from the study
* Proportion of subjects (%) who prematurely discontinued from the study due to
AEs
Secondary outcome
The secondary objectives of the study are to assess the effects of long-term,
open-label dosing with pridopidine on motor symptom severity, overall patient
function, physical performance, and health-related quality of life.
Efficacy endpoints include the following
* Unified Huntington*s Disease Rating Scale * Total Motor Score (UHDRS-TMS)
* Modified Physical Performance Test (mPPT)
* Unified Huntington*s Disease Rating Scale - Total Functional Capacity
(UHDRS-TFC)
* Short Form 12 (SF-12) questionnaire (acute version)
* Problem Behaviors Assessment-Short form (PBA-s) (also part of safety
assessments)
* Quantitative motor (Q-motor) assessment
Background summary
Huntington*s disease (HD) is a fatal neurodegenerative disorder with an
autosomal dominant mode of inheritance. The disease is associated with a triad
of motor, behavioral, and cognitive symptoms. Motor disturbances are the
defining feature of the disease and, with chorea the most evident motor
symptom. Although useful for diagnosis, chorea is a poor marker of disease
severity. Rather, disability and disease severity best correlate with negative
motor features such as impairment in fine motor skills, bradykinesia, and gross
motor coordination skills, including speech difficulties, gait, and postural
dysfunction (Mahant et al 2003).
Dopamine is widely regarded as an important neurotransmitter modulating several
aspects of brain functions including motor function (Nieoullon and Coquerel,
2003). A disrupted dopaminergic signaling has been implicated in a number of
neurological and psychiatric conditions, (Zhan et al 2011; Dunlop and Nemeroff,
2007) and there is considerable clinical and preclinical evidence suggesting
that dopaminergic functions are also compromised in HD (Kung et al 2007; Huot
et al 2007).
A number of medications are prescribed to ameliorate the motor and emotional
problems associated with HD; however, the scientific evidence for the
usefulness of various drugs in HD is poor (Mestre et al 2009a; Mestre et al
2009b). Only 1 drug, tetrabenazine, which reduces dopamine availability and
transmission, is registered specifically for the treatment of patients with HD
for the management of chorea. No registered drugs are available for the
management of the multifaceted motor symptoms. As such, there is a significant
unmet medical need to develop medications to ameliorate symptoms of HD.
Pridopidine (TV 7820, formerly known as ACR16) is a drug under development from
a class of pharmaceutical agents, the dopidines, which are considered to have
dopaminergic stabilizing properties. Dopaminergic stabilizers are compounds
that can both enhance and counteract dopamine dependent functions in the
central nervous system (CNS), depending on the initial level of dopaminergic
activity. Dopaminergic stabilizers suppress the hyperactive behavior induced by
stimulants such as amphetamine. In contrast, at low levels of dopamine
function, the dopamine stabilizers enhance behavioral activity. The primary
effect of pridopidine on HD related motor symptoms is therefore expected to
occur via the dopamine transmissions modulating properties of pridopidine
(Ponten et al 2010).
Study objective
Primary Objective: The primary objective of this study is to evaluate safety
and tolerability of pridopidine in patients with HD.
Secondary Objectives: The secondary objectives of the study are to assess the
effects of long-term, open-label dosing with pridopidine on motor symptom
severity, overall patient function, physical performance, and health-related
quality of life.
Sub-study title: Objective quantification of chorea using a wearable
sensor-mobile application tool (Digital Health)
Date: 31 March 2016
Version: included in main Clinical Study Protocol Amendment 02
Objective: To test the hypothesis of using wearable sensor data to estimate
clinically relevant measures of HD in patients while on their
medication regimen. The aim is to develop algorithms to objectively quantify
chorea by analyzing the data from the wearable sensors.
Study design
This is an open-label, multi-center study to evaluate the safety, tolerability,
and efficacy of pridopidine 45 mg twice-daily (bid) in patients with HD.
It is planned to enroll up to 300 patients from the PRIDE-HD study or
transitioned from the Open-HART.
The following titration scheme will be followed:
* Week 1: Patients will receive 1 capsule of 22.5 mg pridopidine bid (22.5 mg
bid, total daily dose of 45 mg pridopidine).
* Week 2 to study completion: Patients will receive 1 capsule of 45 mg
pridopidine bid (total daily dose of 90 mg pridopidine).
Patients will be treated with study drug for 104 weeks. Safety will be assessed
after 4, 12, 26, 52, 78 and 104 weeks of treatment and at the End-of-study
(Eos) visit (week 106). Safety evaluation telephone calls will be performed at
weeks 18 and 38..
Doses of up to 112.5 mg bid are currently being investigated in the ongoing
PRIDE-HD study. Upon completion of PRIDE-HD and following analysis of safety,
tolerability, and efficacy data the dose administered in this study may be
adjusted to a maximum of 112.5mg bid after a titration period at the discretion
of the sponsor.
During the study, an independent Data and Safety Monitoring Board (DSMB) will
review accumulating safety data. The DSMB will meet as detailed in the charter.
In case of a significant emerging safety concern the DSMB will have the
authority to discontinue enrolled patients from study drug administration, and
stop enrollment of new patients. Thereafter, the DSMB will decide whether there
is a need for additional meetings, and, if needed, will determine when these
will take place.
Intervention
Pridopidine will be provided as a white hard gelatin capsule, size 2 containing
45 mg pridopidine and a white hard gelatin capsule, size 4 containing 22.5 mg
pridopidine or a light pink/white hard gelatin capsule, size 2 with black color
imprinting containing 45 mg pridopidine and a white hard gelatin capsule, size
4, with black imprinting containing 22.5 mg pridopidine.
The mode of administration is oral. Capsules will be swallowed whole with
water. One capsule should be taken in the morning and 1 in the afternoon, 7 to
10 hours after the morning dose. Study drug can be taken irrespective of meals.
Each medication pack will contain distinct labeled bottles in accordance with
the associated dose strength. The capsules will be provided in 2
configurations: Each bottle will contain 30 capsules (of 22.5 mg or 45 mg white
capsules; or 22.5 mg white imprinted capsules) or 60 capsules (of 45 mg light
pink/white imprinted capsules). Bottles will be used to accomplish the dosing
of possible treatment options including possible dose escalation and
de-escalation. Each bottle will be labeled with a unique pack number.
All medication supplied in connection with this study must be used only for
this study and no other purpose.
Study burden and risks
See section E9.
Moores Rd 41
Frazer PA 19355
US
Moores Rd 41
Frazer PA 19355
US
Listed location countries
Age
Inclusion criteria
a. Patient has completed the PRIDE-HD trial within the last 6 months, including the follow-up period, or transitioned from Open-HART.
For patients that have failed to complete PRIDE-HD or those who completed the PRIDE-HD study over 6 months prior to the screening visit, and meet all other inclusion criteria, eligibility should be discussed with the Open-PRIDE medical monitor and clinician on a case-by-case basis.;b. For patients that experienced a drug-related serious adverse event (SAE) or had a major compliance violation during PRIDE-HD or Open-HART, eligibility approval should be discussed with PRIDE-HD*s or Open-HART medical monitor and clinician. Patients that experienced an adverse event/ serious adverse event of suicidal ideation/ behavior will be excluded without discussion.;c. Able and willing to provide written informed consent prior to any study related procedure being performed. Patients with a legal guardian should be consented according to local requirements.;d. Females of child bearing potential have to be compliant in using adequate birth control throughout the duration of the study. Adequate birth control is defined as consistent practice of an effective and accepted method of contraception according to local regulations (hormone-based, intrauterine device, or double barrier contraception, i.e., condom and diaphragm). Abstinence is an acceptable method of contraception only when this is the preferred and usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male study participants have to be compliant in using adequate birth control with their partners (as defined above) throughout the duration of the study.;e. Body weight *50 kg. Patients that meet this criterion at screening but fail to meet it at a subsequent visit may be discontinued based on Investigator or Sponsor discretion. It is allowed to repeat the weight measurement once, if clinically appropriate. ;f. Willing and able to take oral medication and able to comply with the study specific procedures. ;g. 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.;h. The patient is in good health as determined by medical examination, ECG, serum chemistry, hematology, and urinalysis. ;i. The patient must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period, and willing to return to the clinic for evaluation as specified in this protocol.
Exclusion criteria
a. A prolonged Fridericia corrected QT (QTcF) interval (defined as a QTcF interval of >450 msec) at the screening visit. ECGs will be performed in triplicate during the screening visit, and the mean of the 3 QTcF measurements will be used to determine whether or not the patient is suitable for inclusion in the study.;b. Patients with clinically significant heart disease at the screening visit, defined as follows: (i) significant cardiac event (eg, myocardial infarction), angina pectoris or episode of congestive heart failure with symptoms >Grade 2 New York Heart Association classification within 12 weeks before randomization, or presence of cardiac disease that in the opinion of the investigator increased the risk of ventricular arrhythmia, (ii) history of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia) that was symptomatic or required treatment (Common Terminology Criteria for Adverse Events Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia, (iii) presence of left bundle branch block.;c. Patients with serum potassium, magnesium, and/or calcium levels outside of the central laboratory*s reference range at the screening visit and considered clinically significantly abnormal by the investigator. Repeat testing is allowed (up to a maximum of 3 tests) if required to establish whether values are within normal range or clinically significantly abnormal.;d. Patients receiving medications (within the last 6 weeks prior to baseline) other than pridopidine 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.;e. Patients receiving medications (within the last 6 weeks prior to baseline) other than pridopidine that are metabolized by Cytochrome P450 (CYP) 2D6 and have the potential of reducing seizure threshold.;f. Patients with a history of epilepsy or of seizures within the last 5 years.;g. Creatinine clearance <60 mL/min at screening, calculated using the Cockcroft Gault equation: (140 age) × mass (kg) × [0.85 if female] / 72 × serum creatinine (mg/ dL). It is allowed to repeat the test once, if clinically appropriate.;h. Any clinically significant, abnormal, screening laboratory result which in the opinion of the investigator, affects the patients* suitability for the study or puts the patient at risk if he/she enters the study.;i. Patients with adverse events of suicidal ideation or attempt at any time in the past or as measured by suicide ideation score of *3 on the C-SSRS, or PBA-s or patients who answer *Yes* on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) if the attempt or acts were performed at any time in the past, or patients who, in the opinion of the investigator, present a serious risk of suicide.;j. Females who are pregnant or breastfeeding.;k. Treatment with any investigational product other than pridopidine within 6 weeks of screening or patients planning to participate in another clinical study assessing any investigational product during the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-000904-24-NL |
| CCMO | NL53501.058.15 |