The purpose of this Phase 3 study is to further evaluate the effect of pridopidine 45*mg BID on functional capacity, as well as motor and behavioral features of HD in early-stage participants (TFC*713).
ID
Source
Brief title
Condition
- Neurological disorders congenital
- Congenital and peripartum neurological conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective Main study:
To assess the effect of pridopidine on functional capacity in participants with
stage 1-2 HD
Primary endpoint Main Study:
Change from baseline to Week*65 in the UHDRS-TFC score.
Primary objective Main study and OLE:
To evaluate the long-term treatment effect of pridopidine in participants with
HD who previously completed the Main study
Primary endpoint OLE:
Change in
-UHDRS-TFC
-UHDRS-TMS
- Quantitative motor (Q-Motor):
o finger tapping (Digitomotography)
o pronation/supination (Dysdiadochomotography)
Secondary outcome
Secundary objectives Main Study:
Multiplicity Adjusted Secondary Endpoints:
Key Secondary (secondary endpoints are listed by order of hierarchy)
1. To assess the effect of pridopidine on a composite measure of disease
progression in participants with HD
Secondary (secondary endpoints are listed by order of hierarchy)
2. To evaluate the effect of pridopidine on functional capacity, motor
function, and other measures of efficacy over time in participants with HD
Non-multiplicity Adjusted Secondary Endpoints:
3. To evaluate the effects of pridopidine in participants with HD
Safety and Tolerability
4. To evaluate the safety and tolerability of pridopidine in participants with
HD
Exploratory
To evaluate the exploratory efficacy effects of pridopidine in participants
with HD
Biomarker
To evaluate changes in disease biomarker plasma neurofilament light chain (NfL)
following treatment with pridopidine in participants with HD
PK
To evaluate the pharmacokinetics (PK) of pridopidine and its main metabolite in
participants with HD
Secundary endpoints Main Study:
Multiplicity Adjusted Secondary Endpoints:
1:
1. Change from Baseline to Week 65 in composite UHDRS (cUHDRS) total score
2:
2. Proportion of participants with no worsening (change >= 0 point) from
baseline to Week 65 in UHDRS-TFC
3. Change from baseline to Week 52 in UHDRS-TFC score
4. Change from baseline to Week 78 in UHDRS-TFC score
5. Change from baseline to Week*65 in Quantitative motor (Q-Motor) finger
tapping inter-onset interval (IOI) mean (Digitomotography)
6. Change from baseline to Week*65 in the UHDRS Total Motor Score (TMS)
7. Change from Baseline to Week 65 in Symbol Digit Modalities Test (SDMT)
8. Change from baseline to Week 52 in UHDRS-TMS score
9. Proportion of participants with no worsening from baseline in Clinical
Global Impression of Change (CGI-C) at Week 65
Non-multiplicity Adjusted Secondary Endpoints:
3:
• Change from Baseline to Week 26 and 39 in the UHDRS-TFC
• Proportion of participants with improvement or no worsening in UHDRS-TFC
(change from Baseline >= 0) at Weeks 26, 39, 52 and 78
• Change from Baseline to Weeks 26, 39, 52 and 78 in cUHDRS
• Proportion of participants with change from Baseline >= -1 in cUHDRS at Weeks
26, 39, 52, 65 and 78
• Change from Baseline to Week 26, 39 and 78 in the UHDRS-TMS score
• Proportion of participants with improvement or no worsening in UHDRS-TMS
(change from Baseline <= 0) at Weeks 26, 39, 52, 65 and 78
• Change from Baseline to Weeks 26, 39, 52, 65 and 78 in:
* UHDRS-TFC Scale sub-items (capacity to undertake domestic chores, activities
of daily living, capacity to manage finances, care level and occupation)
* UHDRS-TMS sub-scores for:
o Gait and balance score (defined as the sum of UHDRS-TMS domains gait, tandem
walking, and retropulsion pull test)
o Eye movement
o Dystonia
• Change from Baseline to Weeks 26, 39, 52 and 78 in SDMT
• Change from Baseline to Weeks 26, 39, 52, 65 and 78 in Stroop Word Reading
(SWR)
• Change from Baseline to Weeks 26, 39, 52 and 78 in Q-Motor finger tapping
speed IOI mean (Digitomotography)
• Proportion of participants with improvement or no worsening (change from
Baseline <= 0 msec) in Q-Motor finger tapping IOI mean (Digitomotography) at
Weeks 26, 39, 52, 65 and 78
• Change from Baseline to Weeks 26, 39, 52, 65 and 78 in Q-motor finger tapping
IOI SD, and pronation/supination IOI mean and SD (Dysdiadochomotography)
• Responder analyses on CGI-C using different thresholds at Weeks 26, 39, 52,
65 and 78
Safety and Tolerability
4:
• Incidence (count and rate) of adverse events (AEs) and serious AEs (SAEs)
overall, by severity, by relationship to study drug, and those that led to
discontinuation of study drug and/or withdrawal from the study
• Incidence and shifts of clinically significant abnormalities in
electrocardiogram (ECG), laboratory tests, vital signs and abnormalities in
physical and neurological exam
• Analysis of Columbia- Suicide Severity Rating Scale (C-SSRS) throughout the
study
• Tolerability:
- The number (%) of participants who complete the study drug treatment period
- The number (%) of participants who fail to complete the treatment period
study drug due to AEs
- The number (%) of participants who fail to complete the study drug treatment
period due to meeting the Fridericia-corrected QT interval (QTcF) change, CrCl
or Psychiatric stopping rules
Exploratory
• Change from Baseline to Weeks 26, 52, 65 and 78 in:
* Problem Behaviors Assessment - Short Form (PBA-s) total score
o PBA-s sub-score for apathy
* Measurement of quality of life (QoL) using HDQoL
Biomarker
• Change from Baseline to Weeks 26, 52, 65 and 78 in plasma NfL protein
• Relationship between Baseline NfL and changes from Baseline in select
efficacy endpoints
• Relationship between changes from Baseline to Weeks 26, 52, 65 and 78 in NfL
and selected efficacy endpoints
• Proportion of participants with different thresholds for change from Baseline
in plasma NFL levels to Weeks 26, 52, 65 and 78
PK
• Plasma concentrations of pridopidine and its main metabolite at Weeks 26, 52,
65, and 78 and at last participants* visit
• Relationship between plasma concentration of pridopidine and clinical outcome
measures
Secundary Objectives OLE:
Efficay:
- To evaluate long-term safety and tolerability of pridopidine in participants
with HD who previously completed the Main Study
Safety and Tolerability:
- To evaluate exploratory long-term efficacy effects of pridopidine in
participants with HD who previously completed the Main Study
Secundary Endpoints OLE:
Efficay:
• Proportion of participants with change from Baseline (Main Study) to each OLE
visit in UHDRS-TFC >= -1
• Proportion of participants with change from Baseline (Main Study) to each OLE
visit in UHDRS-TFC >= 0
• Change from Baseline (Main Study) to OLE visits in:
* UHDRS-TFC
* cUHDRS
* UHDRS-TMS
* Quantitative motor (Q-Motor):
o finger tapping (Digitomotography)
o pronation/supination (Dysdiadochomotography)
* SDMT
* SWR
• Change from Baseline (Main Study) to OLE visits in:
* CGI-C
* PBA-s
* HDQoL
Safety:
• Incidence (count and rate) of AEs and SAEs overall, by severity, by
relationship to study drug, and those that led to discontinuation of study drug
and/or withdrawal from the study
• Incidence and shifts of clinically significant abnormalities in ECG (refer to
Section 7.1.17.1.1), laboratory tests and vital signs
• Analysis of C-SSRS throughout the study
Tolerability:
• The number (%) of participants who complete the OLE treatment period
• he number (%) of participants who fail to complete the OLE treatment period
due to AEs
Exploratory:
Change from Baseline (defines as start of treatment with pridopidine) in:
* CGI-C
* PBA-s (this is also part of safety assessments)
* HDQoL
* SDMT
* SWR
Biomarker:
• Change from Baseline (Main Study) in NfL protein level to each OLE visit
• Relationship between changes from baseline in NfL and selected efficacy
endpoints in the OLE period
Background summary
Huntington Disease (HD) is an autosomal dominant, progressive fatal
neurodegenerative disorder characterized by motor, cognitive, and behavioral
abnormalities. No therapy has yet proven able to modify the progressive and
inexorable functional decline of the disease. A therapy that maintains
functional capacity and prevents or delays the development of disability
represents a critically unmet clinical need.
Pridopidine demonstrates neuroprotective properties (in-vitro / in-vivo). In HD
cortico-striatal cultures, pridopidine increases brain-derived neurotrophic
factor (BDNF) transport, enhances synaptic activity, and promotes
phosphorylation of the prosurvival protein extracellular-signal-regulated
kinase (ERK). Furthermore, pridopidine restores mitochondrial function, spine
density, and aberrant calcium signaling, all known features of HD.
In a recently completed Phase 2 clinical study of pridopidine in HD (PRIDE-HD),
45 mg BID was associated with maintenance of functional capacity from baseline
compared to placebo at 52 weeks.
Study objective
The purpose of this Phase 3 study is to further evaluate the effect of
pridopidine 45*mg BID on functional capacity, as well as motor and behavioral
features of HD in early-stage participants (TFC*713).
Study design
This is a randomized, double-blind, placebo-controlled study to evaluate the
efficacy and safety of pridopidine administered orally at a dose of 45 mg BID
in participants with early HD defined as stages 1 and 2.
The study will consist of a screening period, a double-blind treatment period
(Main study) and an Open-label Eextension (OLE) as described below.
For each participant, the total duration of study participation in the Main
Study (Screening and Double- -blind period) will be up to 86 weeks.
Main Study:
Screening period: Up to 6 weeks
Double-Blind Treatment period: Up to 78 weeks as follows:
• On Day 1 (Baseline visit), eligible participants will be randomized in a 1:1
ratio to active (pridopidine 45 mg BID) or control (placebo) arm. Randomization
will be stratified by baseline HD stage (HD1 vs. HD2) and baseline Neuroleptic
use (Yes/No)
• 2 weeks titration period
• 63 weeks full-dose treatment
• Up to 13 weeks variable double-blind period (until the last randomized
participant completes 65 weeks of treatment = 2 weeks titration + 63 weeks full
dose)
Follow-up period: 2 weeks (only for participants not continuing to OLE)
OLE Open-Label Extension: Until12 months after the last participant completes
the double-blind treatment period. OLE duration may be extended pending
emerging data from the double-blind portion of the study.
Intervention
Pridopidine 45 mg BID or placebo BID
Study burden and risks
Burden:
Blood samples: 8 times during Main, 4 times during OLE.
Urine samples: 8 times during Main, 4 times during OLE.
Pregnancy tests urine: 8 times during Main, 4 times during OLE, plus1 time
blood test at SCR,
Physical examination:8 times during Main, 4 times during OLE.
Vital signs: 8 times during Main, 4 times during OLE.
12 lead ECG: 4 times during Main, 3 times during OLE.
Efficacy assessments (see par. 8.1 of the protocol): 10 times during Main, 3
times during OLE (incl. Q-motor).
Questionnaires and cognitive tests: 8 times during Main, 3 times during OLE.
C-SSRS scale at every visit, 24 times total.
Risks:
1) QT Prolongation: Known risk identified in preclinical and clinical studies.
Exposure response modeling based on dosing of pridopidine up to 112.5 mg BID
suggests a linear response of QTcF to increasing drug exposure. At 45 mg BID,
the dose evaluated in this trial, the estimated QTcF prolongation is 6.6 ms and
not considered clinically meaningful. Mitigation: patients at risk will be
excluded. Furthemore ECGs will be measured throughout the study.
2) Decreased creatinine renal clearance: Identified risk in clinical studies.
There have been no serious outcomes relating to the decrease, and
discontinuation of the pridopidine treatment results
in the return of creatinine to normal values. Mitigation:patients at risk will
be excluded. Creatinine values will be monitored throughout the study and
patients discontinued if needed.
Benefit:
Participants in the study may experience symptomatic improvement and, possibly,
the rate of disease progression may be reduced. However, there is no guarantee
that participation in the current study will help the participant; the
participant may receive a placebo treatment.
Risk - benefit analysis:
There are currently no disease-modifying drugs for the treatment of HD. The
results from completed studies with pridopidine suggest a potential benefit of
pridopidine to fulfill a critical unmet need in the treatment of patients with
HD, and support further clinical development.
Taking into account the measures taken to minimize risk to participants taking
part in this study, the potential risks identified in association with
pridopidine are justified by the anticipated benefits that may be afforded to
participants with HD.
Hamenofim St. 10
Herzliya 4672561
IL
Hamenofim St. 10
Herzliya 4672561
IL
Listed location countries
Age
Inclusion criteria
Main study:
1. Twenty-five years of age (inclusive) and older, at the time of signing the
informed consent.
2. Diagnosis of HD based on clinical features and the presence of >=36 CAG
repeats in the HTT, confirmed by historical laboratory quantified results or by
a diagnostic test at screening.
3. Diagnostic confidence level (DCL) of 4 (unequivocal motor signs, >= 99%
confidence) on the standardized motor exam UHDRS-TMS.
4. Adult-onset HD with onset of signs and symptoms >=18 years of age.
5. Stage 1 or Stage 2 HD, defined as a UHDRS-TFC score of >=7, at screening.
6. UHDRS-Independence scale (IS) score <=90% at screening.
7. UHDRS-TMS >=20 at the Screening visit.
8. Must meet all criteria required to move forward with the Randomization
Authorization Flow (RAF) and be considered eligible by the RAF Reviewer.
9. Male or female.
10. Female participants of childbearing potential must have a negative β-human
chorionic gonadotropin (β-HCG) test at screening and baseline, be sterile, or
be postmenopausal.
11. Female participants of childbearing potential whose male partners are
potentially fertile (i.e., no vasectomy) must use highly effective birth
control methods stable for at least 3 months prior to screening, for the
duration of the study and for 30 days after discontinuation of the study drug.
12. Male participants must be sterile, or if they are potentially
fertile/reproductively competent (not surgically [e.g., vasectomy] or
congenitally sterile) and their female partners are of childbearing potential,
they must use, together with their female partners, effective birth control
methods for the duration of the study and for 90 days after study drug
discontinuation.
13. For participants taking allowed antipsychotic, antidepressant, or other
psychotropic medication, the dosing of medication as listed in Section 10.6,
must be stable for at least 4 weeks before the Baseline visit and throughout
the study (unless clinically necessary to change).
14. For participants taking allowed concomitant medications, dosing of
medications must be stable for at least 4 weeks prior to the Baseline visit
(note: Amiodarone is not allowed within 6 weeks of Baseline Visit)
15. Capable of providing signed informed consent.
Inclusion criteria - Open-label Extension
1. Completed the EoS visit of the Main study on treatment without important
protocol
deviations impacting efficacy and safety assessments.
2. Capable of providing signed informed consent for the OLE.
3. Must meet all criteria required to move forward with the OLE assessments.
Exclusion criteria
Exclusion criteria Main study:
1. Prolonged QTcF interval (defined as a QTcF interval of >450 ms for male
and >470 ms for female) at screening.
2. Clinically significant heart disease within 12 weeks before randomization,
defined as follows:
a. Participants with clinically significant heart disease, a clinically
significant history of arrhythmia, symptomatic or uncontrolled atrial
fibrillation despite treatment, or confirmed ventricular tachycardia, or
presence of left bundle branch block.
b. Participants with a known history of congenital long QT syndrome or a first
degree relative with this condition.
c. Clinically significant bradycardia, sick sinus syndrome, complete
atrioventricular block, congestive heart failure, polymorphic ventricular
tachycardia, clinically relevant hypocalcemia, hypokalemia or hypomagnesemia.
3. History of epilepsy or seizures within the last 5 years.
4. Serious medical illness (includes, but not limited to, uncontrolled
hypertension; respiratory disease, including severe forms of asthma; severe
hepatic disease (confirmed Hepatitis B virus [HBV], Hepatitis C virus [HCV];,
confirmed human immunodeficiency virus [HIV]); renal disease; acquired immune
deficiency syndrome; and unstable psychiatric or other neurologic disorders)
and metastatic cancer. For serious kidney and and liver liver illnesses see
also exclusion criterion 12 (laboratory test abnormalities)
5. Known intracranial neoplasms, vascular malformations, history of
cerebrovascular accident, or intracranial hemorrhage.
6. Female participants who are pregnant, planning to become pregnant or
breastfeeding
7. Medications that prolong QT interval, taken within 4 weeks of the Baseline
visit (note, Amiodarone is not allowed within 6 weeks of the Baseline visit) or
at any timepoint during the study, including non-allowed antipsychotic
medications, tricyclic antidepressants, and/or Class I antiarrhythmics
8. Use of pridopidine within 12 months before the Baseline visit.
9. Treatment with any investigational product within 6 weeks or 5 half-lives
(whichever is longer) before the Screening visit or a plan to participate in
another clinical study that assesses any investigational product during the
study.
10. Gene therapy at any time
11. Prior particpation in studies with tominersen at any time
12. Laboratory values that fall outside of the central laboratory*s reference
range at screening and are considered clinically significantly abnormal by the
Investigator, and affect the participant's suitability to participate in the
study or put the participant at risk if he/she enters the study in the
Investigator*s opinion.
13. Have any of the following laboratory test abnormalities at screening
a. CrCl <30 mL/min at screening, calculated using the CockcroftGault
equation: (140-age) × mass (kg) × [0.85 if female] / 72 × serum creatinine
(mg/dL).
b. Aspartate aminotransferase (AST) >=2.5 × upper limit of normal (ULN)
c. Alanine aminotransferase (ALT) >=2.5 × ULN
d. Gamma- glutamyl transferase (GGT) >=3.0 × ULN
e. Total bilirubin >1,5 mg/dL, except participants with unconjugated
hyperbilirubinemia without other liver function derangements or other
explanations for the elevated bilirubin
(consistent with diagnosis of Gilbert*ssyndrome)
14. Alcohol and/or substance use disorder within the 6 months prior to
screening, as defined by the Diagnostic and Statistical Manual-Fifth Edition
(DSM-5) Text Revision criteria for substance use.
15. Active suicidal ideation as measured by a most severe suicide ideation
score of 4 (Active Suicidal Ideation with Some Intent to Act, without Specific
Plan) or 5 (Active Suicidal Ideation with Specific Plan and Intent) on the
C-SSRS if the ideation occurred within 1 year of Screening, or participants who
answered *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 within 1 year of screening, or participants who,
in the opinion of the investigator, present a serious risk of suicide.
16. Known allergy to any ingredient of the study drug (pridopidine, silicified
microcrystalline cellulose, or magnesium stearate)
17. Vulnerable participant (e.g., people kept in detention), or participant
unfit to participate in a clinical study due to living circumstances, e.g.
without sufficient family or social support, stable residence, sustainable
financial and general healthcare and resources.
18. An employee or a family member of an employee of the Sponsor, Investigator
or investigator study site, or otherwise dependent on the Sponsor, the
Investigator or the investigator study site.
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 | EUCTR2020-002822-10-NL |
| ClinicalTrials.gov | NCT04556656 |
| CCMO | NL74907.068.20 |