Study to Assess the Safety, Tolerability and Preliminary Efficacy of NLX-112 Versus Placebo in L-dopa-induced Dyskinesia

NCT05148884 | Completed Phase 2 Results FDA Drug

• 1 other identifier: NLX-112-DYS-101
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 5

Brief Summary

This is a double-blind, randomized, placebo-controlled Phase 2a study evaluating the safety, tolerability, and preliminary efficacy of up to 2 mg/day (1 mg BID) of NLX-112 versus placebo in patients with moderate to severe L-DOPA induced dyskinesia (LID) in Parkinson's disease (PD). NLX-112 will be up-titrated to either 2 mg/day or to the highest well-tolerated dose less than 2 mg/day over 4 weeks, maintained at the well-tolerated dose for an additional 2 weeks, and then down-titrated over 2 weeks.

Conditions

Medication-Induced Dyskinesia

Keywords

Levodopa; Dyskinesia; Parkinson´s disease; L-dopa; NLX-112; Befiradol; LID

Outcome Measures

Primary Outcomes (6)

• Number of Participants With Adverse Events (AEs)

  Number of patients with Adverse events (AEs) divided into categories of severity/intensity (grade 1 to grade 5 following the common terminology criteria for AEs (CTCAE) v5.0) and assessed relationship to IMP (unlikely, possibly or probably related). AEs (including SAEs) were collected from the start of IMP administration until the end-of-study visit.

  AEs (including SAEs) were collected from the start of IMP administration until the end-of-study visit. Through study completion, an average of 10 weeks.

• Number of Participants With Any Clinically Significant Changes From Baseline in Electrocardiogram (ECG)

  Number of patients with clinically significant changes from baseline in Electrocardiogram (Rate, PR interval, QRS duration, QT, QTcB, and QTcF). Any abnormalities were specified and documented as either clinically significant or not clinically significant.

  Visit 1 (Screening), Visit 2 (Baseline, Day 1), Visit 4 (Clinic Safety Visit, Day 14), Visit 5 (Clinic Safety Visit, Day 21), Visit 6 (Clinic Efficacy Visit, Day 28), Visit 7 (Clinic Efficacy Visit, Day 42) and Visit 9 (Follow-up Clinic Visit, Day 70).

• Number of Patients With Any Clinically Significant Changes From Baseline in Vital Signs

  Number of patients with clinically significant changes from baseline in vital signs (Systolic blood pressure (mmHg), diastolic blood pressure (mmHg), Heart rate, respiratory rate, body temperature). Any vital signs outside the normal ranges at each site were judged as either not clinically significant or clinically significant by the clinician.

  Visit 1 (Screening), Visit 2 (Baseline, Day 1), Visit 4 (Clinic Safety Visit, Day 14), Visit 5 (Clinic Safety Visit, Day 21), Visit 6 (Clinic Efficacy Visit, Day 28), Visit 7 (Clinic Efficacy Visit, Day 42) and Visit 9 (Follow-up Clinic Visit, Day 70).

• Number of Patients With Any Clinically Significant Changes From Baseline in Safety Laboratory Parameters

  Number of patients with clinically significant changes from baseline in safety laboratory parameters. Any lab values outside the normal ranges at each site were judged as not clinically significant or clinically significant.

  Visit 1 (Screening), Visit 2 (Baseline, Day 1), Visit 4 (Clinic Safety Visit, Day 14), Visit 5 (Clinic Safety Visit, Day 21), Visit 6 (Clinic Efficacy Visit, Day 28), Visit 7 (Clinic Efficacy Visit, Day 42) and Visit 9 (Follow-up Clinic Visit, Day 70).

• Number of Patients With Clinically Significant Abnormalities in Physical Examinations

  Number of patients with clinically significant abnormalities in physical examination investigated by general appearance, head, ears, eyes, nose, throat, neck, skin, cardiovascular system, respiratory system, abdominal system, and nervous system. Any abnormalities were specified and documented as either clinically significant or not clinically significant.

  Visit 1 (Screening) and Visit 9 (Follow-up Clinic Visit, Day 70).

• Number of Patients With Suicidal Ideation/Behavior as Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)

  Number of patients with change from baseline in suicidal ideation/behavior as assessed by C-SSRS questionnaire with no total score summation. The scale contains 6 "yes" or "no" questions in which respondents were asked to indicate whether they have experienced several thoughts or feelings relating to suicide over the past 3 months and behavior over their lifetime using a baseline scale at visit 1 and any cahnges since last visit using a follow-up scale at subsequent visits. Each question addresses a different component of the respondent's suicide ideation severity and behavior. Q1: wish to be dead, Q2: non-specific suicidal thoughts, Q3-5: more specific suicidal thoughts and intent to act, Q6: suicidal behavior over the respondent's lifetime and past 3 months or since last visit for visits after the visit 1.

  The baseline scale was used at screening (Visit 1) and the follow-up scale at all subsequent visits (Visit 2, 4-7, 9)

Secondary Outcomes (8)

• Change From Baseline at the Final Efficacy Clinic Visit (Day 42), After a 150% L-dopa Dose Challenge, in the Unified Dyskinesia Rating Scale (UDysRS) Total Score - Change From Baseline

  At baseline (Day 1, Visit 2), and Day 42 (Visits 7)

• Change From Baseline in UDysRS Total Score at Day 28, After a 150% L-DOPA Dose Challenge - Change From Baseline

  At baseline (Day 1, Visit 2) and Day 28 (Visits 6)

• Change From Baseline in Total Objective Score (Parts 3, 4) of the UDysRS at Day 28 and Day 42, After a 150% L-DOPA Dose Challenge - Change From Baseline

  At baseline (Day 1, Visit 2), Day 28 and Day 42 (Visits 6 and 7)

• Change From Baseline in ON Time Without Troublesome Dyskinesia (ON Without Dyskinesia Plus ON With Non-troublesome Dyskinesia) Based on a PD Home Dyskinesia Diary - Change From Baseline

  Baseline - prior to Day 1 (Visit 2), Titration - prior to Day 28 (Visit 6), and Steady state prior to Day 42 (Visit 7).

• Change From Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) Scores (Part III, Motor Examination) - Change From Baseline

  At baseline (Day 1, Visit 2), Day 28 (Visit 6), Day 42 (Visit 7) and Day 70 (Visit 9).

Study Arms (2)

NLX-112

EXPERIMENTAL

Patients will self-administer NLX-112 2 times each day, once in the morning and once in the evening. Up-titration over 4 weeks, maximal dose of 2 mg/day during 2 weeks, down-titration over 2 weeks.

Drug: NLX-112

Placebo

PLACEBO COMPARATOR

Patients will self-administer placebo 2 times each day, once in the morning and once in the evening. Up-titration of number of tablets over 4 weeks, number of tablets equivalent to maximal dose of 2 mg/day NLX-112 during 2 weeks, down-titration over 2 weeks.

Drug: Placebo

Interventions

NLX-112 DRUG

NLX-112 will be supplied as tablets containing 0.25 mg NLX-112. NLX-112 is a structurally novel centrally acting, high-efficacy selective 5-HT1A receptor agonist with nanomolar affinity for 5-HT1A receptors. Proposed as a treatment for L-DOPA-induced-dyskinesia in Parkinson's disease.

Also known as: F13640, befiradol, 4-piperidinemethanamine, 1-(3-chloro-4-fluorobenzoyl)-4-fluoro-N-[(5-methyl-2-pyridinyl)-methyl], (2E)-2-butenedioate

NLX-112

Placebo DRUG

Placebo will be matching tablets (identical weight, shape and color) without NLX-112.

Placebo

Eligibility Criteria

• Age: 30 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient is 30 - 85 years old (inclusive) with a diagnosis of idiopathic PD according to the UK Parkinson's Disease Society Brain Bank Clinical Diagnosis criteria.
• PD patient is stably and optimally treated with L-DOPA; other anti-PD treatments are allowed if used for at least 4 weeks of previous continuous treatment.
• Patient agrees to be challenged with 150% of their normal L-DOPA dose (maximum L-DOPA dose 250 mg) 30 minutes prior to efficacy assessments at baseline (Visit 2) and at the 2 efficacy clinic visits (Visits 6 and 7).
• PD patient exhibits troublesome peak-dose LID, confirmed by a score of at least 1 on part IV, item 33 (disability) of the UPDRS at screening (Visit 1) and at Day 1 (baseline, Visit 2).
• At least 90 minutes in total for each 24-hour period during 2 days are indicated as "ON with troublesome dyskinesia" (according to the PD Home Dyskinesia Diary) prior to Day 1 (baseline, Visit 2).
• Patient (and/or caregiver) demonstrates ability to accurately complete the PD Home Dyskinesia Diary entries during the screening visit.
• Patient can read well enough to understand the informed consent document and other subject materials.
• Female patients of child-bearing potential must have a negative urine pregnancy test at screening (Visit 1) and on Day 1 (Visit 2), must agree to avoid pregnancy during the study, and must practice abstinence (only allowed when this is the preferred and usual lifestyle of the subject) or must agree to use a highly effective method of contraception with a failure rate of \< 1% to prevent pregnancy (combined \[oestrogen and progestogen containing\] hormonal contraception associated with inhibition of ovulation \[oral, intravaginal, transdermal\], progestogen-only hormonal contraception associated with inhibition of ovulation \[oral, injectable, implantable\], intrauterine device \[IUD\] or intrauterine hormone-releasing system \[IUS\]) starting from 4 weeks prior to administration of the study drug and continuing during the course of the study until 4 weeks after last after IMP administration. Female subjects must agree to refrain from donating eggs from the date of dosing until 3 months after dosing with the IMP. Their male partner must agree to use a condom during the same time frame if he has not undergone vasectomy.
• Females of non-childbearing potential are defined as pre-menopausal females who are sterilised (tubal ligation or permanent bilateral occlusion of fallopian tubes); or females who have undergone hysterectomy or bilateral oophorectomy; or post-menopausal defined as 12 months of amenorrhea (in questionable cases a blood sample with detection of follicle stimulating hormone \[FSH\] 25-140 IE/L is confirmatory).
• Male patients must be either vasectomised, consent to use condom or practice sexual abstinence to prevent pregnancy and drug exposure of a partner and refrain from donating sperm from the date of dosing until 3 months after dosing with the IMP. Their female partner of child-bearing potential must use highly effective contraceptive methods with a failure rate of \< 1% to prevent pregnancy (see above) during the same period.

You may not qualify if:

• Patient has severe PD with a Hoehn and Yahr stage = 5.
• Patient has unstable medical status, prior brain surgery against tumors or hemorrhage (excluding deep brain stimulation \[DBS\], i.e., DBS patients will be allowed to be enrolled) or is scheduled to receive surgery during the trial period.
• Patient has dementia (MMSE \<20).
• Patient has clinically significant renal or liver disorder.
• Patient currently exhibits generalized obsessive-compulsive disorder, panic disorder, bipolar disorder, post-traumatic stress syndrome (PTSD), clinically significant parasomnias or any other psychotic disorder as established by structured clinical interview for DSM disorders (SCID). Visual hallucinations are allowed.
• Any suicidal actions in the past 2 years (per investigator judgement i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior).
• Any suicidal ideation of type 4 or 5 in the C-SSRS in the past 3 months (i.e. active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent).
• Patient has taken an anti-convulsant, an anti-psychotic (except quetiapine), pindolol, tertatolol or buspirone within 4 weeks of baseline (Day 1, Visit 2).
• Patient has taken any medication, within 4 weeks of baseline (Day 1, Visit 2) that inhibits or up-regulates CYP4503A4.
• Patient is concurrently participating in another investigational drug trial or has participated in another investigational drug trial within the past 3 months.
• Patient is at high risk of non-compliance in the Investigator's opinion.

Sponsors & Collaborators

• Neurolixis SAS: lead
• Michael J. Fox Foundation for Parkinson's Research: collaborator
• Parkinson's UK: collaborator
• CTC Clinical Trial Consultants AB: collaborator

Study Sites (5)

Sahlgrenska Hospital

Gothenburg, 413 45, Sweden

Location

Skåne University Hospital

Lund, 221 85, Sweden

Location

ASC Torsplan

Stockholm, 113 65, Sweden

Location

Karolinska University Hospital, Solna

Stockholm, 171 76, Sweden

Location

CTC Clinical Trial Consultants AB (CTC)

Uppsala, 752 37, Sweden

Location

MeSH Terms

Conditions

Dyskinesia, Drug-Induced; Dyskinesias; Parkinson Disease

Interventions

befiradol; PHA-568487E

Condition Hierarchy (Ancestors)

Movement Disorders; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurotoxicity Syndromes; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Poisoning; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Synucleinopathies; Neurodegenerative Diseases

Results Point of Contact

• Title: Adrian Newman-Tancredi, PhD, DSc, CEO
• Organization: Neurolixis

contact@neurolixis.com

(+33) 605 14 09 64

Study Officials

• Adrian Newman-Tancredi, PhD

  Neurolixis SAS

  STUDY DIRECTOR

• Per Svenningsson, Professor

  ASC Torsplan

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Double-blind, randomized, placebo-controlled Phase 2a study

Study Record Dates

• First Submitted: October 7, 2021
• First Posted: December 8, 2021
• Study Start: November 9, 2021
• Primary Completion: January 18, 2023
• Study Completion: January 18, 2023
• Last Updated: April 23, 2024
• Results First Posted: April 23, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

SE (5)