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

NCT ID: NCT05148884

Last Updated: 2024-04-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 27 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-11-09
• Study Completion Date: 2023-01-18

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.

Detailed Description

This is a two-arm, double-blind, randomized, placebo-controlled Phase 2a study evaluating the safety, tolerability, and preliminary efficacy of up to 2 mg/day 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 (1 mg BID) 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.

Patients will report to the study clinic for a screening visit (Visit 1), followed by a baseline visit on Day 1 (Visit 2) where patients will be randomized and begin treatment. Two remote safety visits over telephone (Days 7 and 49 [Visit 3 and Visit 8]) will be conducted. Once treatment has commenced, there will be 2 in-person safety visits to the clinic (Days 14 and 21 [Visit 4 and Visit 5]), 2 in-person efficacy visits to the clinic (Days 28 and 42 [Visit 6 and Visit 7]) and one follow-up in person final safety visit (Day 70 [Visit 9]). In total, patients will report to the clinic for 7 in-person visits. Patients entering the study will be randomized in a 2:1 ratio (16:8 patients) to receive either NLX 112 or placebo.

At Visits 2, 6 and 7, efficacy assessments will start 30 minutes after the patient has taken 150% of his or her regular L-DOPA dose, when the patient is ON and experiencing typical dyskinesia.

A PD Home Dyskinesia Diary (electronic) will be completed by the patients and/or caregiver with concordance in ON time with dyskinesia between study staff and patient. Two consecutive 24-hour diaries will be completed prior to randomization (baseline, Visit 2) and prior to the clinic visits on Days 28 and 42 (Visits 6 and 7).

A wearable dyskinesia assessment device will be used to monitor dyskinesias during a 2-day period prior to the baseline visit (Day 1, Visit 2) and a 2-day period prior to the clinic visits on Days 28 and 42 (Visits 6 and 7, respectively).

Blood will be collected for possible NLX-112 plasma concentration measurements on Days 14, 21, 28, 42 and 70 (Visits 4, 5, 6, 7 and 9).

Conditions

Medication-Induced Dyskinesia

Keywords

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

NLX-112

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.

Group Type: EXPERIMENTAL

NLX-112

Intervention Type: 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.

Placebo

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Interventions

NLX-112

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.

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Other Intervention Names

F13640; befiradol; 4-piperidinemethanamine; 1-(3-chloro-4-fluorobenzoyl)-4-fluoro-N-[(5-methyl-2-pyridinyl)-methyl]; (2E)-2-butenedioate

Eligibility Criteria

Inclusion Criteria

1. 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.

2. 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.

3. 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).

4. 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).

5. 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).

6. Patient (and/or caregiver) demonstrates ability to accurately complete the PD Home Dyskinesia Diary entries during the screening visit.

7. Patient can read well enough to understand the informed consent document and other subject materials.

8. 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.

Exclusion Criteria

1. Patient has severe PD with a Hoehn and Yahr stage = 5.

2. 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.

3. Patient has orthostatic hypotension: a decrease in systolic blood pressure (at least 20 mm Hg) or diastolic blood pressure (at least 10 mm Hg) within 3 minutes of the patient standing up, compared to pressures obtained while in a sitting position for at least 5 minutes. At screening and baseline visits (Visit 1 and Visit 2), vital signs to assess orthostatic hypotension will be conducted in triplicate, 15-20 minutes apart, with the average of the 3 assessments used for exclusion.

4. Patient has dementia (MMSE <20).

5. Patient has clinically significant renal or liver disorder.

6. 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.

7. Any suicidal actions in the past 2 years (per investigator judgement i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior).

8. 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).

9. Patient has taken an anti-convulsant, an anti-psychotic (except quetiapine), pindolol, tertatolol or buspirone within 4 weeks of baseline (Day 1, Visit 2).

10. Patient has taken any medication, within 4 weeks of baseline (Day 1, Visit 2) that inhibits or up-regulates CYP4503A4.

11. Patient is concurrently participating in another investigational drug trial or has participated in another investigational drug trial within the past 3 months.

12. Patient is at high risk of non-compliance in the Investigator's opinion.

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Michael J. Fox Foundation for Parkinson's Research

OTHER

Sponsor Role: collaborator

Parkinson's UK

OTHER

Sponsor Role: collaborator

CTC Clinical Trial Consultants AB

INDUSTRY

Sponsor Role: collaborator

Neurolixis SAS

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Adrian Newman-Tancredi, PhD

Role: STUDY_DIRECTOR

Neurolixis SAS

Per Svenningsson, Professor

Role: PRINCIPAL_INVESTIGATOR

ASC Torsplan

Locations

Sahlgrenska Hospital

Gothenburg, , Sweden

Skåne University Hospital

Lund, , Sweden

ASC Torsplan

Stockholm, , Sweden

Karolinska University Hospital, Solna

Stockholm, , Sweden

CTC Clinical Trial Consultants AB (CTC)

Uppsala, , Sweden

Countries

Sweden

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

NLX-112-DYS-101

Identifier Type: -

Identifier Source: org_study_id