Study to Assess the Safety, Tolerability and Preliminary... | NCT05148884

NCT05148884

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

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Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Michael J. Fox Foundation for Parkinson's Research	OTHER
Parkinson's UK	OTHER
CTC Clinical Trial Consultants AB	INDUSTRY

Description Module

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).

Label	Type	Description	Intervention Names
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

Name	Type	Description	Arm Group Labels	Other Names
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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.

Secondary Outcomes

Measure	Description	Time Frame
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	The Unified Dyskinesia Rating Scale (UDysRS) is a rating instrument designed to assess the core features of dyskinesia in Parkinson´s Disease. The UDysRS consists of 4 parts: Part 1, historical disability with regard to the patient's perceptions of the impact on activities of daily living (ADL) of on-dyskinesia (11 items). Part 2, historical disability with regard to the patient's perceptions of the impact on ADL of off-dystonia (4 items). Part 3, objective impairment, which assesses severity of dyskinesia, affected body parts, and type of impairment (choreic vs. dystonic) (7items). Part 4, objective disability, based on an evaluation of Part 3 activities (4 items). Each item in the UDysRS was scored from 0 to 4, with a possible maximum total score sum of 104 where a higher score indicates a worse outcome. The UDysRS Parts 3 and 4 were repeated 3 times after each L-dopa challenge, and the timepoint with the worst outcome was used to calculate total score sum

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

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.

Exclusion Criteria:

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 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.
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.

Name	Affiliation	Role
Adrian Newman-Tancredi, PhD	Neurolixis SAS	Study Director
Per Svenningsson, Professor	ASC Torsplan	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Sahlgrenska Hospital		Gothenburg		413 45	Sweden
Skåne University Hospital

ID	Title	Description
FG000	NLX-112	Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received NLX-112 oral tablets, uptitrated over 4 weeks to a maximal daily dose of 2 mg for 14 days given as 1mg two times a day.
FG001	Placebo	Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received placebo.

ID	Title	Description
BG000	NLX-112	Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received NLX-112.
BG001	Placebo	Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received placebo.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

Full analysis set.

Posted

Count of Participants

Participants

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.

ID	Title	Description
OG000	NLX-112	Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received NLX-112.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	NLX-112	Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received NLX-112.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Mar 7, 2022	Oct 18, 2023	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Feb 20, 2023	Apr 10, 2024	SAP_002.pdf

ID	Term
D004409	Dyskinesia, Drug-Induced
D020820	Dyskinesias
D010300	Parkinson Disease

ID	Term
D009069	Movement Disorders
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D009461	Neurologic Manifestations

ID	Term
C473959	befiradol
C514026	PHA-568487E