An open-label sleep laboratory study of efficacy and safety of piromelatine in patients with idiopathic Rapid Eye Movement Behavior Disorder (iRBD).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Neurim Pharmaceuticals (1991) Ltd.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

5 Mar 2024 → 12 Aug 2025

Decision date (initial)

2024-01-29

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Neurim Pharmaceuticals (1991) Ltd.

External identifiers

EU CT number

2023-506713-22-00

WHO UTN

U1111-1296-9291

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Assess the efficacy and safety of short-term (6 weeks) treatment with piromelatine as compared to baseline measures.

Secondary objectives 3

1. If found efficacious in the short term, the following parameters will be assessed: 1. Symptomatic efficacy and safety of longterm (52 weeks) treatment with piromelatine as compared to baseline measures
2. 2. [CCI] of progression or [CCI] into Parkinsonian syndrome compared to baseline
3. 3. Evaluate the safety and tolerability of piromelatine

Conditions and MedDRA coding

idiopathic (isolated) Rapid Eye Movement Behavior Disorder

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 1. The participant must understand the study procedures and agree to participate by providing written informed consent.
2. 2. The participant must be willing and able to comply with all trial procedures and restrictions.
3. 3. Male or female adult participants aged 50 to 70 years diagnosed with iRBD based on the criteria established by the ICSD-3 and confirmed by vPSG.
4. 4. PSG demonstrates that the participant does not have other comorbid sleep disorders or clinically significant nocturnal hypoxemia (O2 saturation ≤90% for ≥5% of total sleep time) and that their apnea-hypopnea index (AHI) is ≤15.
5. 5. Permitted medications (those that are not prohibited medications) must be on stable dose for 3 months.
6. 6. Body mass index (BMI) between 18 and 32 kg/m2 , inclusive.
7. 7. Normal physical examination findings, vital signs, clinical laboratory test results, and electrocardiogram (ECG) results or abnormal results that are judged not clinically significant by the Investigator.

Exclusion criteria 27

1. 1. Any contraindication to perform [CCI], such as participants who are treated with psychotropic drugs, anti-Parkinson’s Disease(PD) drugs and drugs that may interfere with [CCI] will be excluded.
2. 2. Participants with narcolepsy type 1 (narcolepsy with cataplexy), and the pathogenesis (orexin deficiency), hypersomnia, excessive daytime sleepiness, has moderate or severe obstructive sleep apnea (OSA, AHI >15) or moderate to severe restless leg syndrome (RLS, IRLS scale >10) diagnosed by previous PSG or interview at Screening.
3. 3. Selective serotonin reuptake inhibitors and benzodiazepine hypnotics are prohibited in the study and up to 3 months before Screening as these medications may worsen or provoke iRBD symptoms.
4. 4. Use of Cyp3A inhibitors, melatonin, and beta blockers, are prohibited in the study and up to 2 weeks before Screening.
5. 5. Participants who are treated with psychotropic drugs, anti-PD medications and medications that may interfere with [CCI] will be excluded.
6. 6. Diagnosis of alpha-synuclein pathology, such as PD, multiple system atrophy, and dementia with Lewy bodies suspected or confirmed by neurological examination, diagnosed according to current international criteria.
7. 7. Diagnosis of non-synuclein neurodegenerative disorders as progressive supranuclear palsy, frontotemporal dementia, amyotrophic lateral sclerosis, AD, spinal cerebellar ataxia type 3, Huntington disease, and myotonic dystrophy type 2.
8. 8. Cognitive impairment as determined by the Montreal Cognitive Assessment (MoCA) score of ≤23.
9. 9. History of seizure disorder, stroke, significant head injury, tumor of the central nervous system, or any other condition that can cause structural lesions in the brainstem due to vascular, demyelinating, neoplastic, and traumatic etiologies.
10. 10. Has a usual bedtime later than 01:00 or an occupation requiring night-time shift work or variable shift work within the past 6 months or travel with significant jet lag within 14 days before baseline.
11. 11. Female patients who meet the following criteria: a. Pregnant, breastfeeding, and/or planning to become pregnant and/or breastfeed during the study; b. Is not at least 1 year postmenopausal or surgically sterile (tubal ligation, tubal occlusion, bilateral oophorectomy, or hysterectomy).
12. 12. Males who are fertile but refuse to practice double-barrier methods of contraception with female partners of childbearing potential, starting from the signing of the ICF until 30 days after the last dose of the trial medication.
13. 13. Any concurrent medical condition that, in the judgment of the Investigator, might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the patient’s well-being.
14. 14. Current or past history of schizophrenia, schizoaffective disorder or any other form of psychotic disorder, obsessive compulsive disorder, personality disorders, bipolar disorder, PTSD or any other significant disorder as assessed by the Investigator.
15. 15. Currently meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) for major depressive disorder and has required initiation of medication or hospitalization within the previous 90 days.
16. 16. Significant suicide risk as defined by (1) suicidal ideation as endorsed on items 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) within the past year, during Screening or at baseline, or during the study; (2) suicidal behaviors within the past year.
17. 17. Current (within the last year) alcohol or substance use disorder.
18. 18. Positive urine drug screen for benzodiazepines, opioids, and/or illicit drugs or drugs of abuse at Screening and/or baseline. Potential participants who test positive for opioids in urine drug testing need not be excluded if in the clinical opinion of the Investigator, this is due to the participant taking prior/concomitant medications containing opioids for a medical condition and not due to drug abuse.
19. 19. Any cardiovascular disease that is clinically significant, unstable, or decompensated. Additionally, patients with any of the following conditions are excluded from participation in the study: a. History of congenital QTc prolongation or presence of QTc prolongation (QTcF >450msec for men and QTcF >470 msec for women on Screening ECG); b. Second-degree (if Mobitz II) or third-degree atrioventricular block; c. History (≤1 year before Visit 1) of clinically manifest ischemic heart disease including myocardial infarction, stable or unstable angina, coronary arteriography, or cardiac stress testing/imaging with findings consistent with coronary occlusion or infarction; d. Heart rate on supine vital sign measurement of <50bpm or >120bpm or any heart rate that is clinically symptomatic; e. Premature ventricular contractions associated with clinical symptoms and/or any complex premature ventricular contractions; f. Atrial fibrillation or flutter that is symptomatic or associated with uncontrolled heart rate or hemodynamic instability, requires anticoagulation, or is of recent (<12 months) or unknown onset; g. Systolic blood pressure >160 mmHg OR diastolic blood pressure >95 mmHg on 3 separate determinations 5 minutes apart, taken at same arm, after the participant feels comfortable and relaxed at the research facility; h. Clinically significant orthostatic hypotension.
20. 20. Gastric bypass or any condition that would be expected to affect drug absorption (gastric banding procedures are acceptable if not associated with absorption problems).
21. 21. Positive test for hepatitis B surface antigen and/or hepatitis B core antibody immunoglobulin M at Screening.
22. 22. Positive hepatitis C antibody at Screening (Visit 1), with the exception of patients for whom the reflex HCV RNA test is negative.
23. 23. The participant has abnormal laboratory values or clinical findings at the Screening Visit or during the evaluation of eligibility for the Long-term Extension Treatment (reviewed at Visit 4 using safety laboratory results from Visit 3) that are judged to be clinically significant including, but not limited to: a. Alanine aminotransferase and/or aspartate aminotransferase >3 × the upper limit of normal (ULN); b. Total bilirubin >3 × ULN; c. eGFR <50; d. Any other clinically significant abnormal laboratory result obtained at the Screening Visit or during the evaluation of eligibility for the Long-term Extension Treatment (reviewed at Visit 4 using safety laboratory results from Visit 3).
24. 24. Any other clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, renal or any other major concurrent illness that, in the opinion of the Investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if they take part in the study in the opinion of the Investigator, trial Physician or designee.
25. 25. Hypersensitivity to the trial medication or any of the excipients.
26. 26. Treatment with any investigational product within 30 days (or at least 5 half-lives, whichever is longer) before Visit 1.
27. 27. Unable or unlikely to comply with the study protocol or is unsuitable for any other reason, as judged by the Investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 9

1. iRBD severity assessed by vPSG performed according to the AASM recommendations, with the addition of electromyography of both FDS muscles in the upper limbs (optional according to the AASM recommendations) and scored by a composite measure of motor events, iRBD episodes, and vocalizations frequency and severity as recommended by the IRBDSG
2. RSWA quantified in the chin (phasic, tonic, and any muscle activity) and in the FDS (phasic muscle activity) on 3-second mini-epochs (manually identified) according to the [CCI], using a validated algorithm, with manual artifact correction after automatic analysis
3. [CCI]
4. Sleep hypnographic variables (SL, WASO, TST, SE, % of N1, N2, N3 and REM sleep) scored in accordance with the AASM
5. EEG power spectral analysis during REM/NREM sleep
6. PSQI score
7. ESS score
8. Relationship between response/no response and the presence of [CCI]. For that reason, blood samples of all enrolled patients will undergo [CCI].
9. Safety parameters (vital signs, physical examination, AEs, SAEs, laboratory assessments, and ECG)

Secondary endpoints 15

1. iRBD severity assessed by vPSG with the addition of electromyography of both FDS muscles in the upper limbs (optional according to the AASM recommendations)
2. RSWA quantified in the chin (phasic, tonic, and any muscle activity) and in the FDS (phasic muscle activity)
3. [CCI]
4. Sleep hypnographic variables (SL, WASO, TST, SE)
5. PSQI score
6. ESS score
7. [CCI]
8. [CCI]
9. RSWA quantified in the chin (phasic, tonic, and any muscle activity) and in the FDS (phasic muscle activity)
10. EEG power spectral analysis during REM/NREM sleep
11. MoCA
12. [CCI]
13. [CCI]
14. [CCI]
15. Safety parameters (vital signs, physical examination, AEs, SAEs, laboratory assessments, and ECG)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Neurim Pharmaceuticals (1991) Ltd.

Sponsor organisation

Neurim Pharmaceuticals (1991) Ltd.

Address

27 Habarzel

City

Tel Aviv-Yafo

Postcode

6971039

Country

Israel

Scientific contact point

Organisation

Neurim Pharmaceuticals (1991) Ltd.

Contact name

Prof. Nava Zisapel

Public contact point

Organisation

Neurim Pharmaceuticals (1991) Ltd.

Contact name

Hadar Elovitch

Third parties 7

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications