Evaluation of Safety, Tolerability, and Explorative Efficacy of NSC001 and Trospium Chloride in Mild to Moderate Alzheimer's Disease
- Trial ID
- 2024-518563-35-00
- Protocol
- NSC24001
- Sponsor
- Nsc Therapeutics GmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to determine the **safety** and **tolerability** of the orthosteric selective muscarinic M1 agonist NSC001, with or without the addition of trospium, in participants diagnosed with mild to moderate **Alzheimer's Disease**. This is clinically relevant as it aims to evaluate the potential of NSC001 as a therapeutic option, ensuring that it is safe for use in this patient population, which is crucial for advancing treatment options for Alzheimer's Disease.
Secondary objectives include determining the pharmacokinetic (PK) profile of different NSC001 dosing regimens, with or without trospium, in the same participant group. Understanding the PK profile is essential for optimizing dosing strategies and ensuring effective and safe drug administration.
Participants
The clinical trial involves participants diagnosed with **Alzheimer's Disease** in its mild to moderate stages. The study population includes both male and female subjects aged between 50 and 85 years. Participants are required to be in reasonably good health to partake in the 21-week trial. The trial does not involve a vulnerable population. Participants must have a clinical diagnosis of Alzheimer's Disease, supported by cognitive decline evidence and biomarker data, such as a positive Amyloid PET scan or plasma p-tau217 concentration. The use of acetylcholinesterase inhibitors is mandatory, with treatment stabilized for at least three months prior to baseline. Participants must have adequate vision, hearing, and motor function, and be able to swallow size 2 capsules. The trial requires the presence of a reliable informant or trial partner to ensure compliance with the study protocol. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is a **Phase 2a**, multi-center, randomized, parallel group, double-blind, and placebo-controlled study designed to assess the safety and tolerability, as well as the exploratory efficacy, of the orthosteric selective muscarinic M1 agonist NSC001 in participants with mild to moderate **Alzheimer's Disease**. The trial will involve the administration of NSC001, with or without trospium, over a maximum treatment period of 16 weeks. The study will include a placebo group for comparison. The trial is expected to commence recruitment in April 2025 and conclude by August 2026.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as a Mini Mental State Examination (MMSE) score between 18 and 26, stable use of acetylcholinesterase inhibitors, and adequate health status for trial participation. Following the screening, eligible participants will be randomized into treatment groups. The trial will include regular follow-up visits to monitor safety and efficacy endpoints, including the frequency and severity of adverse events, changes in clinical and neurological findings, and pharmacokinetic parameters of NSC001. The end-of-study visit will assess the overall outcomes and gather final data.
The expected length of participant involvement is approximately 21 weeks, including the screening period, treatment phase, and follow-up assessments. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with study protocols, or withdrawal of consent by the participant. The trial will ensure that all procedures adhere to ethical standards and regulatory requirements, with informed consent obtained from all participants and their caregivers prior to any study-specific procedures.
Treatment
The clinical trial involves the administration of **NSC001**, a selective M1 muscarinic acetylcholine receptor agonist. The investigational medicinal product (IMP) is formulated as a **capsule** and is administered **orally**. The active substance in NSC001 is **(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspir[4.5]decan-3-one**, also known by its synonyms AF267B, NI004, and NGX-267. The maximum daily dose of NSC001 is 40 mg, with a total maximum dose of 4060 mg over a treatment period of 16 weeks. The trial aims to assess the safety and tolerability of NSC001 in participants with mild to moderate Alzheimer's Disease.
In addition to NSC001, the trial includes the administration of **Trospium Aristo 20 mg Filmtabletten**, which serves as a comparator treatment. Trospium chloride, the active substance, is an antispasmodic and antimuscarinic agent. It is provided in the form of a **film-coated tablet** and is also administered **orally**. The maximum daily dose for Trospium Aristo is 20 mg, with a total maximum dose of 2240 mg over the same 16-week treatment period. This comparator treatment is used to evaluate the effects of NSC001 when administered with or without trospium.
The trial also includes a **placebo** group, which receives a product identical to the IMP NSC001 but without the active substance. This placebo is used to maintain the double-blind nature of the study and to provide a baseline for evaluating the efficacy and safety of NSC001. The placebo is administered in the same pharmaceutical form and route as the active treatment, ensuring consistency across all participant groups.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the frequency and severity of adverse events (AEs) and serious adverse events (SAEs), changes in clinical and neurological findings, alterations in vital signs and electrocardiograms (ECG), modifications in laboratory assessments, and changes in suicidal ideation and behavior as evaluated by the Columbia-Suicide Severity Rating Scale (C-SSRS). These parameters will provide a comprehensive overview of the safety and tolerability of the investigational product, NSC001, in participants with mild to moderate **Alzheimer's Disease**.
Secondary endpoints focus on pharmacokinetic (PK) parameters of NSC001, such as area under the curve (AUC) from time zero to the last measurable concentration (AUC(0 last)), AUC extrapolated to infinity (AUCinf), maximum concentration (Cmax), time to reach maximum concentration (tmax), clearance (CL/F), volume of distribution (Vd/F), and half-life (t½). Additionally, parent exposure ratios for Cmax and AUC(0-last) will be evaluated. These PK assessments will be crucial in understanding the drug's behavior in the body and its potential therapeutic effects.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants and competent trial partner/caregiver are willing and able to give signed informed consent for participation in the trial including compliance with the requirements and restrictions according to local regulations for the trial Informed Consent Form (ICF). ). Signed informed consent by the patient (examined and verified to be mentally capable by an independent physician/ neurologist) prior to the initiation of any study specific procedure.
- Must have an informant or trial partner who, in the Investigator's judgment, has frequent and sufficient contact with the participant (at least 10 hours/week), who is considered reliable by the Investigator in providing support to the participant to ensure compliance with the trial intervention, including the proper and consistent intake of the study medication, who can accompany the participant to trial visits and help with protocol procedures, and who is also able and willing to provide input for completing the caregiver scales and sign the caregiver consent form.
- Male or female aged 50 to 85 years, inclusive at the time of consent.
- Female trial participants must be post-menopausal for at least 2 consecutive years or surgically sterile (bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months prior to screening
- Male trial participants with partners who are women of childbearing potential (WOCBP) must agree to use a reliable means of contraception (e.g., minimum condom + spermicide) during the trial and 6 months after discontinuing the trial intervention
- Participants who have a clinical diagnosis of AD, which falls into the stages of mild to moderate dementia (Stage 4 to 5) according to the utilized by the NIA-AA 2018 criteria at screening.
- Patients who show CSF biomarker data supporting the diagnosis of AD measured within the last 3 years or patients with a positive Amyloid Pet Scan within the last 3 years or have a test on p-tau217 in plasma indicating brain amyloid positivity will qualify for the study. Plasma pTau217 concentration of ≥ 2.0 pg/mL
- Evidence of cognitive decline over the last year must be present based on informant observation, medical records, or objective neurocognitive testing.
- Magnetic resonance imaging (MRI) or computed tomography (CT) scan performed within 12 months before screening, with findings consistent with the clinical diagnosis of mild to moderate AD without any other clinically significant comorbid pathologies, especially cerebrovascular lesions. If an MRI or CT scan is unavailable within 12 months before screening, an MRI assessment should be completed, and the findings confirmed before the participant's treatment start (V1).
- Mini Mental State Examination (MMSE) score of ≥18 and ≤26 at screening
- Modified Hachinski Ischemic (mHIS) Scale ≤4 unless recent MRI study demonstrates no vascular causes for dementia.
- Use of AChEIs (e.g., donepezil, galantamine, or rivastigmine) is mandatory and treatment must be on a stable dose for at least 3 months prior to baseline
- Adequate vision, hearing, and motor function to comply with testing
- Ability to swallow size 2 capsules.
- In the opinion of the Investigator is in reasonably good health for 21-week trial participation
- Trial participants must consent to ApoE genotyping. Their ApoE status may be disclosed to the participant at the Investigator's discretion.
Exclusion Criteria
- Inability to comply with visit schedule or other protocol requirements and failure to perform screening and baseline first treatment visit (V1) assessments.
- A current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of active major depression, schizophrenia, or bipolar disorder or are at suicide risk, as determined by meeting any of the following criteria: a) Suicide attempt within the past 12 months prior to screening. b) Suicidal ideation as defined by a positive response to questions 4 and 5 on the C SSRS within 60 days of screening.
- Have a history of substance abuse (based on DSM-IV criteria) within the past 12 months prior to screening, a positive urine drug (due to nonprescription drug) or alcohol test at screening, or use of cannabinoids (prescription or recreational).
- Significant acute or chronic infection at screening including, among others: History of, or positive test result at screening visit for, human immunodeficiency virus (HIV) or known current hepatitis C or hepatitis B virus infection, or positive test result at screening (defined as hepatitis B virus [HBV] surface Ag positive or positive HCV with reflex to positive hepatitis C virus [HCV] RNA).
- Clinically significant, advanced, or unstable disease that may interfere with primary or secondary variable evaluations, and which may bias the assessment of the clinical or mental status of the trial participant or put the participant at special risk, such as: a) Respiratory insufficiency. b) Heart disease (myocardial infarction, unstable angina, heart failure, cardiomyopathy within 6 months before screening). c) Bradycardia (heartbeat <50/min) or tachycardia (heartbeat >100/min), confirmed by repeat measurement. d) Higher degree AV block (Mobitz type II and III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcF-interval (males >450 msec and females >470 msec). e) Uncontrolled hypertension (>180/95 mm Hg) or hypotension (<90/60 mm Hg or higher if symptomatic), confirmed by repeat measurement.
- Indication of impaired renal function at screening defined as creatinine clearance ≤60 mL/min according to Chronic Kidney Epidemiology Collaboration (CKD-EPI) formula (confirmed by repeat measurement).
- Indication of uncontrolled diabetes at screening defined by HbA1c >8.5%.
- Indication of chronic liver disease, liver function test abnormalities, or other signs of hepatic insufficiency (alanine transaminase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase (GGT), or alkaline phosphatase [ALP] >2.5 upper limit of normal [ULN]; confirmed by repeat measurement).
- History of pre-malignant or malignant disease. The following exceptions may be made after discussion with the Sponsor: a) Participants with cancers in remission ≥5 years prior to screening. b) Participants with a history of excised or treated basal cell or squamous carcinoma of the skin. c) Participants with localized prostate cancer with treatment cycles that were completed at least 6 months prior to screening.
- Suspected or known allergy to any components of the trial interventions.
- Any condition, which, in the opinion of the Investigator, makes the trial participant unsuitable for inclusion
- Planned start of NMDA receptor antagonist memantine during the trial period (i.e., the next 13 weeks) or use of memantine within the past 4 weeks before screening, unless at a stable dose for at least 8 weeks prior to screening.
- If the trial participant is in any way dependent on the Sponsor or the Investigator or if the trial participant is accommodated in an establishment on a judicial or administrative order.
- Female participants who are pregnant or currently breastfeeding or who plan to become pregnant
- Male participants with a partner who is pregnant or currently breastfeeding or who plans to become pregnant
- In case an MRI is needed at screening, contraindications to having a brain MRI (e.g., MRI-incompatible pacemaker, MRI-incompatible aneurysm clips, artificial heart valves, or other metal foreign body; claustrophobia that cannot be medically managed).
- Any contraindication to trospium chloride, including known hypersensitivity to trospium chloride or any of the excipients listed in the SmPC, myasthenia gravis, urinary retention, gastric retention, toxic megacolon, ulcerative colitis or uncontrolled narrow-angle glaucoma.
- Prior use of anti-beta-amyloid immunotherapy (e.g., Aducanumab, Leqanemab, Donanemab) or administration of anti-amyloid vaccine.
- Enrollment in another investigational clinical trial and, respectively, administration of investigational drug within the previous 3 months small molecules. Previous participation in investigational clinical trials with monoclonal antibodies against amyloid or other anti-beta amyloid immunotherapy and other biologicals.
- Current use of anticholinergics, including trospium within the past 2 weeks before screening.
- Use of the following medications: a) Long-acting benzodiazepines (e.g., valium), except for sedation prior to screening MRI scans for those participants requiring sedation and should not be administered within 24 hours prior to cognitive testing. b) Short/medium-acting benzodiazepines (e.g., alprazolam, lorazepam, oxazepam, temazepam) except if used chronically for sleep and on a stable dose for ≥4 weeks prior to screening and throughout the trial. May not be taken within 12 hours prior to cognitive testing. c) Sedating antihistamines if taken within 12 hours prior to cognitive testing (Non-sedating antihistamines [e.g., fexofenadine, cetirizine] are allowed). d) Anticonvulsants that have significant effects on cognition per the Investigator's opinion and/or anticonvulsants used for treatment of seizures. Anticonvulsants with limited cognitive effects, such as lamotrigine, pregabalin, levetiracetam for the treatment of pain, and other non-epilepsy indications are allowed if, in the opinion of the Investigator, they are not producing sedation or contributing to cognitive impairment. The participant must have been on a stable dose for ≥4 weeks prior to screening and throughout the trial. e) Antidepressants that may, in the Investigator's opinion, affect the participant's cognition (e.g., tricyclic antidepressants). Mild depression or depressive mood arising in the context of AD are not criteria for exclusion. Use of antidepressants is allowed if at stable doses for ≥4 weeks prior to screening and throughout the trial. f) Antipsychotics used regularly, except for low doses of atypical antipsychotics (e.g., risperidone, aripiprazole, or quetiapine) if used on an as-needed basis or if used at a stable dose for ≥4 weeks prior to screening and throughout the duration of the trial. The definition of "low doses" should be judged by the Investigator, and the Medical Monitor can be consulted if needed. g) Prior use of levodopa or anti-Parkinsonian medications including dopaminergic agents, amantadine, selegiline, benztropine, and monoamine oxidase (MAO) inhibitors prescribed for the treatment of Parkinsonism or Parkinson's disease. h) Use of prescription narcotic medications within 4 weeks prior to screening. After randomization, short-term use of prescription narcotics is allowed for specific situations (e.g., after surgical procedures) and if administered at least 24 hours prior to cognitive testing. i) Use of drugs with known QT-prolonging effects36, unless used at a stable dose for ≥12 weeks prior to screening and throughout the duration of the trial, and with demonstrated stable QT interval on treatment. j) Use of any drug of abuse, including but not limited to, amphetamine, cannabis, cocaine, opiate, propoxyphene, methadone, methaqualone, phencyclidine, or barbiturates. k) Centrally active anti-hypertensive drugs (clonidine, l-methyl DOPA, guanidine, guanfacine, etc.).
- Hospitalization or change of chronic concomitant medication within 4 weeks prior to screening or during screening period.
- Clinical, laboratory or neuro-imaging findings consistent with: a) Other primary degenerative dementia, (e.g., dementia with Lewy bodies, fronto temporal dementia, Parkinson’s disease, Huntington's disease, Creutzfeldt Jakob’s disease, Down's syndrome, etc.). b) Other neurodegenerative condition (e.g., Parkinson's disease, Amyotrophic Lateral Sclerosis, etc.). c) Cerebrovascular disease (major infarct, 1 strategic or multiple lacunar infarcts, extensive white matter lesions >one quarter of the total white matter) based on historical or current CT or MRI. d) Other CNS diseases (e.g., severe head trauma, tumors, subdural hematoma, or other space-occupying processes, etc.). e) Seizure disorder, except history of febrile seizures in childhood. f) Other infectious, metabolic, or systemic diseases affecting the CNS (e.g., syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, serum electrolytes out of normal range, juvenile-onset diabetes mellitus, etc.).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 01 Apr 2025 | 40 |
 Czechia | Recruiting | 01 Apr 2025 | 30 |
 Germany | Recruiting | 01 Apr 2025 | 50 |
 Italy | Recruiting | 01 Apr 2025 | 30 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Trospium Aristo 20 mg Filmtabletten | Test | FILMTABLETTEN | ORAL | 20 | 16 | PRD6484657 |
Identical with the IMP NSC001 but without the active substance | Placebo | N/A | — | — | — | N/A |