Evaluation of Masupirdine (SUVN-502) Efficacy and Safety in Treating Agitation in Alzheimer's Dementia: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2024-513835-25-00
Protocol: CTP3S1502HT6
Sponsor: Suven Life Sciences Limited

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Diseases & Conditions

Dementia Alzheimer's type

Objectives

The primary objective of this Phase 3, double-blind, randomized, placebo-controlled, parallel group, multicenter study is to evaluate the **efficacy** of masupirdine (50 mg and 100 mg) compared to placebo in treating **agitation** in participants with dementia of the Alzheimer's type. This is measured by the Cohen-Mansfield Agitation Inventory (CMAI) items score, which aligns with the International Psychogeriatric Association (IPA) agitation criteria domains, including physical aggression, excessive motor activity, and verbal aggression, after 12 weeks of treatment. The clinical relevance of this objective lies in addressing the challenging symptoms of agitation in Alzheimer's disease, which significantly impact patient quality of life and caregiver burden.

Secondary objectives include:

To measure whether the effects of masupirdine (50 mg and 100 mg) are substantial enough to be detected by a skilled and experienced clinician based on a direct examination of the participant and an interview of the participant's caregiver.
To assess the safety of masupirdine.

These objectives aim to provide a comprehensive understanding of the therapeutic potential and safety profile of masupirdine in this patient population.

Participants

The clinical trial involves a total of **218 participants** diagnosed with **Agitation with Dementia of the Alzheimer's Type**. The study population includes both male and female subjects aged 50 years and older, with a diagnosis of dementia according to the NIA-AA 2011 criteria. Participants were selected based on their ability to understand and provide informed consent, and they must have had the onset of agitation symptoms at least two weeks prior to the initial visit. The trial includes individuals who are receiving stable doses of cholinesterase inhibitors or memantine, and those who have not changed medications targeting behavioral manifestations of Alzheimer's disease within four weeks prior to the second visit. Participants are permitted to use certain medications for insomnia and anxiety, provided the doses are stable. The study population is characterized by a lack of clinically significant abnormalities in general health, with a body mass index greater than 18.5 kg/m². Participants must have a caregiver who can provide accurate information regarding their cognitive and functional abilities and ensure the administration of the study drug. The trial includes individuals living independently, with in-home services, or in assisted living or nursing homes. The population is considered vulnerable, and the study ensures that participants have sufficient vision and hearing to comply with testing procedures.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, parallel-group, multicenter study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of **Masupirdine** (SUVN-502) for the treatment of agitation in participants with dementia of the Alzheimer's type. The trial will involve participants aged 50 years and older who have a confirmed diagnosis of dementia of the Alzheimer's type and exhibit symptoms of agitation. The study will compare two dosages of Masupirdine (50 mg and 100 mg) against a placebo over a treatment period of 12 weeks. The primary endpoint is the change in the CMAI items score aligning to the IPA agitation criteria domains from baseline to Week 12. Secondary endpoints include improvements in mADCS-CGI-C, changes in CGI-S and CaGI-S scores, and changes in behavioral and psychological symptoms as measured by NPI-12, among others.

The trial is expected to commence recruitment on June 1, 2022, and conclude by March 1, 2027. Participants will be involved in the study for a maximum of 12 weeks, with the possibility of early termination if they experience significant adverse effects or fail to comply with the study protocol. The sequence of study visits includes an initial screening visit to confirm eligibility, followed by regular follow-up visits at Weeks 2, 4, 8, and 12 to monitor efficacy and safety outcomes. The end-of-study visit will occur at Week 12, where final assessments will be conducted. Participants must have a caregiver who can provide accurate information regarding their cognitive and functional abilities and accompany them to study visits. The trial will ensure that all participants are on stable doses of any concomitant medications for at least four weeks prior to the first visit and throughout the study duration.

Treatment

The clinical trial involves the administration of **Masupirdine**, a chemical compound developed by Suven Life Sciences Ltd, as the experimental medication. **Masupirdine** is provided in a **tablet** form and is intended for **oral use**. The trial includes two dosage regimens: 50 mg and 100 mg. Participants will receive the medication once daily, with a maximum daily dose of 100 mg and a total maximum dose of 8400 mg over a 12-week treatment period. The primary objective is to assess the efficacy of **Masupirdine** in treating agitation in participants with dementia of the Alzheimer's type, as measured by the Cohen-Mansfield Agitation Inventory (CMAI) items score.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, randomized, placebo-controlled study. The placebo is administered in a similar **tablet** form and follows the same **oral** route and dosing schedule as the active treatment. This design ensures that any observed effects can be attributed to the active compound rather than other variables. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol and to maintain the integrity of the trial results.

Efficacy

The efficacy of **Masupirdine** in the treatment of agitation in participants with dementia of the Alzheimer's type will be assessed using several parameters. The primary endpoint is the change in the Cohen-Mansfield Agitation Inventory (CMAI) items score, aligning with the International Psychogeriatric Association (IPA) agitation criteria domains, from baseline to Week 12. Secondary endpoints include improvement in the modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGI-C) at Week 12, change in Clinical Global Impression-Severity (CGI-S) score related to agitation from baseline to Week 12, and change in Caregiver Global Impression-Severity (CaGI-S) score related to agitation from baseline to Week 12. Additional secondary endpoints involve improvement in Caregiver Global Impression-Change (CaGI-C) at Week 12, change in behavioral and psychological symptoms as measured by the Neuropsychiatric Inventory (NPI-12) from baseline to Week 12, change in memory and cognitive behaviors using the Mini-Mental State Examination (MMSE) total score from baseline to Week 12, change in CMAI items score aligning to the IPA agitation criteria domains from baseline to Weeks 2, 4, and 8, and change in the Cornell Scale for Depression in Dementia (C-SDD) from baseline to Week 12.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participant and/or the participant’s LAR/caregiver can understand the written informed consent, provide signed and witnessed written informed consent, and agree to comply with protocol requirements prior to beginning any study procedures. 2. Is ≥50 years of age at Visit 1 and has a diagnosis of dementia of the Alzheimer’s type according to the NIA-AA 2011 criteria. Biomarkers will not be considered for eligibility. 3. Has onset of agitation symptoms at least 2 weeks prior to Visit 1. 4. Has confirmed agitation using the IPA Consensus Provisional Definition of Agitation in Cognitive Disorders. 5. Has an MRI or CT scan performed after onset of Alzheimer's disease symptoms and prior to randomization with findings consistent with the diagnosis of dementia of the Protocol CTP3S1502HT6, Page 49 and without any other clinically significant comorbid pathologies. 6. Has a score between 5 and 26 (both inclusive) on MMSE at Visit 1. 7. Has a clinically significant agitation/aggression (score of ≥4) as measured by the NPI-12 A/A at Visits 1 and 2. 8. Must be receiving treatment with stable doses of either a cholinesterase inhibitor or memantine or both for ≥3 months prior to Visit 1 and likely to be maintained on his/her current dose for the duration of the study. 9. Has no change to medications targeting behavioral manifestations of AD within 4 weeks prior to Visit 2. Lorazepam can be administered in a dose ≤1.5 mg/day and not to exceed 3 days in a 7-day period. Concomitant use of lorazepam must be recorded during visits. 10. Is permitted to use low-dose trazodone (up to 100 mg/day), eszopiclone, zolpidem, zopiclone, or zaleplon for nighttime management of insomnia. Insomnia medications must not be administered within 8 hours prior to the efficacy and/or safety assessments. 11. Is permitted to use anxiolytic medications (including benzodiazepine), and antidepressants (with the exclusion of tricyclic antidepressants), provided they have been on a stable dose for ≥4 weeks prior to Visit 1.
Is permitted to use supplements, medical foods, or pharmaceuticals specifically for the treatment of dementia, agitation, or sleep, containing omega-3 fatty acids, melatonin, vitamin B12, folate, or valerian root. However, the dose should be stable for ≥4 weeks prior to Visit 1 and must remain stable throughout the study. All stable supplements require review and approval by the medical monitor prior to randomization. 13. Has a person (ie, caregiver) who is qualified, willing, and able to provide accurate information regarding the participant's cognitive and functional abilities and will accompany the participant to study visits. The caregiver should have face-to-face contact with the participant for a minimum of approximately 8 hours per week spread over 3 to 5 days during the week. 14. Participants who are independent living, having in-home services, or living in assisted living or nursing homes. The participant can participate in this study if his/her caregiver ensures the administration of the study drug. 15. Has vision and hearing (corrected) sufficient to comply with the testing procedures. Both participant and caregiver must be able to read and understand the written information and have literacy skills to ensure compliance with the visit procedures. 16. Has no clinically significant abnormalities in general health, physical examination, neurological examination, ECG recording, or laboratory assessments. For ALT, AST, or TBL, clinically significant is defined as greater than 1.5 times the upper limit of normal. 17. Has a BMI >18.5 kg/m2 at Visit 1. 18. Is willing and able to participate in all aspects of study design including blood sampling (PK and laboratory tests). 19. Has ability to travel to the study site at the scheduled visit times (except participants living in nursing homes).

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Exclusion Criteria

1.Female participants who are pregnant or breast feeding. 2.Sexually active females of childbearing potential and male participants are not practicing two different methods of birth control with their partner. 3.Has history of confirmed COVID-19 within 3 months prior to Visit 1. 4.Has a diagnosis of dementia due to other non-Alzheimer disorders. 5.Has a history of stroke, documented TIAs, and/or pulmonary embolism within the last 12 months. 6.Has a diagnosis of schizophrenia, bipolar disorder, or current untreated/uncontrolled MDD or participants whose C-SDD scores are suggestive of probable depression (ie, scores ≥12) at Visits 1 or 2. 7.Has symptoms of agitation that are not secondary to AD. 8.Has symptoms of delirium or history of delirium within 1 month prior to Visit 1. 9.Has used or will continue to use MAOIs, linezolid, tricyclic antidepressants, or intravenous methylene blue within 14 days prior to Visit 1. 10.Has uncontrolled cardiac disease or hypertension. 11.All antipsychotics are prohibited and should be discontinued as appropriate. 12.Centrally acting anticholinergic medications are prohibited. 13.CYP3A4 substrates with narrow therapeutic index are prohibited and should be discontinued as appropriate. 14.Use of any medications/supplements/foods with known inhibitoryinducer effects on CYP3A4 should be discontinued from screening through EOT visit. 15.Use of herbal and dietary supplements that cause liver injury. Participants on stable use for at least 4 months prior to Visit 1 are allowed; however, herbal and dietary supplement dose changes and new herbal and dietary supplements are not allowed during the study.
16.Has a history or current evidence of QT prolongation syndrome, or Torsade de Pointes, as determined by ECG at Visits 1 or 2. 17.Has bradycardia (100 bpm) on the ECG at Visits 1 or 2. 18.Has uncontrolled type-1 or type-2 diabetes (defined as HbA1c >6.5% at Visit 1). 19.Has cancer, a malignant tumor, or has been treated for an active malignancy within the past 5 years. Participants with stable untreated prostate or cervical cancer, localized squamous cell cancer, or basal cell cancer are permitted. 20.Has clinically significant hepatic impairment. 21.Is treated or likely to require treatment during the study with any medications prohibited by the study protocol. 22.Is at imminent risk of self-harm, based on clinical interview and responses on the C-SSRS, or of harm to others in the opinion of the investigator at Visits 1 or 2. 23.History of significant head injury, seizures, or any other unexplained, recurrent loss of consciousness for more than 15 minutes within 12 months of Visit 1. 24.Poorly controlled psychosis and other psychiatric disorder that, in the opinion of the investigator, would interfere with the participant’s ability to be compliant with the study protocol. 25.Known history of substance use disorder within 1 year prior to first dose of study drug, not including caffeine and nicotine. 26.Current implantable intracranial stimulator or history of intracranial ablation surgery. 27.Repetitive transcranial magnetic stimulation within 3 months prior to Visit 1. 28.Participation in experimental interventional treatments, including immunotherapy, for any aspects of AD in the past 6 months or 5 half-lives of the experimental drug product (whichever is longer), prior to the first dose of study drug. If the participant was on placebo arm of disease-modifying treatments, participation in this study is allowed. 29.Has been previously treated with masupirdine. 30.Use of recreational or medical marijuana within 4 weeks prior to the first dose of study drug or any time during the study. 31.Positive screen for illicit drugs of abuse, including phencyclidine, barbiturates, benzodiazepines, opiates, methadone, cocaine, cannabinoids, and amphetamines. 32.Participant (or caregiver) is deemed otherwise ineligible for participation in this study in the investigator’s judgment.