| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Agitation with Dementia of the Alzheimer's Type |
|
| E.1.1.1 | Medical condition in easily understood language |
| Agitation symptoms associated with memory loss |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012271 |
| E.1.2 | Term | Dementia Alzheimer's type |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the efficacy of masupirdine (50 mg and 100 mg) compared
to placebo for agitation as measured by the CMAI items score aligning to the IPA agitation criteria domains (physical aggression, excessive motor activity, and verbal aggression) after 12 weeks of treatment. |
|
| E.2.2 | Secondary objectives of the trial |
| 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 primary caregiver. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.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 male or female ≥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 Visit1
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 Alzheimer's type and without any other clinically significant comorbid pathologies
6.Has a score between 5 and 26 (inclusive) on MMSE at Visit 1. Participant can be rescreened after 1 month if MMSE is not within range and can be rescreened more than once with agreement of the medical monitor
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 Visit1 and likely to be maintained on his/her current dose of cholinesterase inhibitor for the entire duration of the study
9.Inclusion criterion #9 was deleted in Protocol Amendment 2
10.Has no change to medications targeting behavioral manifestations of AD within 4 weeks prior to Visit 2 including starting, stopping, or dosage modifications. Concomitant medications should be reviewed to determine their effects on behavioral manifestations of AD with agreement of the medical monitor prior to randomization. Oral lorazepam as rescue medication is allowed for the short-term treatment of symptoms of agitation if deemed necessary by the investigator. 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 the regularly scheduled telephone visits between the caregiver and site staff. Any use or increase in dose of lorazepam will be documented as a rescue medication, even if given to participants for symptoms other than agitation and aggression. Lorazepam must not be administered within 12 hours prior to the efficacy and safety assessments. If lorazepam is not available, another intermediate-acting benzodiazepine may be used at doses equivalent to lorazepam doses.
11.Is permitted to use low-dose trazodone (up to 100 mg/day),eszopiclone, zolpidem, zopiclone, or zaleplon for nighttime management of insomnia. If a bedtime dose of a sleep agent for insomnia is being taken on a regular basis prior to screening a stable dose (≥4 weeks) of the sleep agent may be continued as needed during the study. If a sleep agent has not been previously taken prior to screening and needs to be initiated medication should be limited to a maximum allowable daily dose approved for the treatment of insomnia. Insomnia medications must not be administered within 8 hours prior to the efficacy and/or safety assessments.
12.Is permitted to use anxiolytic medications (including benzodiazepine) and antidepressants (eg selective serotonin re-uptake inhibitors, serotonin norepinephrine re-uptake inhibitors with the exclusion of tricyclic antidepressants) provided they have been on a stable dose for ≥4 weeks prior to Visit 1. Participants who have recently stopped taking these medications must discontinue use ≥4 weeks prior to Visit 1. All stable psychotropic medications require review and approval by the medical monitor. Participants should remain on the same dose throughout the duration of the study except when medically indicated due to a change in the underlying medical condition
13.Is permitted to use dietary 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 unless a shorter duration is reviewed and approved by the medical monitor. Multivitamins as a daily supplement is permitted. All stable supplements require review and approval by the medical monitor prior to randomization
14.Has a person (ie caregiver) who, in the investigator's judgment, has frequent and sufficient contact with the participant such that this person 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 dedicated contact with the participant for a minimum of approximately 8hours per week spread over 3 to 5 days during the week
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|
| E.4 | Principal 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 during the study and for 90 days after the last dose of study drug or who will not remain abstinent during the study and for 90 days after the last dose. If employing birth control, each couple must use two of the following precautions: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pill, birth control implant, birth control depot injections, condom with spermicide, or sponge with spermicide
3. Has history of confirmed COVID-19 within 3 months prior to Visit 1
4. Has a diagnosis of dementia due to other causes including vascular disease, (large infarct [>10 mm] cortical/subcortical), Parkinson's disease, Lewy Body disease, AIDS, Creutzfeldt-Jakob disease, frontotemporal dementia, Huntington's disease, major head trauma, primary or secondary cerebral neoplasia, or 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. Participants with history of MDD who are currently treated and controlled on medication for ≥3 months may be enrolled
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. This includes participants with history of congestive heart failure, history of unstable angina or myocardial infarction within 6 months of Visit 1, clinically significant ECG findings at Visits 1 or 2, and participants whose hypertension has not been controlled on medication for ≥3 months prior to Visit 1.
11. All antipsychotics are prohibited and should be discontinued as appropriate (2 weeks or at least 5 half-lives [whichever is longer] prior
to Visit 2).
12. Exclusion Criterion #12 was deleted in Protocol Amendment 2
13. Centrally-acting anticholinergic medications are prohibited and should be tapered off and discontinued at least 2 weeks prior to Visit 2.
14. CYP3A4 substrates with narrow therapeutic index are prohibited and should be discontinued as appropriate (2 weeks or at least 5 half-lives [whichever is longer] prior to Visit 2).
15. Use of any medications, herbal supplements and/or ingestion of foods with known inhibitory /inducer effects on CYP3A4 should be discontinued from screening through EOT visit.
16. Use of herbal and dietary supplements that cause liver injury (eg, supplements that contain aloe vera, black cohosh, cascara, chaparral, comfrey, ephedra, or kava). 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.
17. Has a history or current evidence of QT prolongation syndrome, QTcF ≥450 msec (for male participants) or ≥ 470 msec (for female participants), or Torsade de Pointes, as determined by ECG at Visits 1 or 2.
18. Has bradycardia (<50 bpm) or tachycardia (>100 bpm) on the ECG at Visits 1 or 2.
19. Has uncontrolled type-1 or type-2 diabetes (defined as HbA1c >6.5%). Participants with HbA1c levels up to 7.5% can be enrolled if the investigator believes the participant’s diabetes is under control and after approval by the medical monitor.
20. 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.
21. Exclusion Criterion #21 was deleted in Protocol Amendment 2
22. Has clinically significant hepatic impairment.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Change in CMAI items score aligning to the IPA agitation criteria
domains from baseline to Week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Evaluated at Day 1; 15 (+/- 3 days); 29 (+/- 3 days); 57 (+/- 3 days); 85 (+/- 3 days) |
|
| E.5.2 | Secondary end point(s) |
| Improvement in mADCS-CGI-C at Week 12 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Evaluated at Day 1; 15 (+/- 3 days); 29 (+/- 3 days); 57 (+/- 3 days); 85 (+/- 3 days) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Serbia |
| United States |
| Croatia |
| Poland |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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