| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Dementia With Lewy Bodies |
|
| E.1.1.1 | Medical condition in easily understood language |
Dementia with Lewy bodies: A form of dementia with abnormal proteins
(Lewy bodies) accumulating in the brain, and symptoms include
impaired memory, concentration, visual hallucinations. |
|
| 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 | 10067889 |
| E.1.2 | Term | Dementia with Lewy bodies |
| 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 |
1: To determine whether E2027 is superior to placebo on the cognitive
endpoint of Montreal Cognitive Assessment (MoCA) in subjects with
dementia with Lewy bodies (DLB) after
12 weeks of treatment.
2: To determine whether E2027 is superior to placebo on the global
clinical endpoint of Clinician's Interview Based Impression of Change
Plus Caregiver Input (CIBIC-Plus) after 12 weeks of treatment. |
|
| E.2.2 | Secondary objectives of the trial |
1: To determine whether E2027 is superior to placebo on the following
secondary endpoints after 12 weeks of treatment:
- Clinician Global Impression of Change in Dementia with Lewy Bodies
(CGIC-DLB)
- Cognitive Fluctuation Inventory (CFI)
- Mini-Mental State Examination (MMSE)
- Neuropsychiatric Inventory (NPI)
To evaluate the safety and tolerability of E2027 in subjects with DLB
To characterize the population pharmacokinetics (PPK) of E2027 in
subjects with DLB, including evaluation of the effects of intrinsic and
extrinsic factors on E2027 pharmacokinetics
(PK). |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Full sub study title: Cerebrospinal Fluid (CSF) Substudy.
Date and version of each sub-study: Participation in the CSF substudy is voluntary. Subjects who do not wish to participate in the CSF substudy may still participate in the main study without CSF collection. CSF will be collected by lumbar puncture (gravity drip method) during Screening and again during the Randomization Phase after 9 weeks of treatment on study drug.
Subjects who participate in the CSF substudy will undertake screening as described in Section 9.1.1 of the protocol.
They will need to provide XML File Identifier: IfEyF6zOtuc3QxDsW6N7SFJC8mk=Page 11/25.
Separate informed consent during screening before they can participate in the CSF substudy. Their informed consent for the CSF substudy should be provided at least 7 days before the Baseline Visit. After they have completed all screening assessments and are considered eligible for the study, they will have a blood test for clotting screen (PT, APTT, and INR)
performed before the lumbar puncture.
If their clotting screen is atisfactory, then a baseline CSF sample will be collected at least 7 days
before the Baseline Visit. If necessary, in these subjects the Screening Period may be extended by 1 week after discussion with the sponsor medical monitor.
Subjects in the CSF substudy then proceed to the Baseline Period, followed by the Treatment Period. After they have completed 9 weeks of treatment, they will have a 2nd CSF sample collected at Visit 7. The CSF samples will be collected in the morning at approximately the same time, either in the fasted state (preferred) or at least 2 hours after breakfast. The timing of the baseline CSF collection during screening needs to be cheduled carefully such that subsequent collection (at Visit 7) can be performed at a similar time of day (±2 hours) for each individual
subject. Subjects will be encouraged to stay at the site after completion of LP for medical observation. If the LP and cognitive tests are erformed on the same day, the LP must be performed after the ognitive tests are completed.
At Visit 7, a predose blood sample for PK will be taken first, followed by LP. Subjects will then be dosed with study drug and a PK sample will be collected at 1 – 4 hours postdose. If Visit 7 occurs after an ED Visit, blood PK samples and CSF will not be collected.
Related objectives: The CSF substudy aims to evaluate the effects of E2027 on CSF cGMP in subjects with DLB. The exploratory objectives are as described in Section 8.3 of the protocol are:
1) To explore the PK/PD relationship between the exposure of E2027 in CSF/plasma and its effects on CSF PD biomarker endpoints, including CSF cGMP, if data permit.
2) To explore the relationship between the E2027 PD effects (including CSF cGMP) with E2027 effects on various efficacy endpoints, if data permit. |
|
| E.3 | Principal inclusion criteria |
1. Male or female, age 50 to 85 years, inclusive at time of consent.
2. Meet criteria for probable DLB (as defined by the 4th report of the DLB Consortium) (Appendix 1). Specific situations regarding the use the imaging are described below:
a. have 1 core clinical feature only by the investigator and who did not have previous reports of DAT brain imaging scan, MIBG scan or polysomnography (PSG) will undertake DAT brain imaging scan or MIBG scan as organized by the investigator.
b. have 2 or more core clinical features by the investigator but who are judged as having only 1 core clinical feature by central reviewer and who did not have previous reports of DAT brain imaging scan, MIBG scan or PSG may undertake DAT brain imaging scan or MIBG scan after
discussion with the sponsor medical monitor.
c. have 2 or more core clinical features by the investigator and the XML File Identifier: tnzd80I4v1FKEXbCW5d92QgJdwI=Page 12/26 central reviewer and who did not have previous reports of DAT brain imaging scan, MIBG scan or PSG may undertake DAT brain imaging scan
or MIBG scan after discussion with the sponsor medical monitor if the investigator considers that imaging is necessary to confirm the diagnosis.
Where there are local/national regulatory requirements for additional central regulatory review of radiation exposure for the use of DAT /MIBG scans, enrollment of subjects is restricted to those who do not require a new DAT / MIBG scan conducted under this study (ie, subjects who have historical DAT/MIBG scan/PSG results, or subjects who have 2 core clinical features of DLB) until such approval is granted by the regulatory authority on radiation exposure. Thereafter enrollment of subjects will extend to those who may require a new DAT / MIBG scan under this study. (revised per Amendment 01).
3. MMSE >14 and <26 at Screening Visit.
4. Has experienced visual hallucinations during the past 4 weeks before Screening Visit.
5. If receiving AChEIs, must have been on a stable dose for at least 12 weeks before Screening Visit, with no plans for dose adjustment during the study. Treatment-naïve subjects can be entered into the study but there should be no plans to initiate treatment with AChEIs from
Screening to the end of the study.
6. If receiving memantine, must have been on a stable dose for at least 12 weeks before Screening Visit, with no plans for dose adjustment during the study. Treatment naïve subjects can be entered into the study but there should be no plans to initiate treatment with memantine from Sreening to the end of the study. (revised per Amendment 03).
7. Must have an identified caregiver or informant who is willing and able to provide follow-up information on the subject throughout the course of the study. This person must, in the opinion
of the investigator, not be suffering from cognitive impairment, be sufficiently familiar with the subject and spend sufficient time with the subject on a regular basis such that the caregiver or
informant can reliably fulfill the study requirements and must provide separate written consent.
The caregiver or informant should normally be residing with the subject.
If the caregiver or informant is not residing with the subject, the investigator has to be satisfied that the subject can contact the caregiver or informant readily during the times when the caregiver or informant is not with the subject. As a guide the caregiver or informant should have
contact with the subject on at least 4 days a week and each day for a total of at least 5 hours. If in doubt about whether a subject's care arrangements are suitable for inclusion, the investigator should discuss this with the medical monitor. At all visits caregivers or informants need to attend the visit in person along with the subject. If during the study, the designated caregiver or informant relinquishes his/her responsibilities as caregiver or informant, a replacement caregiver or informant who meets the criteria above and who has similar knowledge of the subject's clinical status from Baseline throughout the Treatment Period must be found. If no such replacement caregiver or informant is available, the subject must be discontinued from the study.
8. Provide written informed consent. If a subject lacks capacity to consent in the investigator's opinion, the subject's assent should be obtained, as required in accordance with local laws, regulations and customs, plus the written informed consent of a legal representative should be obtained (capacity to consent and definition of legal representative should be determined in accordance with applicable local laws and regulations). In countries where local laws, regulations, and customs do not permit subjects who lack capacity to consent to participate in this study, they will not be enrolled (revised per Amendment 02). |
|
| E.4 | Principal exclusion criteria |
1. Any neurological condition that may be contributing to cognitive impairment above and beyond those caused by the subject's DLB, including any comorbidities detected by clinical assessment or MRI.
2. History of transient ischemic attacks or stroke within 12 months of Screening.
3. Modified Hachinski Ischemic Scale >4.
4. Parkinsonian (extrapyramidal) features with Hoehn & Yahr stage IV or higher.
5. Any major psychiatric diagnosis, including schizophrenia, bipolar disorder and current major depressive disorder as per Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-V).
6. GDS score >8.
7. Severe visual or hearing impairment that may interfere with the Subject study assessments including cognitive testing.
8. History of deep brain stimulation or other neurosurgical procedure for Parkinson's disease.
9. Have thyroid stimulating hormone (TSH) above normal range. Other tests of thyroid function with results outside the normal range should only be exclusionary if they are considered clinically significant by the investigator. This applies to all subjects whether or not they are
taking thyroid supplements.
10. Abnormally low serum Vitamin B12 levels (less than the lower limit of normal [LLN]) for the testing laboratory (if subject is taking Vitamin B12 injections, level should be at or above the LLN for the testing laboratory).
11. Contraindications to MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic
metal implants (eg, in skull and cardiac devices other than those approved as safe for use in MRI scanners). Subjects who require sedation for MRI or positron emission tomography (PET)
scanning as per local guidelines need not be excluded.
12. Evidence of other clinically significant lesions that suggest a dementia diagnosis other than DLB on brain MRI at Screening. All MRIs will be acquired using a standardized procedure that will be outlined in the Imaging Charter and Imaging Acquisition Guidelines (IAG) and will
be read by an approved centralized reader.
13. Other significant pathological findings on brain MRI at Screening, including but not limited to:
any macrohemorrhage (greater than 10 mm at greatest diameter); an area of superficial siderosis; evidence of cerebral contusion, encephalomalacia, aneurysms, arteriovenous malformations, or infective lesions; evidence of multiple lacunar infarcts or stroke involving
a major vascular territory, severe small vessel or white matter disease; space occupying lesions; or brain tumors [however, lesions diagnosed as meningiomas or arachnoid cysts and less
than or equal to 1 cm at their greatest diameter need not be exclusionary])
14. Hypersensitivity to E2027 or any of the excipients.
15. A prolonged corrected QT interval calculated using Fridericia's formula (QTcF) as demonstrated by triplicate ECG at the Screening or Baseline Visit (ie, mean value >450 msec).
16. Had symptomatic orthostatic hypotension or symptomatic orthostatic tachycardia which resulted in hospitalization or urgent medical review in hospital in the past 12 months before Screening.
17. Any other clinically significant abnormalities that in the opinion of the investigator, require further investigation or treatment or that may interfere with study procedures or safety in the
following:
Physical examination, ECG, vital signs at Screening or Baseline Visit
Laboratory tests at Screening Visit |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Change from baseline in the MoCA total score at 12 weeks of treatment
2. CIBIC-Plus scale at 12 weeks of treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. CGIC-DLB scale at 12 weeks of treatment
2. Change from baseline at 12 weeks of treatment in the following endpoints:
o CFI score
o MMSE total score
o NPI total score, subscores and caregiver or informant distress score
3. Safety and tolerability of E2027 as measured by (revised per Amendment 02):
o Incidence of adverse events including severe AEs, serious AEs, AEs resulting in discontinuation
o Incidence of orthostatic hypotension and orthostatic tachycardia
o Incidence of markedly abnormal laboratory values and shifts from baseline of laboratory
values
o Incidence of abnormal ECG parameters and abnormal ECG findings
o Incidence of suicidality based on C-SSRS
o Changes from baseline in the total score of Unified Parkinson's Disease Rating Scale
Part III: Motor Examination (UPDRS-III). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
12 weeks for : (1) Change from baseline at 12 weeks of treatment in the following endpoints:
o NPI total score, subscores and caregiver or informant distress score
o MMSE total score
o CFI score 12 weeks for : (2) CGIC-DLB scale at 12 weeks of treatment Over the period of 12 weeks for : (3) Safety and tolerability of E2027 |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 2 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Japan |
| United Kingdom |
| United States |
|
| 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
|
The end of study is defined as the last subject completing the Follow-
Up Visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 20 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 20 |
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