E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Early Alzheimer Disease including mild cognitive impairment (MCI) due to AD/Prodromal AD and the early stages of mild AD |
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E.1.1.1 | Medical condition in easily understood language |
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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 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001896 |
E.1.2 | Term | Alzheimer's disease |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 | 10074616 |
E.1.2 | Term | Prodromal Alzheimer's disease |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 |
Core To determine whether elenbecestat (E2609) is superior to placebo on the change from baseline in the Clinical Dementia Rating - Sum Of Boxes (CDR-SB) at 24 months in subjects with Early Alzheimer's Disease (EAD) pooled across studies E2609-G000-301 and E2609-G000-302
Extension To evaluate the long term safety and tolerability of daily dosing with elenbecestat in subjects with EAD |
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E.2.2 | Secondary objectives of the trial |
Core Key Secondary Objectives • Determine whether elenbecestat is superior to placebo on the change from baseline in ADCOMS at 24 months in subjects with EAD pooled across studies 301 & 302 • Determine whether elenbecestat is superior to placebo on brain amyloid levels at 24 months as measured by amyloid PET in subjects with EAD pooled across studies 301 & 302 • Determine whether elenbecestat is superior to placebo on brain amyloid levels at 24 months as measured by amyloid PET in subjects with EAD in study E2609-G000-302
Extension Secondary Objectives • Evaluate the long-term effects of elenbecestat on CDR SB, ADCOMS, MMSE, FAQ, ADAS- cog14, and ADAS-cog14 Word List • Evaluate the time to conversion to dementia, for subjects who were not clinically staged as having dementia at Core Study baseline, based on a clinical diagnosis • Evaluate whether the treatment benefit of elenbecestat at the end of the Core Study is maintained over time in the OLE |
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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 |
Two longitudinal biomarker substudies will evaluate the effects of study treatment on the underlying pathophysiology of AD using Amyloid PET and/or CSF biomarkers. Participation in the substudies is optional and will require specific consent that will not affect enrollment or treatment in the main study. |
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E.3 | Principal inclusion criteria |
1. MCI due to Alzheimer’s disease or Mild Alzheimer’s disease according to the National Institute of Aging – Alzheimer’s Association (NIA-AA) core clinical criteria and must have all of the following at screening: a. MMSE score equal to or greater than 24 b. CDR global score of 0.5 c. CDR Memory Box score of 0.5 or greater 2. A history of subjective memory decline with gradual onset and slow progression over the last 1 year before Screening; this MUST be corroborated by a study partner 3. Cognitive impairment of at least 1 SD from age-adjusted norms in total recall or delayed recall on the ISLT. 4. Positive biomarker for brain amyloid pathology as indicated by at least 1 of the following: a. PET assessment of amyloid imaging agent uptake into brain. Note: Amyloid PET screens will be performed according to local regulatory guidelines and thus may be restricted for those subjects who are not suitable for lumbar puncture (LP) to obtain CSF for testing of eligibility. b. CSF AD assessment (eg, Aβ(1-42), tau:Aβ(1-42) ratio) NOTE: Subjects may undergo both the Amyloid PET and CSF assessments, but need a positive amyloid result in only 1 of the 2 procedures to confirm eligibility. Subjects who consent to Amyloid PET or CSF for eligibility purposes are not required to participate in the Amyloid PET or CSF longitudinal substudies. Use of a historical amyloid positive PET (conducted within 12 months before the planned date of randomization) is acceptable for determination of eligibility but will not suffice for the baseline assessment if the subject wishes to consent to the Amyloid PET longitudinal substudy. The historical imaging data must be made available to the sponsor. Historical CSF samples, if collected, processed, and stored under appropriate conditions and approved by the sponsor, may be analyzed to determine CSF amyloid positivity. 5. Male or female subjects between 50 and 85 years of age, inclusive at the time of consent 6. If receiving an AChEI or memantine or both for AD, must be on a stable dose for at least 12 weeks before Randomization. Treatment-naïve subjects with AD can be entered into the study. 7. Subjects must have been on stable doses of all other (ie, non-AD related) permitted concomitant medications for at least 4 weeks before Randomization, except for medications that are administered as short courses (eg, up to 3 weeks unless discussed and agreed with medical monitor) of treatment (eg, anti-infectives) or which are to be used on a Pro re nata (PRN) basis. Subjects who require a short course of treatment, such as an anti-infective, may be randomized once the acute illness has completely resolved, even if the concomitant medication continues. 8. Must have an identified study partner (defined as a person able to support the subject for the duration of the study and who spends at least 8 hours per week with the subject). The study partner must be literate and able to provide written informed consent. In addition, this person must be 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, spend sufficient time with the subject on a regular basis such that they can reliably fulfill the requirements of being a study partner. A study partner need not be living in the same residence with the subject. For such a study partner not residing with the subject, the investigator has to be satisfied that the subject can contact the study partner readily during the times when the study partner is not with the subject. Study partners need to provide input to the following assessments: CDR, FAQ, EQ-5D, QOL-AD, Zarit’s Burden Interview, and the clinical assessment of suicidality. Consideration can occur for the investigator to decide whether the study partner can provide information over the telephone or whether the study partner must attend the study visits in person with the subject. 9. Provide written informed consent. Subjects must, in the investigator's judgment, have the capacity to consent (capacity to consent should be determined in accordance with applicable professional standards and local laws/regulations).
Extension 1. Subjects who complete the 24-month Treatment Period and the 3-month Follow-up Period (Visit 15) of the Core Study, and whose Visit 15 falls within a 4-week window from the start of the Extension Phase. Subjects who discontinue study drug early are not considered to have 'completed' the Core Study. 2. Provide written informed consent. Subjects must, in the investigator's judgment, have the capacity to consent (capacity to consent should be determined in accordance with applicable professional standards and local laws/regulations). 3. Subjects must continue to have an identified study partner who is willing and able to provide follow-up information on the subject throughout the course of the Extension Phase. |
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E.4 | Principal exclusion criteria |
1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin test). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. Females of child-bearing potential who: •Within 28 days before study entry, did not use a highly effective method of contraception, which includes any of the following: o total abstinence (if it is their preferred and usual lifestyle) o an intrauterine device or intrauterine hormone-releasing system o an oral contraceptive (Subject must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 28 days after study drug discontinuation.) o have a vasectomized partner with confirmed azoospermia. •Do not agree to use a highly effective method of contraception (as described above) throughout the entire study period and for 28 days after study drug discontinuation. For sites outside of the European Union, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of contraception, ie, double-barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide. NOTE: All females will be considered to be of child-bearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing) 2. Any condition that may be contributing to cognitive impairment above and beyond that caused by the subject’s AD 3. Subjects with a history of seizures within 5 years of Screening or subjects with disturbance likely to be due to seizures within 5 years of Screening 4. History of transient ischemic attacks (TIA) or stroke within 12 months of Screening 5. Modified Hachinski Ischemia Score greater than 4 at Screening 6. Any of the following psychiatric symptoms: • Psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or delusions) that, in the opinion of the investigator, could interfere with study procedures • Has a “yes” answer to C-SSRS suicidal ideation items 4 or 5, or any suicidal behavior within 6 months before Screening, at Screening, or at the Randomization Visit, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening 7. Have any 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) or • Have any evidence of other clinically significant lesions that could indicate a dementia diagnosis other than AD on brain MRI at Screening. • Exhibit other significant pathological findings on central read of the brain MRI at Screening, including but not limited to: an area of superficial siderosis; evidence of cerebral vasogenic edema; evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective lesions; evidence of multiple lacunar infarcts; evidence of stroke involving a major vascular territory, severe small vessel, or diffuse white matter disease as defined by a score of 3 on the age-related white matter changes scare; space occupying lesions; or brain tumors (however, lesions diagnosed as meningiomas or arachnoid cysts and less than 1 cm at their greatest diameter need not be exclusionary). 8. Subjects who have a history of moderate to severe hepatic impairment (eg, Child-Pugh Class B or C). Any 2 of the following criteria at Screening would exclude the subject: INR ≥ 1.7; bilirubin ≥ 1.5 × ULN; albumin < lower limit of normal (LLN); ascites or hepatic encephalopathy. Please note that a single significant abnormality could meet criteria for moderate impairment. (revised per Amendment 01) 9. Results of laboratory tests conducted during screening that are outside the following limits: • Absolute lymphocyte count (ALC) below Lower Limit of Normal (LLN) or below 800 per mm3 (whichever is higher); ALC will be derived from the complete blood count (CBC) with differential representing the normal lymphocytes (with atypical lymphocytes removed and presented as a separate count if they are present) and calculated by the white blood cell count × percentage of lymphocytes. • 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) ..See study protocol for further exclusion criteria |
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E.5 End points |
E.5.1 | Primary end point(s) |
Core Change from baseline in the CDR-SB at 24 months in the combined studies
Extension Safety endpoints: AE, vital sign, ECG, physical examination, neurological examination, laboratory safety test, suicidality assessment, events of possible signals of drug abuse potential, and MRI safety parameters |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Core at 24 months Extension at 48 months |
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E.5.2 | Secondary end point(s) |
Core Secondary Endpoints • Change from baseline in ADCOMS at 24 months in the combined studies • Change from baseline in amyloid PET SUVR at 24 months for brain amyloid levels in the combined studies • Change from baseline in amyloid PET SUVR at 24 months for brain amyloid levels in the individual studies
Other Secondary Endpoints • Change from baseline in the CDR-SB at 24 months for subjects enriched by baseline PET SUVR, eg, between 1.2 and 1.6, in the combined studies • Change from baseline in the ADCOMS at 24 months for subjects enriched by baseline PET SUVR, eg, between 1.2 and 1.6, in the combined studies • The rate of change over time (mean slope) based on CDR-SB score over 24 months in the combined studies • Time to worsening of CDR scores by 24 months (eg, the worsening of global CDR score is defined as an increase from baseline by at least 0.5 points on the global CDR scale on 2 consecutive scheduled visits at which global CDR is undertaken) in the combined studies • Time to conversion to dementia by 24 months for subjects who were not clinically staged as dementia at Baseline based on clinical diagnosis in the combined studies • Change from baseline in CDR-SB at 27 months (ie, 24 months of treatment plus 3 months posttreatment follow up) in the combined studies • Change from baseline in ADAS-cog14, MMSE, and FAQ at 24 months in the combined studies • Change from baseline in ADAS-cog14 Word List (immediate recall and delayed recall) at 24 months in the combined studies Extension Secondary Endpoints • Changes from Core Study baseline in CDR-SB, ADCOMS, MMSE, FAQ, ADAS-cog14, and ADAS-cog14 Word List (immediate recall and delayed recall) • Time to conversion to dementia for subjects who were not clinically staged as dementia at Core Study baseline based on clinical diagnosis |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to the relevant endpoint for the specific timepoint |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 130 |
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 |
Canada |
China |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Hong Kong |
Hungary |
Italy |
Japan |
Korea, Republic of |
Poland |
Portugal |
Singapore |
Slovakia |
South Africa |
Spain |
Taiwan |
United States |
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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
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The end of the Core Study will be the date of the last study visit (Visit 15) for the last subject in the double-blind Randomization Phase.
The end of the Extension Phase will be the date of the last study visit for the last subject enrolled in the Extension Phase. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |