| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mild Cognitive Impairment and Mild Dementia due to Alzheimer’s Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Mild Cognitive Impairment and Mild Dementia due to Alzheimer’s Disease. |
|
| 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 | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
| E.1.2 | System Organ Class | 100000004852 |
|
| 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 assess the safety and tolerability of PQ912
• To evaluate the efficacy of PQ912 on working memory and attention |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of long-term PQ912
• To evaluate the efficacy of PQ912 on brain activity (EEG)
• To evaluate the efficacy of PQ912 on cognition
• To evaluate the efficacy of PQ912 on activities of daily living
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated written informed consent obtained from the subject in accordance with local regulations.
2. Male or female, aged ≥ 50 to ≤ 80 years
3. A biomarker profile reflecting AD, according to the Alzheimer Association – National Institute on Aging (AA-NIA) Research Framework (Jenkins, Hardy, and McMurray 2002) (Jack et al. 2018) defined as follows:
c) Screening CSF sample with an Aβ42 concentration of <1000 pg/ml AND p-tau >19 pg/ml, or a ratio of p-tau/Aβ42 of ≥0.024 as assessed by central laboratory, (Elecsys assay), OR, in case of subjects in whom CSF sampling is not feasible due to medical or technical reasons.
d) Existing Positive amyloid Positron-Emission Tomography (PET) evidence within six months of the screening visit.
4. Clinical syndrome of MCI or mild dementia according to the AA-NIA Research Framework (Jack et al. 2018)
5. A cognitive impairment in the WAIS-IV Coding Test of at least 0.5 standard deviations below the normative data
6. Meeting the completion and performance criteria for the CogState NTB.
7. Be in a stable therapeutic condition with respect to the current AD condition: either without specific current approved treatment (minimum wash-out period from a prior treatment is 10 weeks) and currently no plan to initiate currently approved treatment or being on an approved treatment for AD on a stable dose for at least 10 weeks.
8. Fluency in local language and evidence of adequate intellectual functioning in the opinion of the investigator.
9. Adequate visual and auditory abilities to perform the cognitive and functional assessments in the opinion of the investigator.
10. Outpatient with study partner capable of accompanying the subject on all applicable clinic visits.
11. The subject and study partner are likely to be able to participate in all scheduled evaluations according to country and site practices. |
|
| E.4 | Principal exclusion criteria |
1. Significant neurological or psychiatric disorders, other than AD, that may affect cognition.
2. Atypical clinical presentations of MCI due to AD or mild dementia due to AD, such as visual variant of AD (including posterior cortical atrophy), frontal variant or language variant (including logopenic aphasia).
3. Moderate and severe dementia with Mini-Mental State Examination score (MMSE) below 20.
4. History of (maximally six months from screening) or screening visit brain MRI scan indicative of any other significant abnormality, including but not limited to severe white matter hyperintensities (Fazekas score 3), history or evidence of a single prior haemorrhage >1 cm3, multiple lacunar infarcts or evidence of single prior infarct >1 cm3, evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or space-occupying lesions (e.g. brain tumours).
5. Current presence of clinically important major psychiatric disorder (e.g. major depressive disorder) as defined by DSM-5 criteria, or symptom(s) (e.g. hallucinations) that could affect subject’s ability to complete study.
6. Current clinically important systemic illness likely to result in clinically relevant deterioration of subject’s condition or might affect subject’s safety during study.
7. History of clinically evident stroke.
8. History of seizures within last two years prior to screening visit.
9. Myocardial infarction within last six months prior to screening.
10. History of cancer within last two years prior to screening, with exception of any of following conditions: non-metastatic basal cell carcinoma, and squamous cell carcinoma of skin. Note: subjects can be included in study with prior history of cancer if evidence of no residual disease has been clinically confirmed within last six months before baseline.
11. History of uncontrolled hypertension (opinion of investigator) within six months prior to screening.
12. Other clinically important diseases or conditions or abnormalities of vital signs, physical examination, neurological examination, laboratory results, or electrocardiogram (ECG) examination (e.g. atrial fibrillation) that could compromise study or safety of subject.
13. Haemoglobin level less than 11 g/dL (6.8 mmol/L) at screening.
14. Clinically important infection within 30 days prior to screening e.g. chronic, persistent, or acute infection, such as bronchitis or urinary tract infection.
15. Known, untreated or insufficiently treated hypothyroidism, vitamin B12 or folate deficiency.
16. Any known hypersensitivity to investigational product PQ912 or any of excipients.
17. Severe hepatic failure (Child-Pugh C) or kidney failure (creatinine clearance (eGFR) ≤ 30 mL/min/1.73m2) as estimated using MDRD method, or serum creatinine above 1.5-fold of Upper Limit of Normal (ULN) or Asparagine-Amino Transferase (AST) or Alanine-Amino Transferase (ALT) above 3 fold of ULN at screening.
18. Blood donation in 90 days prior to screening.
19. History of alcohol or drug dependence or abuse as defined by DSM-5 criteria within last two years prior to screening.
20. Claustrophobia or presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, CSF shunts, or metal fragments or foreign objects in eyes, skin, or body that would contraindicate a brain MRI scan.
21. Inadequate venous access to allow multiple blood draws.
22. Personnel involved in conduct of the study.
23. Previous participation in any investigational trial within last 60 days of screening visit (see section 7.6).
24. Use of prohibited medications or of measures/ interventions (see 7.6)
o Immunosuppressive medications within last 90 days prior to baseline
o Chemotherapeutic agents for malignancy within last year prior to baseline
o Concomitant treatment which may impair cognitive function requires a wash out phase of at least 5 half-lives of treatment prior screening (short acting hypnotics are not permitted 72 hours before EEG or cognitive testing).
o Anticoagulants within 30 days prior to screening and V8 (week 48)/ EOT. Combination of clopidogrel & carbasalate calcium or aspirin not allowed during time of lumbar puncture. Clopidogrel or aspirin alone is allowed.
Strong inhibitors or inducers of CYP2C19 (washout phase of at least two weeks before baseline).
o Substrates of CYP2C19 with narrow therapeutic margin (washout phase of at least two weeks before baseline).
o St. John’s Wort (washout phase of at least 2 weeks prior to baseline is required).
25. For women of childbearing potential:
(a) Pregnancy (i.e. positive pregnancy test at Screening) or breastfeeding
(b) Failure to agree to practice a highly effective method of contraception (see Section 7.8.1), from enrolment up to at least 3 months after the study end.
26. For sexually active men with female partner of childbearing potential: failure to agree to use condom (see Section 7.8.2) from enrolment up to at least 3 months after study end. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• all spontaneously reported AEs, vital signs (heart rate and blood pressure), clinical laboratory tests, physical and neurological examinations.
• ECG measurements and changes on brain MRI scans as judged by the investigational site rater (Amyloid-related Imaging Abnormalities – Edema/Effusion [ARIA-E], Amyloid-related Imaging Abnormalities – Haemorrhage/Haemosiderin deposition [ARIA-H], infarcts).
• Change with time on working memory and attention as measured by the combined Z-score of the Detection test, Identification test and the ‘One Back’ test (attention and working memory domains) of the NTB. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of Treatment visit (week 48, 60, 72, 84 or 96 weeks of treatment, depending on time of randomization.) |
|
| E.5.2 | Secondary end point(s) |
• Change from baseline in global relative theta power in the EEG (4-8 Hz) at week 48
• Change with time in overall cognition as measured by the CBB Z-score • Change with time of overall cognition as measured by the composite Z- score of the complete NTB
• Change from baseline in daily activities as measured by A-IADL-Q total score at Week 48 and EOT |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 48 and End of Treament (i.e. week 60, 72, 84 or 96 weeks of treatment, depending on time of randomization.) |
|
| 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 | No |
| 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 | 5 |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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