| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mild to Moderate Alzheimer’s Disease |
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| E.1.1.1 | Medical condition in easily understood language |
| Mild to Moderate Alzheimer’s Disease/Dementia |
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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 | 14.1 |
| 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 |
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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 |
| To evaluate the efficacy of two different doses of LND101001 in improving cognitive function in patients with dementia of the Alzheimer's type in comparison with placebo, using the Alzheimer's Disease Assessment Scale - Cognitive Subscale - 13 (ADAS Cog-13) total score. |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of two different doses of LND101001. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female outpatients.
2. Patients with a diagnosis of dementia of the Alzheimer's type according to the Diagnostic and Statistical Manual, 4th Edition, Text Revision (DSM-IV TR™) criteria and a clinical diagnosis of probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria, 2011 Edition17, of AD and DSM-IV criteria of dementia.
3. Age of 50 to 85 years.
4. Brain MRI study to support the clinical diagnosis of AD within the last 12 months prior to the screening visit or during the screening period.
5. Mild to moderate stage of AD according to a MMSE score of 12 to 22 (inclusive) at the screening visit.
6. Clinical evidence of cognitive decline in the past 6 months (based on clinical assessments and patient history data, including reports from caregivers).
7. Patients who are treatment-naïve, have received treatment for AD in the past or currently receiving treatment for AD (in the latter case, Investigators should find it clinically justifiable to switch treatment, and patients should undergo a minimum adequate washout period of 14 days prior to randomization).
8. The patient, if a female, should:
● Have a FSH value indicating menopause with high reliability, AND
● Have had her last natural menstruation ≥ 12 (or a different period, depending on region) months prior to the screening visit, OR
● Have been surgically sterilized prior to the screening visit, OR
● Have had a hysterectomy with oophorectomy prior to the screening visit.
9. The patient, if a male, should:
● Use two methods of contraception in combination; if his female partner is of childbearing potential; e.g., barrier methods such as condom or occlusive cap (diaphragm or cervical/vault cap) with spermicidal foam/gel/film/cream/suppository. (Failure rates indicate that, when used alone, the diaphragm and condom are not highly effective forms of contraception. Therefore, the use of additional spermicides does confer additional theoretical contraceptive protection. However, spermicides alone are inefficient at preventing pregnancy when the whole ejaculate is spilled. Therefore, spermicides are not a barrier method of contraception and should not be used alone.). This combination of contraceptive methods should be used from the baseline visit to ≥ 3 months after the last dose of study medication, OR
● Have been surgically sterilized prior to the screening visit.
● Should not perform or plan to perform sperm donation from the baseline visit to ≥ 3 months after the last dose of study medication.
10. Have good general health, hydration and nutrition status for participating in this clinical study, as assessed by the Investigator.
11. Ability to swallow capsules.
12. Patient living at home or in long-stay residential or care settings not requiring continuous and extensive nursing care; able to walk independently with or without a walking aid (e.g., cane or walker).
13. Patient has an identified, reliable caregiver (at least every day for a minimum of 1 to 2 hours) who is willing to provide support, ensure compliance, correct storage, preparation and administration of the study medication and ready to accompany the patient to study visits whenever required, as well as to provide information about the patient’s physical and behavioral symptoms and changes.
14. The patient and the caregiver are fluent in the language used for administration of the rating scales and cognitive tests and have sufficient visual and hearing skills, and capabilities to perform all the planned assessments.
15. Willing to adhere to protocol specified requirements.
16. Signed informed consent by patient (and/or legal representative if applicable) and caregiver prior to the initiation of any study-specific procedures
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|
| E.4 | Principal exclusion criteria |
1. Clinical, laboratory or neuro-imaging findings consistent with:
● Other primary degenerative dementia, (dementia with Lewy bodies, Parkinson’s disease with dementia, frontotemporal dementia, Huntington’s disease, Jakob Creutzfeldt disease, Down’s syndrome, etc.) and/or vascular dementia.
● Other central nervous system lesions (hydrocephalus, severe head trauma, tumors, subdural hematomas or other relevant space occupying processes, etc.).
● Other relevant infectious, metabolic or systemic diseases (syphilis, juvenile onset diabetes mellitus, clinically significant vitamin B12, folate or thyroid deficiency, clinically significant serum electrolyte disturbances, etc.) affecting central nervous system.
● Any other significant brain pathology/condition (hypoxia, brain infection, mental retardation) that can compromise the safety of the patient as determined by the Investigator.
2. Any current DSM-IV axis I diagnosis other than dementia of the Alzheimer’s type, specifically schizophrenia, schizoaffective disorder, bipolar disorders or major depressive disorder.
3. Patients with major risk of suicidal tendencies and suicide-related behavior, in particular, non-fatal suicide attempt, interrupted attempt, aborted attempt, and preparatory acts or behavior.
4. The patient has experienced/experiences hallucinations, delusions or any psychotic symptomatology.
5. The patient has one or more clinical laboratory test values outside the reference range, based on the blood and urine samples taken at the screening visit, that are of potential risk to the patient’s safety or the patient has, at the screening visit:
● A serum total bilirubin value > 1.5 times the upper limit of normal (ULN).
● A serum alanine aminotransferase (ALAT) or aspartate aminotransferase (ASAT) value > 2 times the ULN.
● A serum creatinine > 2 mg/dL and creatinine clearance ≤ 60 mL/min according to Cockcroft-Gault formula.
6. The patient has, at the screening visit:
● An abnormal ECG that is, in the Investigator’s opinion, clinically significant.
● A PR interval > 250 ms.
● A QRS interval > 130 ms (if not caused by a bundle branch block).
● A QTcF interval > 450 ms (for males and females) (based on the Fridericia correction where QTcF = QT/RR0.33).
● A history of additional risk factors for Torsade de Points (e.g., heart failure, hypokalemia, family history of long QT syndrome).
7. Any clinically significant, advanced or unstable disease or history of that may interfere with primary or secondary variable evaluations, may bias the assessment of the clinical or mental status of the patient or put the patient at special risk. see protocol for more detail
8. In the judgment of the Investigator, the patient is not considered to be euthyroid. If the patient has a TSH level outside the laboratory established reference range, reflex test from TSH will be utilized to test for T4 to support the diagnosis whether the patient is clinically euthyroid. Patients who were previously diagnosed with hyperthyroidism or hypothyroidism and are receiving treatment should have been treated with a stable dose of thyroid supplement for at least the past 3 months.
9. The patient takes or has taken disallowed recent or concomitant medication within the period specified, or it is anticipated that the patient will require treatment during the study with at least one of the disallowed concomitant medications/treatments during the study.
10. The patient has clinically significant abnormal vital signs at the screening visit.
11. Clinical or historical evidence of active hepatitis or positive serology for Hepatitis B or C or HIV.
12. History of hepatic drug intolerance or any significant drug allergy.
13. Suspected or known allergy to any components of the study treatments.
14. Suspected or known history of drug abuse or excessive alcohol intake (as specified in the protocol).
15. Patient is currently enrolled in, or discontinued 12 weeks prior to screening from, a clinical study or planned participation during this study involving an investigational drug or device, or participate in the off-label use of a drug or device (other than the study medication used in this study), or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
16. Any condition which in the opinion of the Investigator makes the patient and/or caregiver likely to be non-compliant. Suspected or confirmed poor compliance, according to Investigator’s judgment, in completing the study and follow-up (for mental, psychological or social reasons).
17. Nursing mother or pregnant woman, as verified by a positive pregnancy test.
18. Evidence or suspicion that the patient might not comply with the study directives and/or that he/she is not reliable or trustworthy.
See protocol for full exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
• Mean change from baseline in the ADAS-Cog-13 total score at 90 days.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
• Mean change from baseline in the following:
- ADCS-CGIC at 30, 60 and 90 days.
- ADAS-Cog-13 total score at 30 and 60 days.
- MMSE at 90 days.
- ADCS-ADL at 30, 60 and 90 days.
- NPI at 90 days.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Various timepoints during the study |
|
| 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 | No |
| 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) | 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 | No |
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| 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 |
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