Study of LM11A-31-BHS in Mild-moderate AD Patients

NCT ID: NCT03069014

Last Updated: 2020-09-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 242 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-02-15
• Study Completion Date: 2020-06-08

Brief Summary

The purpose of this study is to determine the safety of 2 doses of LM11A-31-BHS in 180 patients with Alzheimer's Disease versus placebo and to access biomarker and clinical exploratory endpoints of LM11A-31-BHS

Detailed Description

The goal of this AD Pilot is to conduct a prospective, double-blind, multicenter, phase IIa exploratory safety, feasibility and proof-of-concept trial in mild to moderate Alzheimer's disease patients with the orally bioavailable p75 neurotrophin receptor ligand LM11A-31-BHS dosed twice daily for 26 weeks. Successful completion of this trial will provide the safety, endpoint and statistical basis for the design and execution of a phase 2b/3 efficacy trial. It will also bring to the AD field a much-needed new set of target mechanisms and will help pioneer the strategy of the concomitant targeting of multiple fundamental AD-related pathological processes.

During the 26 weeks study period the eligible patients will be invited to 5 visits.

Safety monitoring will include the full extent of phase 2 clinical, electrophysiological and laboratory testing.

Conditions

Mild to Moderate Alzheimer's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

400mg LM11A-31-BHS

400mg LM11A-31-BHS and 400mg Placebo per day

Group Type: ACTIVE_COMPARATOR

400mg LM11A-31-BHS

Intervention Type: DRUG

1 Oral Capsules (200mg of LM11A-31-BHS and 200mg of placebo) twice daily (morning \& evening) for 26 weeks

Placebos

Intervention Type: DRUG

2 Oral Capsules (200mg of Placebo) twice daily (morning \& evening) for 26 weeks

800mg LM11A-31-BHS

800mg LM11A-31-BHS

Group Type: ACTIVE_COMPARATOR

800mg LM11A-31-BHS

Intervention Type: DRUG

2 Oral Capsules (200mg of LM11A-31-BHS) twice daily (morning \& evening) for 26 weeks

Placebos

800mg (microcrystalline cellulose with 0.5 - 1% magnesium stearate) per day

Group Type: PLACEBO_COMPARATOR

Placebos

Intervention Type: DRUG

2 Oral Capsules (200mg of Placebo) twice daily (morning \& evening) for 26 weeks

Interventions

400mg LM11A-31-BHS

1 Oral Capsules (200mg of LM11A-31-BHS and 200mg of placebo) twice daily (morning \& evening) for 26 weeks

Intervention Type: DRUG

800mg LM11A-31-BHS

2 Oral Capsules (200mg of LM11A-31-BHS) twice daily (morning \& evening) for 26 weeks

Intervention Type: DRUG

Placebos

2 Oral Capsules (200mg of Placebo) twice daily (morning \& evening) for 26 weeks

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Men and women (non-childbearing potential) with a diagnosis of Alzheimer's disease according to McKhann (2011) criteria

2. Age 50-85 years (50-80 in Czech Republic)

Exclusion Criteria

4. CSF AD specific biomarker profile; positive, defined as CSF Aβ42 < 550 ng l-1 or an Aβ 40/42 ratio < 0.89

5. Mild to moderate stage of Alzheimer's disease according to MMSE ≥ 18 and ≤ 26

6. Absence of major depressive disease according to GDS of < 5

7. Modified Hachinski Ischemic Scale ≤ 4

8. Formal education for eight or more years

9. Previous decline in cognition for more than six months as documented in patient medical records

10. A caregiver available and living in the same household or interacting with the patient a sufficient time each week (in Czech Republic: providing personal care for the patient during at least 10 hours per week ) and available if necessary to assure administration of drug

11. Patients living at home or nursing home setting without continuous nursing care

12. General health status acceptable for a participation in a 6-month clinical trial

13. Ability to swallow capsules

14. Stable pharmacological treatment of any other chronic condition for at least one month prior to screening

15. Stable treatment with one of the acetylcholinesterase inhibitors donepezil (Aricept ®), galantamine (Razadyne®), or rivastigmine (Exelon) or the partial NMDA receptor antagonist with memantine (Namenda®) at least 3-months before baseline Visit or Combination of both treatments mentioned above

16. No regular intake of prohibited medications as noted in Section 11.8 of the protocol

1. Failure to perform screening or baseline examinations

2. Hospitalization or change of chronic concomitant medication one month prior to screening or during screening period

3. Clinical, laboratory or neuro-imaging findings consistent with:

• Other primary degenerative dementia, (dementia with Lewy bodies, fronto-temporal dementia, Huntington's disease, Creutzfeldt-Jakob Disease, Down's syndrome, etc.)
• Other neurodegenerative condition (Parkinson's disease, amyotrophic lateral sclerosis, etc.)
• Cerebrovascular disease (major infarct, one strategic or multiple lacunar infarcts, extensive white matter lesions > one quarter of the total white matter)
• Other central nervous system diseases (severe head trauma, tumors, subdural hematoma or other space occupying processes, etc.)
• Seizure disorder
• Other infectious, metabolic or systemic diseases affecting central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, serum electrolytes out of normal range, juvenile onset diabetes mellitus, etc.)

4. A current DSM-IV diagnosis of active major depression, schizophrenia or bipolar disorder

5. Clinically significant, advanced or unstable disease that may interfere with primary or secondary variable evaluations, and which may bias the assessment of the clinical or mental status of the patient or put the patient at special risk, such as:

• chronic liver disease, liver function test abnormalities or other signs of hepatic insufficiency (ALT, AST, Gamma GT, alkaline phosphatase > 2.5 ULN)
• Respiratory insufficiency
• Renal insufficiency (serum creatinine > 2mg/dl) or creatinine clearance ≤ 30 mL/min according to Cockcroft-Gault formula). In case of creatinine clearance ≤ 30mL/min, an alternative verification of the renal function must be completed using Cystatin C analysis. In case of normal level of Cystatin C, the patient can be included
• Heart disease (myocardial infarction, unstable angina, heart failure, Cardiomyopathy within six months before screening)
• Bradycardia (heart beat < 50/min.) or tachycardia (heart beat > 95/min.)
• Hypertension (> 180/95 / Czech Republic >160/95) or hypotension (< 90/60) requiring treatment with more than three drugs
• AV block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcB-interval (males > 450 and females > 470 msec.)
• Uncontrolled diabetes defined by HbA1c > 8.5
• Malignancies within the last five years except skin malignancies (other than melanoma) or indolent prostate cancer
• Metastases

6. Disability that may prevent the patient from completing all study requirements (e.g. blindness, deafness, severe language difficulty, etc.)

7. Women who are fertile and of childbearing potential

8. Chronic daily drug intake of ≥ 14 days or expected for ≥ 14 days:

• benzodiazepines (except lorazepam ≤ 1mg for sleeping disorders only), neuroleptics or major sedatives
• Antiepileptics
• Centrally active anti-hypertensive drugs (clonidine, l-methyl DOPA, guanidine, guanfacine, etc.)
• Opioid containing analgesics

9. Nootropic drugs with exception of Ginko Biloba

10. Suspected or known drug or alcohol abuse, i.e. more than approximately 60 g alcohol (approximately 1 liter of beer or 0.5 liter of wine / in Czech Republic: 20 g alcohol per day for females (500 ml of beer or 250 ml of wine) and 30g alcohol per day for males (approximately 750 ml of beer or 375 ml of wine)) per day indicated by elevated MCV significantly above normal value at screening

11. Suspected or known allergy to any components of the study treatments

12. Enrollment in another investigational study or intake of investigational drug within the previous three months

13. Any condition, which, in the opinion of the investigator, makes the patient unsuitable for inclusion

14. If patient is in any way dependent on the sponsor or the principal investigator or if the patient is accommodated in an establishment on judicial or administrative order

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

PharmatrophiX Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Manfred Windisch, PhD

Role: PRINCIPAL_INVESTIGATOR

NeuroScios GmbH

Locations

University Hospital Graz

Graz, Styria, Austria

Landeskrankenhaus Hall

Hall in Tirol, Tyrol, Austria

Vestra clinics s.r.o

Rychnov nad Kněžnou, Kralovehadrecky Kraj, Czechia

NEUROHK s.r.o

Choceň, Pardubický kraj, Czechia

Charles University

Prague, Prague, Czechia

Neurology Clinic of Martin Urbanek

Brno, South Moravian, Czechia

Nordwestkrankenhaus Sanderbusch

Sande, Friesland, Germany

Zentrum für klinische Forschung

Bad Homburg, Hesse, Germany

Studienzentrum Nordwest

Westerstede, Lower Saxony, Germany

Universitätsklinik Magdeburg, Klinik für Neurologie

Magdeburg, Sachsen Anthal, Germany

Sächsisches Krankenhaus Arnsdorf

Arnsdorf, Saxony, Germany

Pharmakologisches Studienzentrum Chemnitz GmbH

Chemnitz, Saxony, Germany

Charité Universitätsmedizin Berlin

Berlin, , Germany

Neurologie Sendlinger Strasse Studien- und Gedächtniszentrum München

München, , Germany

LMU München Klinik für Psychiatrie und Psychotherapie

München, , Germany

Fundació ACE

Barcelona, Catalonia, Spain

Fundación de Gestión Sanitaria del Hospital de la Santa Creu I Sant Pau, C

Barcelona, Catalonia, Spain

Hospital Clínic de Barcelona

Barcelona, Catalonia, Spain

Hospital la Paz

Madrid, , Spain

Hospital Virgen del Rocío

Seville, , Spain

Karolinska University

Stockholm, Stockholms Iän, Sweden

Countries

Austria; Czechia; Germany; Spain; Sweden

References

Shanks HRC, Chen K, Reiman EM, Blennow K, Cummings JL, Massa SM, Longo FM, Borjesson-Hanson A, Windisch M, Schmitz TW. p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial. Nat Med. 2024 Jun;30(6):1761-1770. doi: 10.1038/s41591-024-02977-w. Epub 2024 May 17.

Reference Type: DERIVED

PMID: 38760589 (View on PubMed)

Liu G, He M, Wu C, Lv P, Sun H, Wang H, Xin X, Liao H. Axonal injury mediated by neuronal p75NTR/TRAF6/JNK pathway contributes to cognitive impairment after repetitive mTBI. Exp Neurol. 2024 Feb;372:114618. doi: 10.1016/j.expneurol.2023.114618. Epub 2023 Nov 27.

Reference Type: DERIVED

PMID: 38029807 (View on PubMed)

Malik SC, Sozmen EG, Baeza-Raja B, Le Moan N, Akassoglou K, Schachtrup C. In vivo functions of p75NTR: challenges and opportunities for an emerging therapeutic target. Trends Pharmacol Sci. 2021 Sep;42(9):772-788. doi: 10.1016/j.tips.2021.06.006. Epub 2021 Jul 29.

Reference Type: DERIVED

PMID: 34334250 (View on PubMed)

Other Identifiers

2015-005263-16

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1R01AG051596-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NSC15001

Identifier Type: -

Identifier Source: org_study_id