Clinical trial NCT03943264: A Biomarker-directed Study of XPro1595 in Patients With Alzheimer's
Official title: Phase 1b Open-Label, Dose-Identification Study of XPro1595 in Patients With Alzheimer's Disease and Biomarkers of Inflammation.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Alzheimer Disease
Keywords: inflammation
Biomarker
TNF
Lead sponsor: Inmune Bio, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Alzheimer's Association
First posted: 2019-05-09
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate safety and target engagement of XPro1595 in Alzheimer's patients with biomarkers of inflammation.

Detailed description: The study is designed as a multicentre, phase 1b open-label study. The objectives of this study are to determine the safety, tolerability, and efficacy of XPro1595 in patients with Alzheimer's disease and at least one of the following inflammatory biomarkers: high sensitivity c-reactive protein (hs-CRP), hemoglobin A1c, erythrocyte sedimentation rate (ESR), or one Apolipoprotein E4 allele.

XPro1595 is a second-generation inhibitor of tumor necrosis factor (TNF) that selectively neutralizes soluble TNF, an inflammatory factor implicated in Alzheimer's pathology.

A key element of this study is to identify Alzheimer's patients that are most likely to benefit from XPro1595 treatment. Enrollment is limited to patients with evidence of inflammation. For instance, hs-CRP is an inflammatory biomarker elevated in the blood of some Alzheimer's patients and elevated CRP has been shown to predict response to TNF inhibitors in multiple other diseases.

Alzheimer's patients with elevated inflammatory biomarkers will be enrolled in a 12-week study to determine the safety and the ability of XPro1595 to reduce neuroinflammation using a combination of invasive and non-invasive biomarkers of inflammation. The study will identify the dose of XPro1595 to be used in a larger Phase II disease modification study.

Eligibility criteria: Inclusion Criteria:

1. Aged 18 years and above at screening;
2. Diagnosed with probable AD defined by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria;
3. Has hsCRP levels ≥1.5mg/L,OR HbA1c ≥ 6DCCT %, OR Erythrocyte Sedimentation Rate (ESR) ≥10 mm/h, OR APOE4 positive (at least one APOE4 allele);
4. Female of childbearing potential (FCBP) must have confirmed negative urine pregnancy test at Screening;
5. All female of childbearing potential (FCBP) and male patients who are sexually active with a female of childbearing potential must agree to use a highly effective contraception during the treatment period and until 90 days after the last dose of treatment for sexually active males whose partners are FCBP or until 30 days after the last dose of treatment for FCBP.
6. Consents to having lumbar punctures;
7. Consents to apolipoprotein E (APOE) genotyping(if status unknown);
8. Provide written informed consent prior to any study procedures being performed;
9. Has a caregiver who either lives in the same household or interacts withthe patient at least 4 hours per day and at least 4 days per week, who is knowledgeable about the participant's daytime and night-time behaviours and who canbe available to attend all clinic visits in personat which caregiver assessments are performed.Patients with caregivers that do not meet this criterionbut are determined by the investigator as able to provide an adequate assessment of the patient may also participate with prior approval from the sponsor.

Exclusion Criteria:

1. Patients taking cholinesterase inhibitors, memantine, or antidepressant medication for less than 45 days from Day 1 (i.e. must be on stable dose for at least 45 days prior to Day 1);
2. Have taken within the last 45 days from Day 1; corticosteroids or other immunosuppressive drugs, thalidomide or other TNF active drugs, minocycline.
3. Enrolled in another clinical trial where patients receive treatment with investigational drug or device or have received treatment on another AD clinical trial within the last 60 days from Day 1;
4. Unable to tolerate lumbar puncture or taking medicine where lumber punctures are contraindicated (anti-coagulants besides daily 100mg of aspirin);
5. A prior organ or stem cell transplant;
6. A major adverse cardiac event within 6 months before screening;
7. Lymphoma, leukaemia, or any malignancy within the past 5 years with the exception of malignancies with negligible risk of metastasis or death, such as basal cell or squamous cell carcinomas of the skin or cervical carcinoma in situ that have been resected with no evidence of metastatic disease for 3 years;
8. Jaundice, active hepatitis, or known hepatobiliary disease (except asymptomatic cholelithiasis);
9. Positive screening assessment for viral hepatitis B surface antigen or hepatitis C virus (HCV) antibody and positive HCV ribonucleic acid or human immunodeficiency virus, or a history of illicit drug injecting;
10. Seated blood pressure of ≥ 165/105 mmHg at screening;
11. Unable to comply with the study procedures and assessments;12.Known hypersensitivity to investigational product or its excipients;

Primary outcomes:
measure: The number of patients with a treatment-emergent adverse event throughout 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
measure: The percentage of patients with a treatment-emergent adverse event throughout 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
Secondary outcomes:
measure: Changes from baseline in high sensitivity C-reactive protein in the blood and cerebral spinal fluid following 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
measure: Changes from baseline in inflammatory cytokines in the blood and cerebral following 12 weeks of treatment with XPro1595 spinal fluid
timeFrame: 12 weeks
measure: Changes from baseline in blood and cerebral spinal fluid levels of amyloid beta following 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
measure: Changes from baseline in cerebral spinal fluid levels of tau following 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
measure: Change from baseline in FreeWater content (edema) using magnetic resonance imaging following 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
measure: Change from baseline in the Mini-Mental State Examination (MMSE) following 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
measure: Change from baseline in the Digit Symbol Substitution Test (DSST) following 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
measure: Change from baseline in the Verbal Fluency Test following 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
measure: Change from baseline in the Neuropsychiatric Inventory (NPI) following 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
measure: Change from baseline in the Bristol Activities of Daily Living Scale (BALDS) following 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
measure: Change from baseline in the Memory-Enhanced Retrospective Evaluation of Treatment Observer Reported Global Impression of Improvement (MERET OBSRO-C) following 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
measure: Evaluate changes in the Memory-Enhanced Retrospective Evaluation of Change from baseline Global Impression of Improvement (MERET PGI-C) following 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
Other outcomes:
measure: Change from baseline in Breath volatile organic compounds (BVOCs) following 12 weeks of treatment with XPro1595
timeFrame: 12 weeks
Locations:
city: Macquarie Park
country: Australia
facility: KaRa MINDS
state: New South Wales
city: Brisbane
country: Australia
facility: Mater Medical Research Institute
state: Queensland
city: Woodville
country: Australia
facility: Central Adelaide Local Health Network
state: South Australia
city: Melbourne
country: Australia
facility: Alfred Heath
state: Victoria
city: Melbourne
country: Australia
facility: Eastern Clinical Research Unit
state: Victoria
Study officials:
affiliation: The Alfred
name: Terrence O'Brien, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: McAlpine FE, Lee JK, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, Das P, Golde TE, LaFerla FM, Oddo S, Blesch A, Tansey MG. Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol Dis. 2009 Apr;34(1):163-77. doi: 10.1016/j.nbd.2009.01.006.
citation: Cavanagh C, Tse YC, Nguyen HB, Krantic S, Breitner JC, Quirion R, Wong TP. Inhibiting tumor necrosis factor-alpha before amyloidosis prevents synaptic deficits in an Alzheimer's disease model. Neurobiol Aging. 2016 Nov;47:41-49. doi: 10.1016/j.neurobiolaging.2016.07.009. Epub 2016 Jul 25.
citation: Sama DM, Mohmmad Abdul H, Furman JL, Artiushin IA, Szymkowski DE, Scheff SW, Norris CM. Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats. PLoS One. 2012;7(5):e38170. doi: 10.1371/journal.pone.0038170. Epub 2012 May 29.
citation: MacPherson KP, Sompol P, Kannarkat GT, Chang J, Sniffen L, Wildner ME, Norris CM, Tansey MG. Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice. Neurobiol Dis. 2017 Jun;102:81-95. doi: 10.1016/j.nbd.2017.02.010. Epub 2017 Feb 24.