Feasibility and Effects of Valaciclovir Treatment in Persons With Early Alzheimer's Disease (VALZ-Pilot)

Feasibility and Effects on Markers in Spinal Fluid in Persons With Early Alzheimer's Disease When Treated With Valaciclovir - Open Fas II Pilot Study (VALZ-Pilot)

This study investigates the effects of Valaciclovir treatment to individuals with Alzheimer's disease or Mild Cognitive Impairment of Alzheimer's Disease Type. It is an open pilot trial where 36 participants will receive 4 weeks of Valaciclovir treatment. Participants will be investigated using different measures before and after the treatment period.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease; Herpes Simplex; Mild Cognitive Impairment
• Intervention / Treatment: Drug: Valaciclovir 500Mg Tablet

Detailed Description

This study investigates the effects of valaciclovir treatment to individuals with Alzheimer's disease (AD) or Mild Cognitive Impairment of Alzheimer's Disease Type. It is an open pilot trial where 36 participants will receive 4 weeks of oral valaciclovir treatment. To find 36 persons fulfilling inclusion criteria, up to 120 persons will be screened. Important inclusion criteria are Herpes Simplex Virus (HSV) Immunoglobulin G (IgG)-positivity (HSV carriage), Apolipoprotein E allele 4 carriage and sufficient kidney function (estimated glomerular filtration rate above 30 ml/min). All participants must give their informed consent to participation.

The valaciclovir dose will be 500 mg three times daily the first week and 1000 mg three times daily week 2-4.

Participants will be investigated using different measures before and after the treatment period: Mini Mental State Examination to assess cognitive function, Cerebrospinal fluid biomarkers of Alzheimer's disease and [18F]-FHBG-PET/CT (9-[4-[18F]fluoro-3-(hydroxymethyl)butyl]guanine positron emission tomography/computed tomography)) to possibly indicate active HSV infection within the central nervous system.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Uppsala, Sweden
    • Memory Clinic, Uppsala University Hospital
  • Västerbotten
    • Umeå, Västerbotten, Sweden, 90185
      • Geriatric Centre, University Hospital in Umeå

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 63 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Man or women, age ≥ 65 years
• Ability to take a stand and to make and to sign an informed consent to participate in the study. This implies that a person with MMSE (Mini Mental State Examination) < 18 will probably not be included.
• Diagnosed with Alzheimer's disease or mild cognitive impairment due to Alzheimer's disease. At least one brain imaging examination should have been done (CT, MR, SPECT or PET/CT) and at least one objective finding should support the diagnosis beyond specific medical history. Reduced perfusion or reduced metabolism bilaterally temporally, hippocampal atrophy or pathological markers for Alzheimer's disease in cerebrospinal fluid is such findings. Persons with vascular brain disorders e.g. severe white matter changes or previous brain infarction will not be included but those with white matter changes considered normal for their age can be included.
• Positive for anti-HSV (Herpes Simplex Virus) Immunoglobulin G (IgG) in plasma, i.e. carrier of HSV.
• Hetero or Homozygote for allele 4 of gene Apolipoprotein E.
• Stable over all medication including medication for Alzheimer's disease (rivastigmine, galantamin, donepezil or memantin) for at least one month.
• No known allergy or oversensitivity against valaciclovir or aciclovir.
• Ability to independently or by support from relative or other caretaker comply to study drug.

Exclusion Criteria:

• Renal insufficiency with estimated GFR (Glomerular Filtration Rate) ≤ 30 ml/min/1.73m2
• Ongoing treatment with anticoagulants (Warfarin, low molecular heparin or other anticoagulant agents). Antiplatelet agents in recommended dose are accepted (i.e. Acetylsalicylic acid 75 mgx1)
• Life expectancy < 1 year due to other comorbidity
• Ongoing severe somatic condition that might interfere with the patients participation in the study (i.e. ongoing cancer treatment)
• Ongoing illness that makes exams in a supine position impossible (i.e. severe heart failure, severe back pain).
• Dementia diagnosis other than Alzheimer's disease, including Vascular dementia.
• Other known neurological/neurodegenerative disorder (i.e. brain tumor, MS (Multiple sclerosis), ALS (amyotrophic lateral sclerosis))
• Claustrophobia or other contraindication for doing a PET/CT scanning.
• Depression or other psychiatric illness that requires treatment (i.e. severe psychosis or other illness with equal grade of seriousness)
• Dementia or cognitive dysfunction to such extent that an informed consent is impossible to obtain, corresponding to about MMSE-SR (Mini Mental State Examination-Swedish revision) <18.
• History of substance abuse (i.e. central nervous system stimulants or alcohol). Nicotine use is accepted.
• Not willing to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Valaciclovir treatment; Valaciclovir 500Mg Tablet	Drug: Valaciclovir 500Mg Tablet; Valaciclovir treatment (oral, 500 mg tablets). First week: 500 mg three times daily, second to fourth week: 1000 mg three times daily.; Other Names: Valtrex (R)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebrospinal fluid (CSF) Total Tau	Change in CSF Total Tau between samples taken before and after drug treatment	Baseline and treatment day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebrospinal fluid (CSF) Neurofilament light chain (NFL)	Change in CSF NFL between samples taken before and after drug treatment	Baseline and treatment day 28
Cerebrospinal fluid (CSF) phosphorylated Tau (p-Tau)	Change in CSF p-Tau between samples taken before and after drug treatment	Baseline and treatment day 28
Cerebrospinal fluid (CSF) Amyloid beta 1-42	Change in Amyloid beta 1-42 between samples taken before and after drug treatment	Baseline and treatment day 28
PET/CT: [18F]-FHBG accumulation within the central nervous system (CNS)	Can [18F]-FHBG-PET/CT detect replicating HSV infection within the CNS?	One week before drug treatment start
PET/CT: Location of [18F]-FHBG accumulation	Do [18F]-FHBG accumulation locate to brain areas affected in AD?	One week before drug treatment start
PET/CT: [18F]-FHBG accumulation	Change in [18F]-FHBG accumulation after, as compared to before, drug treatment	One week before and one week after drug treatment
Mini Mental State Examination - Swedish Revision (MMSE-SR)	Change in MMSE-SR scores from baseline to after drug treatment	Baseline and treatment day 28
Cerebrospinal fluid (CSF) acyclovir concentration	Cerebrospinal fluid (CSF) acyclovir concentration	Treatment day 28
Cerebrospinal fluid (CSF) 9-carboxymethoxymethylguanine (CMMG) concentration	Concentration of CMMG, main acyclovir metabolite	Treatment day 28
Serum acyclovir concentration	Serum acyclovir concentration	Treatment day 28
Serum 9-carboxymethoxymethylguanine (CMMG) concentration	Concentration of CMMG, main acyclovir metabolite	Treatment day 28
Proportion completing the [18F]-FHBG-PET/CT investigations	Is [18F]-FHBG-PET/CT a feasible examination among persons with Alzheimer's disease	For the investigations one week before and one week after drug treatment
Proportion completing the 28 days treatment with valaciclovir at specified doses	Feasibility of valaciclovir treatment as measured by the number of participants completing the full treatment period at the specified dose	Treatment day 28

Collaborators and Investigators

• Sponsor: Hugo Lovheim
• Investigators: Principal Investigator: Hugo Lövheim, M.D., Ph.D., Umea University, Umea, Sweden

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Actual): March 4, 2020
• Study Completion (Actual): March 4, 2020

Study Registration Dates

• First Submitted: December 6, 2016
• First Submitted That Met QC Criteria: December 15, 2016
• First Posted (Estimate): December 20, 2016

Study Record Updates

• Last Update Posted (Actual): April 3, 2020
• Last Update Submitted That Met QC Criteria: April 1, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; Herpes Simplex Virus; HSV; Antiviral Drugs
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Virus Diseases; Infections; Neurocognitive Disorders; Neurodegenerative Diseases; DNA Virus Infections; Skin Diseases, Infectious; Skin Diseases, Viral; Dementia; Tauopathies; Cognition Disorders; Herpesviridae Infections; Alzheimer Disease; Cognitive Dysfunction; Herpes Simplex; Anti-Infective Agents; Antiviral Agents; Valacyclovir
• Other Study ID Numbers: UmU-2016-390-31M; 2016-002317-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No