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

Sponsor

Hugo Lovheim (Other)

Overall Status

Completed

CT.gov ID

NCT02997982

Collaborator

(none)

Enrollment

Locations

Arm

39.1

Actual Duration (Months)

16.5

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer Disease Mild Cognitive Impairment Herpes Simplex	Drug: Valaciclovir 500Mg Tablet	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

33 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Dec 1, 2016

Actual Primary Completion Date :

Mar 4, 2020

Actual Study Completion Date :

Mar 4, 2020

Arms and Interventions

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)

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)

Outcome Measures

Primary Outcome Measures

Cerebrospinal fluid (CSF) Total Tau [Baseline and treatment day 28]
Change in CSF Total Tau between samples taken before and after drug treatment

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

65 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.