Clinical trial NCT02997982: Feasibility and Effects of Valaciclovir Treatment in Persons With Early Alzheimer's Disease
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer Disease
Mild Cognitive Impairment
Herpes Simplex
Keywords: Alzheimer's Disease
Herpes Simplex Virus
HSV
Antiviral Drugs
Lead sponsor: Umeå University
Sponsor class: OTHER
First posted: 2016-12-20
Enrollment: 33
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Cerebrospinal fluid (CSF) Total Tau
timeFrame: Baseline and treatment day 28
Secondary outcomes:
measure: Cerebrospinal fluid (CSF) Neurofilament light chain (NFL)
timeFrame: Baseline and treatment day 28
measure: Cerebrospinal fluid (CSF) phosphorylated Tau (p-Tau)
timeFrame: Baseline and treatment day 28
measure: Cerebrospinal fluid (CSF) Amyloid beta 1-42
timeFrame: Baseline and treatment day 28
measure: PET/CT: [18F]-FHBG accumulation within the central nervous system (CNS)
timeFrame: One week before drug treatment start
measure: PET/CT: Location of [18F]-FHBG accumulation
timeFrame: One week before drug treatment start
measure: PET/CT: [18F]-FHBG accumulation
timeFrame: One week before and one week after drug treatment
measure: Mini Mental State Examination - Swedish Revision (MMSE-SR)
timeFrame: Baseline and treatment day 28
measure: Cerebrospinal fluid (CSF) acyclovir concentration
timeFrame: Treatment day 28
measure: Cerebrospinal fluid (CSF) 9-carboxymethoxymethylguanine (CMMG) concentration
timeFrame: Treatment day 28
measure: Serum acyclovir concentration
timeFrame: Treatment day 28
measure: Serum 9-carboxymethoxymethylguanine (CMMG) concentration
timeFrame: Treatment day 28
measure: Proportion completing the [18F]-FHBG-PET/CT investigations
timeFrame: For the investigations one week before and one week after drug treatment
measure: Proportion completing the 28 days treatment with valaciclovir at specified doses
timeFrame: Treatment day 28
Other outcomes:
Locations:
city: Umeå
country: Sweden
facility: Geriatric Centre, University Hospital in Umeå
state: Västerbotten
city: Uppsala
country: Sweden
facility: Memory Clinic, Uppsala University Hospital
Study officials:
affiliation: Umeå University, Umeå, Sweden
name: Hugo Lövheim, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: