Clinical trial NCT03998423: Oral Fecal Microbiota Transplant Feasibility Study in Alzheimer's Disease
Official title: Oral Fecal Microbiota Transplant Feasibility Study in Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Alzheimer Disease
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
Collaborators: name: Wisconsin Partnership Program
First posted: 2019-06-26
Enrollment: 5
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A single dose of 30 capsules (22.5g) of oral FMT will be given once (week 0), twice (week 0 and week 8), or three times (week 0, week 8, and week 24). Participants are randomly assigned to 1, 2, or 3 doses of FMT.
Primary purpose: TREATMENT

Brief summary: The goal of this study is to assess the safety and feasibility of an oral fecal microbiota transplant (FMT) intervention for Alzheimer's disease (AD).

Detailed description: Studies suggests that microbes, including those derived from the gut, may play a role in the development or progression of AD. Gut microbiome composition among individuals with the Alzheimer's clinical syndrome is reduced in microbial diversity and shows compositional differences relative to control groups. Further, genera identified as more abundant in AD are associated with greater AD pathology while genera identified as less abundant in AD are associated with less AD pathology, as shown using CSF biomarkers.

The goal of this study is to assess the safety and feasibility of an oral fecal microbiota transplant (FMT) intervention.

* Primary Objective: To assess the safety and feasibility (recruitment, eligibility, enrollment, completion, and follow-up) of an oral FMT intervention in people with and without the Alzheimer's clinical syndrome.
* Secondary Objective: To demonstrate the effects of FMT on the composition and function of the gut microbiota. To collect preliminary data in order to estimate sample size and other parameters for a larger study.

Eligibility criteria: Inclusion Criteria:

* Current enrollment in the Wisconsin ADRC clinical core study (2011-0030), ADCP (26695, MCW IRB), or referred from clinic
* At least 45 years of age
* Good general health (other than dementia) with no conditions/medications affecting the gut microbiome (see exclusion criteria below)
* Willing and able to comply with all study procedures for the duration of the study
* Able to provide signed and date informed consent form
* Participant is not pregnant, lactating or of childbearing potential (ie women must be two years post-menopausal or surgically sterile
* Males must agree to avoid impregnation of women during and for four weeks after completing study treatment through use of an acceptable method of contraception
* Able to take oral medications
* Able to take the test capsule successfully with no signs or symptoms of dysphagia

Additional inclusion criteria for participants with Alzheimer's disease:

* Abnormal memory function documented by neuropsychological testing
* Wisconsin ADRC (HS IRB# 2015-0030) Consensus Diagnosis Conference indicates probable AD diagnosis as per NINDS/ADRDA criteria for probable AD (for ADRC and ADCP participants only).

Exclusion Criteria:

* Active or previous (within 6 months) participation in an Alzheimer's clinical intervention/trial
* Significant neurologic disease: Any significant neurologic disease, such as Parkinson's disease, stroke, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, subdural hematoma, multiple sclerosis, seizure disorder, or other significant deficits (other than Alzheimer's dementia)
* Alcohol/substance: history of alcohol/substance dependence since joining the cohort
* Psychiatric disorders: Untreated current axis 1 DSM-V disorder such as major untreated depression, current untreated bipolar 1 disorder, untreated schizophrenia spectrum disorders, or other conditions potentially affecting study adherence.
* Significant medical illness: any significant systemic illness or unstable medical condition occurring that could affect cognition (other than Alzheimer's). Examples include malignant cancer, chemotherapy, untreated thyroid disease, heart failure, or renal insufficiency.
* Illiterate, blind, or non-English speaking
* Known periodic antibiotic use (i.e. prior to dental appointments)
* Oral FMT-specific exclusion criteria:

  * Inability (e.g. dysphagia) or unwilling to swallow capsules - assessed using the Eating Assessment Tool (EAT-10) and bedside 3oz water swallow test administered by CRU nurse or study coordinator
  * Active gastrointestinal infection at time of enrollment
  * Known or suspected toxic megacolon and/or known small bowel ileus
  * History of total colectomy or bariatric surgery
  * Concurrent intensive induction chemotherapy, radiation therapy, or biological treatment for active malignancy
  * Unable or unwilling to comply with protocol requirements
  * Expected life expectancy \< 6 months
  * Previous FMT or microbiome-based products at any time excluding this study
  * Patients with severe anaphylactic or anaphylactoid food allergy
  * Solid organ transplant recipients ≤ 90 days post-transplant or on active treatment for rejection
  * Immunocompromised/ at risk of CMV/EBV associated disease
  * A condition that would jeopardize the safety or rights of the subject, would make it unlikely for the subject to complete the study, or would confound the results of the study
* Exclusionary factors affecting the microbiome:

  * Use of systemic antibiotics (intravenous, intramuscular, or oral) in the previous 3 months
  * Oral, intravenous, intramuscular, nasal or inhaled corticosteroids (except PRN use for allergies)
  * Immune stimulating medications
  * Methotrexate or immunosuppressive cytotoxic agents
  * Large doses of commercial probiotics consumed (greater than or equal to 108 cfu or organisms per day). Includes tablets, capsules, lozenges, chewing gum or powders in which probiotic is a primary component (ordinary dietary components such as fermented beverages/milks, yogurts, foods do not apply).
  * Unstable dietary history during the previous month, which is defined as major changes in diet by eliminating or significantly increasing a major good group
  * Major surgery of the GI tract, with the exception of cholecystectomy and appendectomy, in the past five years
  * Major bowel resection at any time
  * Active uncontrolled gastrointestinal disorders or disease including: inflammatory bowel disease including ulcerative colitis (mild-moderate-severe), Crohn's disease (mild-moderate-severe), or indeterminate colitis; irritable bowel syndrome (moderate-severe); persistent, infectious gastroenteritis, colitis or gastritis; persistent or chronic diarrhea of unknown etiology, Clostridium difficile infection (recurrent) or Helicobacter pylori infection (untreated), or chronic constipation

Primary outcomes:
measure: Safety: Proportion of participants with treatment-related adverse events, serious adverse events, or adverse events of special interest.
timeFrame: 1 year
measure: Feasibility: Participant recruitment rate
timeFrame: 1 year
measure: Feasibility: Eligibility
timeFrame: 1 year
measure: Feasibility: Procedures completed.
timeFrame: 1 year
measure: Feasibility: Retention
timeFrame: 1 year
measure: Change in gut composition: Engraftment of fecal microbial transplant as assessed by 16S rRNA sequencing of recipient stool sample
timeFrame: baseline, 8 weeks, 24 weeks, 1 year
Secondary outcomes:
measure: Cognition: Change in Montreal Cognitive Assessment (MoCA) score
timeFrame: baseline and 1 year
measure: Cognition: Change in results of Repeatable Battery for the Assessment of Neuropsychological Status
timeFrame: baseline and 1 year
measure: Cognition: Change in the results of Trail Making Test Part A and Part B
timeFrame: baseline and 1 year
measure: Metabolic/physiological measure: Change in the level of Hemoglobin A1C
timeFrame: baseline, 8 weeks, 24 weeks, and 1 year
measure: Metabolic/physiological measure: Change in the level of fasting glucose
timeFrame: baseline, 8 weeks, 24 weeks, and 1 year
measure: Metabolic/physiological measure: Change in the level of fasting insulin
timeFrame: baseline, 8 weeks, 24 weeks, and 1 year
measure: Metabolic/physiological measure: Change in the level of C-reactive protein
timeFrame: baseline, 8 weeks, 24 weeks, and 1 year
measure: Metabolic/physiological measure: Change in the blood lipid profile
timeFrame: baseline, 8 weeks, 24 weeks, and 1 year
measure: Metabolic/physiological measure: Change in the blood pressure
timeFrame: baseline, 8 weeks, 24 weeks, and 1 year
measure: Metabolic/physiological measure: Change in body weight
timeFrame: baseline, 8 weeks, 24 weeks, and 1 year
measure: Metabolic/physiological measure: Change in the body composition by measuring body fat percentage
timeFrame: baseline and 1 year
measure: Change in insulin resistance indexed by the homeostatic model assessment-insulin resistance (HOMA-IR) method
timeFrame: baseline, 8 weeks, 24 weeks, and 1 year
measure: Change in physical activity as measured by Actigraphy watch
timeFrame: baseline, 24 weeks, and 1 year
measure: Change in Sleep as measured by Actigraphy watch
timeFrame: baseline, 24 weeks, and 1 year
measure: Change in CSF biomarkers
timeFrame: baseline and 1 year
measure: Change in serum/plasma metabolites on an average of one week pre and post FMT
timeFrame: baseline, week 8, week 24, and 1 year
measure: Function: Change in total score on the Bristol Activities of Daily Living Scale
timeFrame: baseline and 1 year
Other outcomes:
Locations:
city: Madison
country: United States
facility: University of Wisconsin - Madison
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: Barbara Bendlin, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, Carlsson CM, Asthana S, Zetterberg H, Blennow K, Bendlin BB, Rey FE. Gut microbiome alterations in Alzheimer's disease. Sci Rep. 2017 Oct 19;7(1):13537. doi: 10.1038/s41598-017-13601-y.