Clinical trial NCT03281044: Fecal Microbiota Transplantation in Depression
Official title: Oral Frozen Fecal Microbiota Transplantation (FMT) Capsules for Depression: a Double-blind, Placebo-controlled, Randomized Parallel Group Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Major Depressive Disorder
Lead sponsor: Psychiatric Hospital of the University of Basel
Sponsor class: OTHER
First posted: 2017-09-13
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The prevalence of psychiatric disorders such as major depression disorder (MDD) is increasing rapidly. Despite advancements in the development of therapeutics, current treatment options have not reached optimal efficacy.

Recent interest has been drawn towards the importance of the biochemical signalling between the gastrointestinal tract and the central nervous system also known as the "microbiome-gut-brain axis". The pathogenesis of gut microbiota in extra intestinal diseases was inspired by massive studies in germ free (GF) animals, which indicated that the gut microbiota plays a role in the normal regulation of behaviour that are relevant to mood, anxiety and stress. However, the exact mechanisms by which intestinal dysbiosis are involved in the development of psychiatric diseases are not completely clarified.

A new method to alter the composition of the gastrointestinal microbiota involves fecal microbiota transplantation (FMT). The goal of FMT is to introduce or restore a stable microbial community in the gut by transplanting intestinal microbiota from a healthy donor to the patient. FMT, as a microbiota-target therapy, is arguably very effective for curing recurrent Clostridium difficile infection and has good outcomes in other intestinal diseases. At the same time, applications in previously unexpected areas, including metabolic diseases, neuropsychiatric disorders, autoimmune diseases, allergic disorders, and tumors have shown health enhancing results. FMT has initially been conducted using colonoscopy. However, recent evidence has shown that treatment with frozen FMT capsules (to be taken orally) is also safe and beneficial in restoring the gut microbiota in patients with various diseases As FMT capsules may be an effective, pragmatical adjuvant therapy (in addition to standard treatment) for depression, this project is aimed at (1) investigating for the first time if single administration of FMT capsules ameliorates depressive symptoms in patients with moderate to severe MDD 4 weeks after treatment and (2) establishing the safety profile of encapsulated FMT in MDD. Furthermore, we will also test if (3) FMT capsules modulates immune signalling and inflammatory processes, (4) Hypothalamic-pituitary-adrenal (HPA) axis responses, (5) neurogenesis, (6) energy balance hormones, (7) gut microbiota composition and (8) brain perfusion, structure and activation.


Eligibility criteria: Inclusion Criteria:

* Age ≥ 18, body mass index 20-30 kg/m²
* Able to provide signed and dated informed consent
* Patients with moderate to severe depression (as expressed by a Hamilton Depression Rating Scale (HAMD-17) \> 17)
* Treatment as usual for depression
* In- and outpatients at the UPK Basel

Exclusion Criteria:

* Patients with mild MDD (HAMD-17 \< 17)
* Comorbid psychiatric disturbances such as substance abuse disorder, bipolar disorder, schizophrenia, eating disorders.
* Current medical conditions such as acute infectious disease,
* Dietary restrictions (vegetarian, vegan, gluten-free, PEG/TPN feeding, and any kind of deviation from the UPK standard catering)
* Recent use of medications besides their anti-depressant medication (within 3 months, mainly antibiotics or probiotic consumption within last six weeks).
* Pregnancy (tested before both MRI scans using the AlereTM TestPack +Plus hCG Urine Test), breast-feeding
* Body Mass Index (BMI) \> 30
* Current or recent use of antibiotics (within 3 months before inclusion)
* Anticipated antibiotic use in upcoming 4 weeks
* Inability to read and understand the participant's information and informed consent form
* Inability (e.g. dysphagia) to or unwilling to swallow capsules
* Active vomiting
* Known or suspected toxic megacolon and/or known small bowel ileus
* Major gastrointestinal surgery (e.g. significant bowel resection) within 3 months before enrolment. This does not include appendectomy or cholecystectomy.
* History of total colectomy or bariatric surgery.
* Concurrent intensive induction chemotherapy, radiation therapy or biological treatment for active malignancy. Patients on maintenance chemotherapy may be enrolled only after consultation with a medical monitor.
* Life expectancy \< 6 months
* Patients with a history of severe anaphylactic or anaphylactoid food allergy
* Solid organ transplant recipients ≤ 90 days post-transplant or on active treatment for rejection
* Neuropenia (≤500 neutrophils/mL) or other severe immunosuppression. Anti-TNF will be permitted. Patients on monoclonal antibodies to B and T cells, glucocorticoids, antimetabolites (azathioprine, 6-mercaptopurine, methotrexate), calcineurin inhbitors (tacrolimus, cyclosporine) and mycophenolate mofetil may be enrolled only after consultation with the medical monitor.
* 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.

Primary outcomes:
measure: Depressive symptoms as measured with the Hamilton Rating Scale for Depression
timeFrame: Change from baseline score to follow-up measurements at 1, 2 and 8 months
Secondary outcomes:
measure: Gut microbiota composition as assessed by 16-S-rRNA sequencing of stool samples
timeFrame: Change from baseline score to follow-up measurement after 1 month
measure: Cerebral blood flow (measured with arterial spin labeling, mL/100 g/min^10)
timeFrame: Change from baseline score to follow-up measurement after 1 month
measure: Brain structure (measured with structural magnetic resonance imaging to assess gray matter volume in mm^3, and diffusion tensor imaging to assess fractional anisotropy (dimensionless) and mean diffusivity (m2/s))
timeFrame: Change from baseline score to follow-up measurement after 1 month
measure: Brain function (measured Blood-oxygen-level dependent contrast imaging)
timeFrame: Change from baseline score to follow-up measurement after 1 month
measure: HPA axis function (measured with salivary cortisol awakening responses).
timeFrame: Change from baseline score to follow-up measurement after 1 month
measure: Neurogenesis (measured with blood levels of BDNF).
timeFrame: Change from baseline score to follow-up measurement after 1 month
measure: Appetite-regulating hormones (measured with blood levels of ghrelin and leptin).
timeFrame: Change from baseline score to follow-up measurement after 1 month
measure: Immunoregulation and inflammation (measured with blood levels of macrophage migration inhibitory factor and interleukin 1 beta).
timeFrame: Change from baseline score to follow-up measurement after 1 month
measure: Cognition (measured with the Trail Making Test)
timeFrame: Change from baseline score to follow-up measurement after 1 month
measure: Physical activity (measured with a portable wristwatch).
timeFrame: Change from baseline score to follow-up measurement after 1 month
measure: Sleep quality (measured with 28-channel electroencephalography)
timeFrame: Change from baseline score to follow-up measurement after 1 month
Other outcomes:
Locations:
city: Basel
country: Switzerland
facility: University Psychiatric Clinics (UPK)
Study officials:
affiliation: University of Basel, Department of Psychiatry (UPK)
name: André Schmidt
role: PRINCIPAL_INVESTIGATOR
References: