Faecal microbiota transplant to improve motor function in patients with advanced Parkinson’s disease: A pilot study

INTERVENTION: Double blind randomised placebo cross over trial of faecal microbiota transplantation (FMT) The study is a comparison of an experimental treatment (FMT) against placebo The placebo arm will cross‐over to treatment arm (FMT) after two placebo treatments and an assessment period To maintain blinding, the treatment arm (FMT) will receive two placebo infusions after active treatment and an assessment period. The 1st and 2nd infusions (FMT or placebo) will occur 2 weeks apart. Following a 4 week gap participants will then cross over. The 3rd and 4th infusions (FMT or placebo) will also occur 2 weeks apart. Assessments will then occur at 4 weeks, 3 months and 6 months. Each participant will receive FMT from one single donor, which will remain the same for both treatment visits. A total of three donors will be used in the trial. The FMT used will be TGA‐approved BiomeBoost. Each treatment/placebo is 100ml and will be infused via Peg‐J tube at a rate of 400ml/hr. FMT/placebo will be administered a total of 100ml of FMT via two 50ml syringes and a pump will ensure the above rate. The infusions will take place in the outpatient department under the supervision of the investigating team (nursing and medical supervision and monitoring). No intervention is required at home following the infusion but participants will contact the investigating team should they experience adverse effects, prompting medical review. Assessments will occur at each visit Assessments will include motor and non‐motor Parkinson's disease rating scales. CONDITION: Neurological ‐ Parkinson's disease Parkinson's disease; ; Parkinson's disease PRIMARY OUTCOME: Absolute change in daily OFF time based on patient’s Hauser diaries; ; Individuals with Parkinson's disease often describe "Off" symptoms as stiffness, slowness and re‐emergence of tremor. Other "off" symptoms may include cognitive fog, temperature dysregulation, freezing of gait, or anxiety. ; [1. at 4 weeks post infusion 2 (ie 2 weeks following 2nd treatment of either FMT or placebo); 2. at 4 weeks post last infusion (post infusion 4 ‐ FMT or placebo); 3. at 4 months post last infusion; 4. at 11 months post last infusion ] Safety and tolerability of faecal microbiota transplant.; Adverse events related to FMT appear to be uncommon, often mild and self‐limiting;; ‐Abdominal discomfort; ‐Infection ‐ rare cases of bacteraemia, PEJ site infection; ‐Gastrointestinal disturbance ‐ nausea, diarrhoea; ; Adverse events related to PEJ‐tube infusion/manipulation not specific to FMT ; ‐ PEJ site leakage ; ‐ PEJ site infection ; ‐ PEJ tube blockage potentially resulting in a delay in receiving Duodopa; At each infusion participants will be monitored ‐ vital signs are monitored and also participants will be asked to report any of the above symptoms. ; At each visit participants will be asked again regarding the above symptoms ; While adverse events will be queried at each appointment and serious adverse events will be monitored and reported, there are specific risk parameters that will be monitored conscientiously during infusion:; • Jejunal tube blockage is a potential complication. The infusion team (PD nurses) will be alerted to a blocked tube by the alarming syringe driver. This can be managed by ceasing the infusion temporarily and flushing the jejunal tube with normal saline. This is a situation not infrequently encountered in LCIG infusions also, and our PD clinical nurse specialists are therefore very experienced at managing this potential complication. ; • Abdomoinal pain – transient, mild, cramping abdominal discomfort has been described with FMT. The infusion rate may be slowed or ceased (see below) should a participant report this. ; • Fever – transient pyrexia has also been reported following FMT and participants will be monitored for one hour post FMT/placebo infusion. Any further signs of infection will be sought by the medical team and acted upon. ; • Diarrhoea – abdominal pain with associated diarrhoea may occur acutely if the FMT is cool. Care will therefore be taken to ensure the sample has been warmed adequately to room temperature as per the standard procedure below. ; • Deterioration in Parkinson’s disease symptoms ; o Acutely at infusion time off LCIG – an extra dose of LCIG / Duodopa will be administered pre‐and post‐infusion to avoid this. Infusion time is expected to not exceed 2 hours. ; o We feel it is unlikely for PD symptoms to deteriorate significantly in the medium/longterm as a result of FMT/placebo infusions. However, the DMC will monitor Hauser diaries and other assessment scores for unexpected results. An participant may be withdrawn if deemed to be experiencing unexpected motor deterioration. The treating neurologist may also titrate their usual PD medication regimen. ; • PEG‐J site infection – this is uncommon in LCIG therapy patients and is typically treated with topical or oral antibiotics. ; . An adverse event or suspected adverse reaction is considered "serious" if, in the view of the investigators, it results in any of the following outcomes: death, a life‐threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life‐threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such events include anaphylaxis and peritonitis from stoma dehiscence. ; [Safety and tolerability are assessed ; 1. during the infusions (ie. infusion 1, 2, 3 and 4) ; 2. at each visit prior to next infusion (ie 2 weeks post first infusion (FMT or placebo), at 4 weeks post infusion 2, at 2 weeks post infusion 3); 3. at 4 weeks post last infusion (post infusion 4); 4. at 4 months post last infusion; 5. at 11 months post last infusion ] SECONDARY OUTCOME: Change in gastrointestinal symptoms of Parkinson's disease as measured by the Patient Assessment Constipation – Symptoms (PAC‐SYM) scale[1. at 4 weeks post infusion 2 (ie 2 weeks following 2nd treatment of either FMT or placebo) ; 2. at 4 weeks post last infusion (post infusion 4 ‐ FMT or placebo) ; 3. at 4 months post last infusion ; 4. at 11 months post last infusion ] change in gastrointestinal symptoms of Parkinson's disease, as measured by the gastrointestinal dysfunction scale for Parkinson's disease ( GIDS‐PD) [1. at 4 weeks post infusion 2 (ie 2 weeks following 2nd treatment of either FMT or placebo) ; 2. at 4 weeks post last infusion (post infusion 4 ‐ FMT or placebo) ; 3. at 4 months post last infusion ; 4. at 11 months post last infusion ] Change in Non‐motor symptoms in PD (New Non‐motor symptoms scale for Parkinson's disease) [1. at 4 weeks post infusion 2 (ie 2 weeks following 2nd treatment of either FMT or placebo) ; 2. at 4 weeks post last infusion (post infusion 4 ‐ FMT or placebo) ; 3. at 4 months post last infusion ; 4. at 11 months post last infusion ] Change in non‐motor symptoms of anxiety and depression as measured by the Hospital Anxiety and Depression Scale[1. at 4 weeks post infusion 2 (ie 2 weeks following 2nd treatment of either FMT or placebo) ; 2. at 4 weeks post last infusion (post infusion 4 ‐ FMT or placebo) ; 3. at 4 months post last infusion ; 4. at 11 months post last infusion ] Change in overall quality of life as measured by the PDQ‐8[1. at 4 weeks post infusion 2 (ie 2 weeks following 2nd treatment of either FMT or placebo) ; 2. at 4 weeks post last infusion (post infusion 4 ‐ FMT or placebo) ; 3. at 4 months post last infusion ; 2. at 4 weeks post last infusion (post infusion 4 ‐ FMT or placebo) ; 3. at 4 months post last infusion ; 2. at 4 weeks post last infusion (post infusion 4 ‐ FMT or placebo) ; 3. at 4 months post last infusion ; 2. at 4 weeks post last infusion (post infusion 4 ‐ FMT or placebo) ; 3. at 4 months post last infusion ; 4. at 11 months post last infusion ] overall change in health status measured by the EQ‐SD[1. at 4 weeks post infusion 2 (ie 2 weeks following 2nd treatment of either FMT or placebo) ; 4. at 11 months post last infusion ] change in overall quality of life as measured by the Schwab and England Activities of Daily living[1. at 4 weeks post infusion 2 (ie 2 weeks following 2nd treatment of either FMT or placebo) ; 4. at 11 months post last infusion ] Change in participant motor state as assessed by unified dyskinesia rating scale[1. at 4 weeks post infusion 2 (ie 2 weeks following 2nd treatment of either FMT or placebo) ; 4. at 11 months post last infusion ] Change in participant motor state rated using serial UPDRS motor subs‐scores [1. at 4 weeks post infusion 2 (ie 2 weeks following 2nd treatment of either FMT or placebo) ; 2. at 4 weeks post last infusion (post infusion 4 ‐ FMT or placebo) ; 3. at 4 months post last infusion ; 4. at 11 months post last infusion ] INCLUSION CRITERIA: Patients with a clinical diagnosis of idiopathic Parkinson disease at time of referral, who are currently receiving levodopa/carbidopa intestinal gel (LCIG) via percutaneous endoscopic jejunostomy tube (either 16 or 24 hours per day) Patients with >/= 3 hours of OFF time (defined as anything other than best ON) Cognitive capacity to provide their own consent, based on clinical judgement of investigator stable LCIG infusion rate for past 4 weeks