Protective Role of Pre-/ Post-biotics on Gut Inflammation, Dysbiosis, and Life Quality in Rett Syndrome (Biotics_RTT)

NCT ID: NCT05420805

Last Updated: 2023-04-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 28 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-04-01
• Study Completion Date: 2023-02-28

Brief Summary

The study will examine the potential efficacy and safety of two pre- and post-biotics on markers for gut inflammation and intestinal microbiota ecology in patients with Rett syndrome. Moreover, this trial will search for possible effects on epileptogenesis and quality of life.

Detailed Description

The gastrointestinal tract is the major site of exposure to environmental molecules where 1) dietary components are chemically transformed by the microbiota, and 2) gut-derived metabolites are disseminated to all organs, including the brain. The human gut microbiota directly affects human health, and its alteration can lead to gastrointestinal abnormalities and inflammation. Indeed, accumulating clinical and experimental evidences indicate that the gut microbiota impacts behavior, modulates neurotransmitter production in the gut and brain, influences brain development and myelination patterns. Specific gut-derived metabolites, such as 4-ethylphenyl sulfate (4-EPS) and isoamylamine (IAA) are known to alter brains activity and anxiety behavior in mice and/ or promoting neural cell death leading to cognitive decline. Rett syndrome (RTT; Online Mendelian Inheritance in Man, OMIM number #312750) is a severe and progressive neurological disorder that almost exclusively affects females with an incidence of ~1:10,000 live births. Loss-of-function mutations of the X-linked methyl-CpG binding protein 2 (MeCP2) gene is the major cause (approximately 90 %) of classical cases of RTT. Although a rare disorder, RTT represents a leading cause of severe cognitive impairment in the female gender. Affected individuals commonly show a period of apparent early normal development, followed by regression of hand and/or communication skills, and subsequent development of hand stereotypies, while gait is often abnormal in those who are learning to walk.

Despite a wide phenotypic variability, RTT is commonly associated with epilepsy, sleep disturbances, and gastrointestinal dysfunction thus suggesting a link between RTT's gastrointestinal abnormalities and the gut microbiota.

RTT is associated with a dysbiosis of both the bacterial and fungal component of the gut microbiota, suggesting that MeCP2 loss-of-function can favour the establishment of a peculiar microbial community with altered production of short chain fatty acids (SCFAs) possibly contributing to the RTT gastrointestinal physiopathology.

Modulation of the systemic inflammatory response using pre- and post-biotics is advocated as a possible global therapeutic approach in neurological diseases such as Alzheimer's dementia.

Alpha-lactalbumin (ALAC), is the predominant whey protein in human milk, provides essential amino acids for protein synthesis in the developing neonates. Its supplementation in adults are associated with improved cognition, better memory and sleep. The bioactive properties of ALAC relate to antimicrobial activity, pre-biotic features and epithelial restoration via selective apoptosis activity. Moreover, the antibacterial peptides released from ALAC during digestion can exert immunostimulatory effects inducing phagocytic activity. Overall, ALAC shows reduction of inflammation and oxidative stress status as well as improvement of insulin resistance and increase in the synthesis of brain serotonin, a central nervous system neurotransmitter with well-known antiepileptic activity.

Butyrate, a bacterial metabolite and one of the main SCFAs, exhibits a broad range of pharmacological activities including microbiome modulating, anti-inflammatory, metabolic pathway regulating and anti-oxidant actions.

This body of knowledge supports testing pre- and post-biotics strategies for benefit in individuals with Rett syndrome with the goal of translating potential new treatments from experimental models to clinical practice. Results of this study could lead to the first approved pre- / post-biotics treatment for common co-morbidities in the disorder.

Conditions

Rett Syndrome; Dysbiosis; Epilepsy; Quality of Life

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Pre- and post-biotic (ALAC, inulin, FOS, and sodium butyrate)

The product (ALAC+butyrate+inulin+fructo oligosaccharides FOS) is a powder for oral suspension. Dosage is dependent on weight. For participants weighing \<50 kg, a 4 g dose (i.e., one 4 g sachet) is intended to be administered orally once a day after dissolving in water. For participants weighing ≥50 kg, a 4 g dose (i.e., 4 g sachets) is intended to be administered orally twice a day (12h interval) after dissolving in water.

Group Type: ACTIVE_COMPARATOR

ALAC, inulin, FOS, and sodium butyrate

Intervention Type: DIETARY_SUPPLEMENT

Pre- and post-biotic supplementation will be administered for 3 month period (i.e. 12 weeks) given the filling out of a supplementation diary by parents/caregivers. At the scheduled visits/ phone contacts (i.e., baseline, 4 weeks and 12 weeks), systemic inflammation, intestinal inflammation, and gut microbiome characterization as well as treatment compliance, clinical and dietary intake will be assessed. A seizure diary will be provided to parents/caregivers in order to check the frequency and entity of the critical episodes. An EEG recording will be performed at enrollment (or within 6 months prior to the baseline visit).

Post-biotic (sodium butyrate and zinc oxide)

The product (sodium butyrate+ zinc oxide) is in the form of tablets. Dosage is dependent on weight. For participants weighing \<25 kg, one 380 mg tablet is intended to be administered orally twice a day . For participants weighing 25 to 40 kg, three 380 mg tablet dose is intended to be administered orally according to the 2+1 tablets per day schedule (12h interval). For participants weighing ≥40 kg, four 380 mg tablet dose is intended to be administered orally according to the 2+2 tablets per day schedule (12h interval).

Group Type: ACTIVE_COMPARATOR

Sodium butyrate and zinc oxide

Intervention Type: DIETARY_SUPPLEMENT

Post-biotic supplementation will be administered for 3 month period (i.e. 12 weeks) given the filling out of a supplementation diary by parents/caregivers. At the scheduled visits/ phone contacts (i.e., baseline, 4 weeks and 12 weeks), systemic inflammation, intestinal inflammation, and gut microbiome characterization, as well as treatment compliance, clinical and dietary intake will be assessed. A seizure diary will be provided to parents/caregivers in order to check the frequency and entity of the critical episodes. An EEG recording will be performed at enrollment (or within 6 months prior to the baseline visit).

Interventions

ALAC, inulin, FOS, and sodium butyrate

Pre- and post-biotic supplementation will be administered for 3 month period (i.e. 12 weeks) given the filling out of a supplementation diary by parents/caregivers. At the scheduled visits/ phone contacts (i.e., baseline, 4 weeks and 12 weeks), systemic inflammation, intestinal inflammation, and gut microbiome characterization as well as treatment compliance, clinical and dietary intake will be assessed. A seizure diary will be provided to parents/caregivers in order to check the frequency and entity of the critical episodes. An EEG recording will be performed at enrollment (or within 6 months prior to the baseline visit).

Intervention Type: DIETARY_SUPPLEMENT

Sodium butyrate and zinc oxide

Post-biotic supplementation will be administered for 3 month period (i.e. 12 weeks) given the filling out of a supplementation diary by parents/caregivers. At the scheduled visits/ phone contacts (i.e., baseline, 4 weeks and 12 weeks), systemic inflammation, intestinal inflammation, and gut microbiome characterization, as well as treatment compliance, clinical and dietary intake will be assessed. A seizure diary will be provided to parents/caregivers in order to check the frequency and entity of the critical episodes. An EEG recording will be performed at enrollment (or within 6 months prior to the baseline visit).

Intervention Type: DIETARY_SUPPLEMENT

Eligibility Criteria

Inclusion Criteria

• Diagnosis of classic/typical Rett syndrome (and proven loss-of-function mutation of the MeCP2 gene) with gastrointestinal dysfunction and/or positive history of epilepsy
• Female gender (age > / = 3 years old)
• Ability to obtain written informed consent from their parent(s)/legal guardian(s)
• Stable medications for at least 4 weeks prior to the baseline visit.

Exclusion Criteria

• Diagnosis not fitting into the Rett syndrome consensus guidelines
• Nonpathogenic MECP2 mutation or mutations in non-MECP2 genes (i.e., cyclin-dependent kinase 5, CDKL5; forkhead box protein G1, FOXG1)
• Male gender
• Percutaneous endoscopic gastrostomy (PEG) tube
• Proven hypersensitivity to one or more components of the dietary supplements (X-biotics)
• Unstable concomitant medications less than 4 weeks prior to enrollment visit.
• Concomitant antibiotic therapy at the enrollment. In the case of antibiotic therapy, a 4-weeks washout period will be undertaken.
• Rejection of the informed consent form by the parents/caregivers and/or lack of compliance to the Study procedures.

• Minimum Eligible Age: 3 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Kolfarma s.r.l. - Italy

UNKNOWN

Sponsor Role: collaborator

European Institute of Oncology

OTHER

Sponsor Role: collaborator

Azienda Ospedaliera Universitaria Senese

OTHER

Sponsor Role: lead

Responsible Party

Claudio De Felice

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Claudio De Felice, MD

Role: PRINCIPAL_INVESTIGATOR

Policlinico "S. Maria alle Scotte" Azienda Ospedaliera Universitaria Senese , 53100 Siena, Italy

Locations

Policlinico "S. Maria alle Scotte" Azienda Ospedaliera Universitaria Senese

Siena, , Italy

Countries

Italy

Other Identifiers

NCT

Identifier Type: -

Identifier Source: org_study_id