Targeting the Gut to Improve Seizure Control in CDKL5 Deficiency Disorder (CDD) (NUTRIENT)

Targeting the Gut to Improve Seizure Control in CDD

Standard anti-seizure medications have limited efficacy in seizure control in cyclin-dependent kinase-like 5 deficiency disorder (CDD).

The study will investigate whether targeting the gut-microbiota-brain axis in CDD patients can alleviate seizures and ameliorate other comorbidities.

Study Overview

• Status: Recruiting
• Conditions: CDKL5
• Intervention / Treatment: Dietary supplement: alpha-lactalbumin, fructooligosaccharides, inulin; Dietary supplement: alpha-lactalbumin, sodium butyrate, fructooligosaccharides, inulin

Detailed Description

CDD is a neurodevelopmental condition characterized by infantile-onset epilepsy, developmental delays, intellectual and motor disabilities, sleep disturbances, and cortical visual impairment. Currently, there is no treatment for CDD, and epilepsy is a prominent and severe feature of the disorder. Standard anti-seizure medications have limited efficacy in seizure control, leading to detrimental effects on cognitive and motor development in CDD.

The gut-brain axis has gained attention in epilepsy research, prompted by evidence of gastrointestinal (GI) symptoms in people with epilepsy. Studies have demonstrated significant changes in gut microbial composition in animal models and between individuals with epilepsy and healthy subjects. Notably, CDD patients experience GI problems, and we discovered that they exhibit alterations in their gut microbiota compared to healthy individuals. The study will investigate whether supplementing CDD patients with alpha-lactalbum and prebiotics alone or with post-biotics can improve neurological features and modulate microbiota composition.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Aglaia Vignoli, MD; Phone Number: +390264443960; Email: aglaia.vignoli@unimi.it

Study Locations

• Italy
  • Milan, Italy
    • Recruiting
    • University of Milan
    • Contact: Aglaia Vignoli, MD; Phone Number: +390264443960; Email: aglaia.vignoli@unimi.it
    • Sub-Investigator: Elisa Borghi, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

clinical diagnosis of CDD and demonstrated CDKL5 pathogenic variant; drug-resistant seizures; ensured participation of a caregiver; willingness to sign the informed consent.

Exclusion Criteria:

organic GI disorders (i.e., food allergies, celiac disease); special diets; percutaneous endoscopic gastrostomy tube; use of antibiotics or probiotics in the previous month.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CDD arm; This is a 32-week pilot, single site, cross-over trial of alpha-lactalbumin+ inulin + fructo-oligosaccharides vs alpha-lactalbumin + sodium butyrate + inulin + fructo-oligosaccharides. Periods I and II of the study are 12-week long together with a 4-week washout period.

Dietary supplement: alpha-lactalbumin, fructooligosaccharides, inulin; The first round supplementation will be administered for 3-month period (i.e. 12 weeks). One dose/day (2g sachet) is intended to be administered orally once a day after dissolving in water. At the scheduled visits/phone contacts [i.e., baseline, 12 weeks, and 16 weeks (post washout)], seizure frequency and entity of the critical episodes will be recorded. Gut microbiome characterization, clinical scales and dietary intake will be assessed.; Dietary supplement: alpha-lactalbumin, sodium butyrate, fructooligosaccharides, inulin; The second round supplementation will be administered for 3-month period (i.e. 12 weeks). For participants weighing <30 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 ≥30 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. At the scheduled visits/phone contacts [i.e., 28 weeks and 32 weeks (post washout)], seizure frequency and entity of the critical episodes will be recorded. Gut microbiome characterization, clinical scales and dietary intake will be assessed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Epilepsy	to evaluate the number of CDD patients considered treatment responders (seizure reduction ≥50%, ≥75% or ≥100% from baseline in monthly seizure counts) during the 12- week treatment period in 1st and 2nd round of supplementation	Change at 3 months from baseline of each round of supplementation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gut microbiota	to evaluate indicator species that could help as biomarkers for guiding clinicians to choose the intervention with the most likelihood of improve patient quality of life.	Change at 3 months from baseline of each round of supplementation
Sleep disturbances	Decreased Sleep SDSC scale (max score=125) by at least 5%	Change at 3 months from baseline of each round of supplementation
gastrointestinal discomfort	Decrease GISI scale (max score = 17), by at least 2 points	Change at 3 months from baseline of each round of supplementation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical features	Clinical Global Impression of Change (CGIC), ranging from 1 (very much improved) to 7 (very much worse), with a score of 4 indicating no change] decrease of at least 1 point	Change at 3 months from baseline of each round of supplementation
Parental stress	Caregiver burden by Parenting Stress Index (PSI-SF); clinically significance > 85%, decrease by at least 5%	Change at 3 months from baseline of each round of supplementation

Collaborators and Investigators

• Sponsor: University of Milan
• Collaborators: Kolfarma s.r.l. - Italy; Fondazione Telethon
• Investigators: Principal Investigator: Aglaia Vignoli, MD, University of Milan

Publications and helpful links

General Publications

• Borghi E, Xynomilakis O, Ottaviano E, Ceccarani C, Vigano I, Tognini P, Vignoli A. Gut microbiota profile in CDKL5 deficiency disorder patients. Sci Rep. 2024 Mar 28;14(1):7376. doi: 10.1038/s41598-024-56989-0.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2024
• Primary Completion (Estimated): January 31, 2025
• Study Completion (Estimated): April 30, 2025

Study Registration Dates

• First Submitted: June 3, 2024
• First Submitted That Met QC Criteria: June 3, 2024
• First Posted (Actual): June 7, 2024

Study Record Updates

• Last Update Posted (Actual): June 7, 2024
• Last Update Submitted That Met QC Criteria: June 3, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: epilepsy, gut microbiota, sleep disorders
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Seizures; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Histamine Antagonists; Histamine Agents; Butyric Acid
• Other Study ID Numbers: GSA23G001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No