Efficacy and Safety of NTI164 in Children and Young Adults With Rett Syndrome
Trial statusNot yet recruiting
Trial phasePhase 2, Phase 3
Trial typeInterventional
Biological sexFemale
Age4-25
SponsorFenix Innovation Group
About this trial
The FENRTT2 study will investigate the efficacy and safety of a medicinal cannabis plant extract with extremely low THC (delta-9-tetrahydrocannabinol), NTI164, on Rett syndrome (RTT) in a crossover design. RTT is a devastating rare genetic condition affecting females and involves debilitating physical and intellectual symptoms. NTI164 is an oil which has demonstrated efficacy in reducing symptoms in several paediatric neurological conditions, including RTT, autism spectrum disorder (ASD), and paediatric acute-onset neuropsychicatric syndrome (PANS). A Phase I/II clinical trial of NTI164 in RTT (FENRTT1/NTIRTT1) showed NTI164 is safe in this population and significantly improved overall clinical severity of illness, as well as core RTT symptoms, including anxiety, mental alertness, communication skills, socialisation/eye contact, and attentiveness. The FENRTT2 study will investigate NTI164 in a larger number of patients, and compare NTI164 to a placebo control. Research tests on patient blood will also be included to further investigate how NTI164 works in the body.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Females aged 4-25 years of age
Weight ≥12 kg
Classical/typical RTT as confirmed with a documented pathogenic variant in the MECP2 gene
At least 6 months post-regression at screening (i.e. no loss or degradation in ambulation, hand function, speech, non-verbal communication, or social skills within 6 months of screening)
Disqualifiers
Current clinically significant cardiovascular, endocrine (such as hypo- or hyperthyroidism, type 1 diabetes, or uncontrolled type 2 diabetes), renal, hepatic, respiratory, or gastrointestinal disease (such as coeliac disease or inflammatory bowel disease), or major surgery planned
Known history or symptoms of long QT syndrome
QTcF interval >450 milliseconds, history of risk factor for torsades de pointes or clinically significant QT prolongation deemed to increase risk
Currently receiving treatment with DAYBUE™ (Trofinetide)
Trial design
Design model
Crossover
Treatments tested in this trial
NTI164
DrugNTI164 is a full-spectrum medicinal cannabis plant extract with \<0.3% THC.
Placebo
DrugPlacebo
Treatment groups
40 Participants
are divided into 2 treatment groupsGroup A: PlaceboPlacebo comparator 1 intervention
Group B: NTI164 activeActive comparator 1 intervention
Trial outcomes
Primary outcomes
1
Rett Syndrome Behaviour Questionnaire (RSBQ)
A validated, FDA-accepted 45-item caregiver-assessed tool to assess a variety of behavioural features impaired in RTT. The caregiver rates items as 0 = not true, 1 = somewhat true or sometimes true, or 2 = very true. Symptoms assessed include maladaptive behaviours, mood disruption, repetitive movements, fear/anxiety, breathing abnormalities, hand behaviours, and gross motor skills. A higher score indicates greater impairment/disease severity.
Time frame
Baseline, Week 12, and Week 28Secondary outcomes
1
Clinical Global Impression - Severity (CGI-S)
7-point scale rating a clinician's impression of disease severity at a given time point, a higher score indicates more severe illness.
Time frame
Baseline, Week 12, and Week 282
Clinical Global Impression - Improvement (CGI-I)
A clinician-rated tool to assess how much an individual's symptoms improve or worsen following an intervention on a 7-point scale. 1-3 = improvement, 4 = no change, 5-7 = worsening. It is anticipated the CGI-I score will be \<4 following NTI164 treatment, indicating moderate-substantial improvement.
Time frame
Baseline, Week 12, and Week 283
RTT-Domain- specific Concerns - Visual Analog Scale (RTT-DSC-VAS)
An 8-point scale assessing areas of functional impairment (0 = normal function, 7 = most severe impairment).
Time frame
Baseline, Week 12, and Week 284
Impact of Childhood Neurologic Disability scale + Quality of Life (ICND + QoL)
Rates the effect of 4 health problems (inattentiveness, impulsivity, or mood; ability to think and remember; neurologic or physical limitations; epilepsy) on 11 aspects of the child and/or family's life (overall health, relationships with parents, relationships with siblings, relationship between your spouse/partner, relationships with child's friends/peers, social life - acceptability by others, social life - number of activities, school - academics, child's self-esteem, loss of original hopes for child/self, and family activities. A higher score indicates a lower level of disability. QoL component rates the QoL of the patient on a 6-point scale (1 = poor, 6 = excellent).
Time frame
Baseline, Week 12, and Week 28Other outcomes
1
Research bloods - transcriptomics
To further clarify the mechanism of action of NTI164, both bulk and single-cell RNA sequencing will be performed on peripheral blood mononuclear cells (PBMCs) from patients at specified time points. This will provide additional information regarding which genes are being expressed in patients at either abnormally low or high levels compared to a non-RTT population, and the effects NTI164 has on gene expression. This workflow includes RNA extraction, depletion of ribosomal RNA via hybrid capture, library preparation, and sequencing. Cleaned sequence reads will then be aligned against the Homo sapiens genome (Build version hg38) and STAR aligner (v2.5.3a) will be used to map unique reads to the genomic sequences. This is exploratory so genes of interest cannot be identified in advance.
Time frame
Baseline, Week 12, Week 16, and Week 282
Research bloods - proteomics (and phosphoproteomics)
To further clarify the mechanism of action of NTI164, proteomics and phosphoproteomics will be performed on peripheral blood mononuclear cells (PBMCs) from patients at specified time points. This will provide additional information regarding which proteins are being expressed at either abnormally low or high levels compared to a non-ASD population, as well as how extensively these proteins are phosphorylated compared to a non-ASD population, and the effects NTI164 has on protein expression and phosphorylation. Samples will be tagged using the TMTpro system and hydrophilic ion liquid chromatography fractionation performed. This is exploratory so proteins of interest cannot be identified in advance.
Time frame
Baseline, Week 12, Week 16, Week 283
Research bloods - methylomics
To further clarify the mechanism of action of NTI164, methylomics will be performed on whole blood from patients at specified time points. This will provide additional information on methylation patterns (e.g. addition of a methyl group to histones or DNA) in patients compared to non-patients, and how NTI164 effects this type of epigenetic modification and how genes of interest may be regulated. This is exploratory so patterns of interest cannot be identified in advance. Genome-wide methylation will be assessed using the Illumina MethylationEPIC v2.0 BeadChip (or the latest version if a new version is available to the study team at the time of analysis).
Time frame
Baseline, Week 12, Week 16, Week 284
Research bloods - cytokine assay
To further clarify the mechanism of action of NTI164, a cytokine assay investigating a panel of inflammatory markers will be performed on plasma from patients at specified time points. The cytokine assay will likely be the LEGENDplex Human Neuroinflammation Panel 1 (13 plex). Cytokines investigated with this panel include VILIP-1, CCL2, sTREM-2, b-NGF, TGF-b1, TNF-a, IL-6, s-TREM-1, sRAGE, CX3CL1, VEGF, BDNF, and IL-18.
Time frame
Baseline, Week 12, Week 16, Week 28Sponsors and contacts
Click on the lead sponsor to view all of their trials.
Fenix Innovation Group
Lead sponsor
Neurotech International Limited
Collaborator
Source ClinicalTrials.gov
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