This study has been transitioned to CTIS with ID 2023-509672-42-00 check the CTIS register for the current data. Primary Objective:-To determine the long-term safety and tolerability of multiple individually titrated doses of radiprodil as an addon…
ID
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
- Encephalopathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Adverse events (AEs), serious adverse events (SAEs), and adverse drug
reactions (ADRs) (frequency, type, severity, and duration)
• Changes in vital signs
• Physical examination findings
• 12-lead electrocardiogram (ECG) findings
• Clinically significant changes in laboratory parameters
• Emergence of new seizure types
• Occurrence of suicidal ideation or behavior
• Determination of the maximum tolerated dose of radiprodil based on safety and
tolerability data
• Plasma concentrations of radiprodil at predefined timepoints
Secondary outcome
• Change from Baseline to end of treatment in seizure frequency from daily
seizure electronic diary (eDiary)
• Percent change from Baseline to end of treatment in video
electroencephalogram (V EEG) seizure burden (e.g., seizure type, severity, and
frequency recorded during V EEGs)
• Seizure free days and longest period with no seizures
Change from Baseline to end of treatment in seizure frequency from daily
seizure electronic diary (eDiary)
• Percent change from Baseline to end of treatment in video
electroencephalogram (V EEG) seizure burden (e.g., seizure type, severity, and
frequency recorded during V EEGs)
• Seizure free days and longest period with no seizures
• Change from Baseline to end of treatment in behavioral features as measured
by Vineland adaptive behavioral scale (VABS), Bayley scale of infant
development (BSID), and the aberrant behavior checklist-community (ABC-C), as
well as other disorder features as measured by gross motor function measure
(GMFM), sleep disturbance scale for children (SDSC), quality of life (Pediatric
Quality of Life Inventory [PedsQL]), Caregiver Burden Inventory (CBI),and
global impression (Caregiver Global Impression of Change [CaGI C] evaluating
seizures, behavioral symptoms and overall condition),]), and Clinical Global
Impression of Change [CGI-C] scales)
• Plasma concentrations of the 2 major metabolites of radiprodil
Background summary
The first description of GRIN2B mutations causing neurodevelopmental disorders
was in 2010 and was followed by reports of patients with drug-resistant
infantile spasms (IS) caused by GRIN2B mutations4 This has since been described
as GRIN2B-related disorder, a severe developmental disorder with onset during
first months of life and characterized by the presence of a variety of
neuropsychiatric symptoms that include developmental delay and intellectual
disability, epilepsy, hypotonia, and movement disorders. GRIN2B-related
disorder is part of a broader category called GRIN related disorders, a group
of neurodevelopmental syndromes caused by mutations in the different subunits
that assemble to form the NMDA glutamate receptor (i.e., GRIN1, GRIN2A, GRIN2B,
and GRIN2D). Since the first description of GRIN2B-related disorder, a few
hundred patients have been identified.
The unmet clinical need for patients with GRIN-related disorders, including
variants in GRIN1, GRIN2A, GRIN2B, and GRIN2D, is significant. Most of the
clinical manifestations and symptoms of GRIN-related disorders are poorly
responsive to available therapies, which aim to manage the most severe
symptoms, such as seizures and behavioral symptoms. The main therapeutic
approach for patients with epilepsy is to control abnormal brain activity, as
observed by electroencephalogram (EEG) recordings, or that manifests as
seizures.
To date, there are no effective nor approved treatments for GRIN-related
disorder. Non-seizure symptoms can be managed through physical, speech,
behavioral, or occupational therapies.
Full Background: see Protocol section 5.1.1
Study objective
This study has been transitioned to CTIS with ID 2023-509672-42-00 check the CTIS register for the current data.
Primary Objective:
-To determine the long-term safety and tolerability of multiple individually
titrated doses of radiprodil as an addon therapy to standard of care (SOC)
in pediatric participants
-To establish a safe and well tolerated dose after 8 weeks of continuous
treatment in Part A
-To determine the PK and plasma exposure of radiprodil and its metabolites
after administration of different doses in pediatric participants
Secondary Objective:
-To evaluate initial signs of efficacy on frequency and severity of epileptic
seizures in those participants with seizures
-To evaluate initial signs of efficacy of radiprodil on additional CNS features
including communication, cognition, behavior, motor symptoms, sleep,
and quality of life, and the maintenance of the treatment effect
-To determine the PK and the plasma exposure of radiprodil major metabolites
obtained at different doses in Part A
Study design
This is an open-label, multicenter phase 1B study to evaluate the safety,
tolerability, and PK of multiple individually titrated doses of radiprodil and
to assess the treatment effect on seizures and behavioral symptoms in 2 cohorts
of pediatric participants: 1 cohort of participants with treatment resistant
seizures (with or without behavioral symptoms) and 1 cohort of participants
with behavioral symptoms (but no qualifying seizures) caused by GoF variants in
the GRIN1- , 2A-, 2B- of 2D- genes.
More information see Protocol Summary 1.1 Synopsis
Intervention
The pediatric radiprodil formulation used in this study is an oral suspension
obtained by reconstitution of dispersible granules with a diluent. The oral
suspension will be prepared extemporaneously at the clinical site.
The volume of radiprodil will be determined based on the participant*s weight
and assigned dose.
Study burden and risks
The following information originate from the ICF:
While it is possible that treatment with radiprodil may improve your child*s
symptoms, he/she might not have any benefits from taking part in this study.
The purpose of this study is to learn more about radiprodil.
- The child may experience the side effects or adverse effects of
radiprodil:
The child may have some unwanted effects and symptoms because of treatment with
radiprodil. In healthy adult study participants who were treated with
radiprodil, the most frequently reported unwanted effects and symptoms were
headache, sleepiness, dizziness, vertigo, disturbance in attention, having
trouble falling and/or staying asleep, changes in mood, sore throat, and
feeling intense excitement and happiness. In adult study participants with
nerve pain related to high blood sugar (diabetes) who were treated with
radiprodil, the most frequently reported unwanted effects and symptoms were
having trouble falling and/or staying asleep, dizziness, headache, and feeling
tired or having low energy.
Because this is a clinical research study, there may be other risks that are
not yet known.
- The child may feel some pressure when the blood pressure cuff is inflated.
- The child may feel discomfort when the blood samples or finger or heel-pricks
are being taken. It may cause pain, bleeding, or bruising at the spot where the
needle is inserted into the skin. The study staff might give your child a
numbing medicine to help it hurt less. Sometimes taking blood causes fainting
or infection. Swelling of a vein or a blood clot occurs in very rare cases.
- The sticky pads used to perform an ECG may cause skin irritation and
itchiness.
- The VEEG procedure (see also Appendix C) will be recorded by video and will
take from between 8 to 24 hours. The test is generally safe and painless, but
there is a small risk of having a seizure during the test. Some children will
find this test unacceptably challenging and may have difficulty completing it.
- Some of the questions in the questionnaires might make the parents and/or
child feel embarrassed or upset.
- Completing all the questionnaires will take you 30 to 45 minutes.
- Parents need to take a note of the child*s treatments, seizures, and symptoms
(if applicable) every day. This will take 5-10 minutes, depending on the number
of seizures per day.
- Attending all the study visits will cost extra time.
- The child will need to stay overnight in the hospital.
- The parents and child must comply with the study agreements
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Listed location countries
Age
Inclusion criteria
Inclusion criteria:
For Part A and Part B (unless stated otherwise):
1. For Part A, pediatric participants aged >=6 months to <=12 years with GRIN 1,
2A, 2B, or 2D gene variants known to result in GoF of the NMDA receptor. For
Part B, pediatric participants aged >=6 months with GRIN 1, 2A, 2B, or 2D gene
variants known to result in GoF of the NMDA receptor.
2. Participant to be enrolled in the first cohort experiences the following
(Part A only):
a) At least 1 observable motor seizure per week and >=4 observable motor
seizures (generalized or focal) during the prospective 4-week Observation
Period.
b) Has failed to obtain adequate seizure control with at least 2 ASMs used at
appropriate dose and duration with assured medication adherence (if applicable).
3. Participant to be enrolled in the second cohort experiences the following
(Part A only):
a) Significant behavioral and/or motor symptoms based on caregiver report with
a CGI-S score >=4 at the Screening Visit and Day -1 of Visit T1.
4. For part A, current therapies need to be on a stable dose for at least 4
weeks prior to Screening and should be maintained stable throughout the whole
study duration, nonpharmacological treatments such as ketogenic diet should be
kept as stable as possible during screening and participation in the study.
Changes in antiseizure medication should be discussed with the sponsor in
consultation with the investigator.
For all inclusion criteria see Protocol.
Rescreening criteria for Part B only:
1. Participant has received at least 8 weeks of treatment (combined Titration
and Maintenance Period) with radiprodil during Part A.
2. The benefit-risk of continuing radiprodil treatment remains favorable as
determined by the investigator*s clinical assessment and is eligible to
continue treatment according to the judgement of the investigator.
Exclusion criteria
Exclusion criteria (at initial Screening and following completion of the
Maintenance Period of Part A, unless stated otherwise): 1. Participant with any
other clinically relevant medical, neurologic, or psychiatric condition and/or
behavioral disorder unrelated to GRIN related disorders that would preclude or
jeopardize participant*s safe participation or administration of study drug or
the conduct of the study according to the judgement of the investigator. 2.
Participant with a body weight <10 kg on Day -1 of Visit T1 for whom a gastric
tube is the only possibility for radiprodil dosing (during treatment with the
first dose in Part A only). 3. Participant with any clinically significant
laboratory or ECG abnormalities. 4. Participant has severe hepatic dysfunction
(Child-Pugh grade C). 5. Participant has a history of brain surgery for
epilepsy or any other reason. For all exclusion criteria see Protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-509672-42-00 |
| EudraCT | EUCTR2022-000317-14-NL |
| CCMO | NL80839.000.22 |