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Trial registered on ANZCTR


Registration number
ACTRN12614000187640
Ethics application status
Approved
Date submitted
11/02/2014
Date registered
20/02/2014
Date last updated
18/01/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase I trial of oral triheptanoin add-on treatment for children with medically refractory epilepsy
Scientific title
To determine to which extent children 3-18yrs with medically refractory epilepsy given treatment with triheptanoin oil will experience fewer seizures and fewer side effects.
Secondary ID [1] 284035 0
2013/008449(007)
Department of Health Theraputic Goods Administration
Clinical Trial Notification
Universal Trial Number (UTN)
Trial acronym
TRIP C1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Medically refractory epilepsy 291090 0
Condition category
Condition code
Neurological 291432 291432 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: Triheptanoin (triglyceride of heptanoate), a stable, edible tasteless oil that has been used in patients with metabolic disorders.
After an 8 week baseline period counting seizures, subjects with > 2 seizures per fortnight will be enrolled and treated with up to 35% of caloric input triheptanoin (max 100 ml oil/day). The oil will be added to a normal diet, starting at 5ml dosed 3 times per day, titrated up over 6weeks and full dose given for a period of 12 weeks. For example, patients eating 2000 Kcal per day, will start with 3 x 5ml triheptanoin daily for the 1st week, followed by 3 x 10 ml in the 2nd, 3 x 15 ml in the 3rd, 3 x 20 ml in the 4th week, and 3 x 25 ml in the 5th week and 3 x 27.5 ml as the final maximal dose (35% of caloric intake, 87.5 ml/day). The full dose will be 35% of caloric intake if tolerated. During the full time of the study seizures, adverse events, side effects, weight and quality of life will be recorded. To improve adherence the participants will have regular contact with a dietitian face-to-face and via phone. Participants/carers will fill in a food diary and treatment diary to monitor compliance and return the used and unused bottles of oil.
Intervention code [1] 288728 0
Treatment: Other
Comparator / control treatment
Comparing results to baseline
Control group
Uncontrolled

Outcomes
Primary outcome [1] 291418 0
To establish the safety and tolerability of triheptanoin in children with epilepsy.
At each visit patients will be assessed for their general medical and neurological health and body weight. Seizure, treatment and food diaries will be reviewed to ensure adequate nutrition. Patients will be specifically asked about adverse events and side effects. Blood tests will be performed for FBE, U&E, LFT, plasma glucose, fasting lipid profile, total ketones, micronutrients including zinc and selenium, acylcarnitine profile, vitamin D and AED levels. While patients are taking triheptanoin a Pediatric Side Effect Questionnaire (PESQ (Morita et al., 2012)) will be filled out by caregivers. This test is a 19-item measure consisting of five subscales: cognitive (six items), motor (four items), behavioural (three items), general neurological (four items), and weight (two items) side effects. We will add five items for gastrointestinal side effects to the questionnaire, including gastrointestinal pain, acid reflux, vomiting, diarrhoea, and constipation.
Timepoint [1] 291418 0
Weeks 14,18,22,26
Secondary outcome [1] 306727 0
To determine to which extent triheptanoin treatment in children with medically refractory epilepsy will result in fewer seizures.

Seizure numbers will be measured using seizure diaries that will be kept by parents of participants.
Timepoint [1] 306727 0
Weeks 14, 18, 22, 26
Secondary outcome [2] 306950 0
To determine to which extent triheptanoin treatment in children with medically refractory epilepsy will result in few side effects.

Side effects will be assessed using the Pediatric Side Effect Questionnaire as described in the Primary Outcome. Examples of possible side effects include diarrhoea, abdominal pain, and nausea.
Timepoint [2] 306950 0
Weeks 14, 18, 22, 26

Eligibility
Key inclusion criteria
1. Male or female subjects (3-18 years old) with epilepsy who have experienced at least two motor seizures per fortnight over two months prior to enrolment despite treatment with at least one antiepileptic drug (AED) at clinically appropriate doses; (*Eligible seizure types are: complex partial seizures (focal dyscognitive seizures), secondary generalised seizures, simple partial seizures with motor features, primary generalised seizures, tonic seizures, atonic seizures);
2.There has been no change in anti-epileptic drugs over the four weeks prior to enrolment;
3.Females of childbearing potential must have a negative serum Beta subunit of human chorionic gonadotropin (Beta hCG) at Visit 1 and a negative urine pregnancy test prior to randomization at Visit 2. Female subjects of childbearing potential must also agree to be abstinent or to use at least 1 medically acceptable method of contraception. If the subject is on a hormonal type of contraceptive, they must agree to use an additional second approved method of contraception.
Minimum age
3 Years
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of major psychiatric morbidity (such as psychiatric illness requiring hospitalisation or history of psychosis or major depression) in patients;
2.Patients and/or parents with history of substance abuse;
3.A history of having had psychogenic non-epileptic seizures;
4.Patients who have seizure clusters or other reasons that make counting of numbers of seizures inaccurate;
5.Females who are breast feeding;
6.Patients with propionic academia or methylmalonic acidemia or with disorders affecting medium and short chain fatty acid oxidation. This includes medium-chain acyl-CoA dehydrogenase deficiency - MCAD, short-chain acyl-CoA dehydrogenase deficiency - SCAD, short-chain-3 hydroxyacyl-CoA dehydrogenase deficiency –SCHAD and HMG CoA (3-hydroxy-3-methyl-glutaryl-CoA) synthase deficiency

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Children with uncontrolled epilepsy will be recruited from the pediatric epilepsy clinics at both the Royal Brisbane and Mater hospitals. Especially, we recruit patients who are on the waiting list for the ketogenic diet or the Modified Atkins Diet, which is approximately four months. Patients who did not find seizure relief on the first AED, as well as those who have tried several AEDs will be included
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Data from 20-50 patients subject to new treatment are traditionally regarded sufficient before larger clinical trials are initiated.
Safe and tolerability: All adverse events as well as number of patients discontinuing treatment will be collected and summarized in table format for evaluation. Data will be compared to those from the literature on established epilepsy treatments.
Seizures: Our power analysis is similar to that published for ketogenic diets, defining a 25% change in seizure frequency as the minimum effect size of clinical importance. We will be testing the null hypothesis that there will be no difference between the seizure frequency during baseline and treatment period for each patient. Assuming a correlation of before and after treatment of r equals 0.5 and an expected outcome range of mean percentage of baseline seizures from 0–200% (standard deviation of 45%), we will need greater than or equal to 35 patients to allow detection of greater than or equal to 25% difference at the 0.05 significance level (two-tailed) with a power of 90%. If we assume r equals 0.5 and an expected outcome range of mean percentage of baseline seizures from 0–150% (standard deviation of 37.5%), we will need greater than or equal to 25 patients.
For the responder rate (% of patients who achieve greater than 50% reduction in seizures) we assume 20% for placebo treated (or untreated) patients as a historical number determined on average in many clinical drug trials. In a chi square test the responder rate would need to be 46% in 30 patients or 38% in 50 patients to be significant at the 0.05 level (two-tailed).

Side effects: For evaluation, all side effects reported on a questionnaire and/or spontaneously mentioned will be summarized in table format for our patient population. Data will be compared to those from the literature on established epilepsy treatments. Statistical analysis will be limited to comparisons across different studies.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
21/02/2014
Actual
14/03/2014
Date of last participant enrolment
Anticipated
31/12/2016
Actual
1/11/2016
Date of last data collection
Anticipated
1/08/2017
Actual
1/08/2017
Sample size
Target
50
Accrual to date
Final
12
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 4473 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 7742 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 288665 0
University
Name [1] 288665 0
University Of Queensland
Country [1] 288665 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
Dr Karin Borges, Senior LecturerSkerman Building 65
Research Rd
University of Queensland
St Lucia
QLD 4027
Country
Australia
Secondary sponsor category [1] 290905 0
Hospital
Name [1] 290905 0
Lady Cilento Children's Hospital
Address [1] 290905 0
Stanley St, South Brisbane Q 4101
Country [1] 290905 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290515 0
Children's Health Services Human Research Ethics Committee
Ethics committee address [1] 290515 0
Level 3, RCH Foundation Building
Royal Children's Hospital
Herston Rd
Herston
QLD 4029
Ethics committee country [1] 290515 0
Australia
Date submitted for ethics approval [1] 290515 0
Approval date [1] 290515 0
29/05/2013
Ethics approval number [1] 290515 0
HREC/13/QRCH/37

Summary
Brief summary
We established that triheptanoin (triglyceride of heptanoate), a stable, edible tasteless oil that has been used in the clinic in patients with metabolic disorders, is an anticonvulsant in four mouse seizure models. This Phase I clinical trial aims to establish the feasibility, safety and tolerability of triheptanoin as add-on treatment in children with treatment-resistant epilepsy, and obtain indications for its efficacy against medically refractory seizures. We propose to initiate a pilot phase I clinical trial of 50 children (3-18 yr of age) with treatment-resistant epilepsy at the Royal and Mater Children’s Hospitals in Brisbane. Eligible patients without contraindications to triheptanoin will count seizures during a baseline period of two months. Subjects with more than two seizures per fortnight will be enrolled and receive slowly increasing doses of triheptanoin (max 35% of caloric intake) during meals until the maximum tolerable dose is reached. All patients will be counselled and monitored by a dietitian before, during and after the treatment to ensure that they receive adequate nutrition.
This treatment would be ideal for patients with epilepsy in the developed and developing world, because: 1) triheptanoin does not require refrigeration and is straightforward to add to meals and 2) it is not expected to change metabolism of other drugs and require “drug monitoring” nor to have significant side effects.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 46042 0
Dr Sophie Calvert
Address 46042 0
Neuroscience Department
Lady Cilento Children's Hospital
501 Stanley St
South Brisbane
QLD 4101
Country 46042 0
Australia
Phone 46042 0
+61 7 3068-1111
Fax 46042 0
Email 46042 0
[email protected]
Contact person for public queries
Name 46043 0
Sharon Gilchrist
Address 46043 0
Neuroscience Department
Lady Cilento Children's Hospital
501 Stanley St
South Brisbane
QLD 4101
Country 46043 0
Australia
Phone 46043 0
+61 7 3068-1111
Fax 46043 0
Email 46043 0
[email protected]
Contact person for scientific queries
Name 46044 0
Karin Borges
Address 46044 0

School of Biomedical Sciences
University of Queensland
Brisbane, QLD 4072
Country 46044 0
Australia
Phone 46044 0
+61 7 3365 3113
Fax 46044 0
Email 46044 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA pilot study of add-on oral triheptanoin treatment for children with medically refractory epilepsy.2018https://dx.doi.org/10.1016/j.ejpn.2018.07.014
N.B. These documents automatically identified may not have been verified by the study sponsor.