Sodium valproate for epigenetic reprogramming in the management of high risk oral epithelial dysplasia

• Register: ISRCTN
• Last refreshed on: 5 August 2022
• Main ID: ISRCTN12448611
• Date of registration: 24/04/2018
• Prospective Registration: Yes
• Primary sponsor: University of Liverpool
• Public title: Sodium valproate for epigenetic reprogramming in the management of high risk oral epithelial dysplasia
• Scientific title: Sodium valproate for epigenetic reprogramming in the management of high risk oral epithelial dysplasia
• Date of first enrolment: 15/10/2019
• Target sample size: 110
• Recruitment status: Ongoing
• URL: https://www.isrctn.com/ISRCTN12448611
• Study type: Interventional
• Study design: Randomised; Interventional; Design type: Treatment, Prevention, Drug (Treatment)
• Phase: Phase II

Countries of recruitment

England, Ireland, Scotland, United Kingdom

Contacts

• Name: Julie Perry

• Name: Trial Manager

Key inclusion & exclusion criteria

Inclusion criteria: Current participant inclusion criteria as of 07/07/2022:
1. Recent (<12 months) histological diagnosis of confirmation of OED according to the World Health Organisation (WHO) criteria (i.e: Patients may be eligible who have a longstanding diagnosis of OED diagnosis but then would need either a recent biopsy (<12 months) or to enter the screening route to randomization)
2. Index lesion* which must be:
2.1. Accessible
2.2. Measurable
2.3. Amenable to clinical photography
2.4. Oral cavity, lip or oropharynx
2.5. Minimum lesion size: 10 mm x 10 mm, or >=100 mm2
(* other ‘non-index’ lesions in the same patient may be present and do not make the patient ineligible)
3. Treatment plan for either surgical resection, or for surveillance of the lesion by means of clinical and photographic follow-up
4. The index lesion must be considered to be deemed at high risk (i.e. estimated >20% over 5 years) of malignant transformation, i.e.:
4.1. WHO severe OED or
4.2. WHO mild or moderate OED, with at least one additional high-risk feature(s) from the list below:
4.2.1. Non-smoker (less than 100 cigarettes or equivalent over whole lifetime)
4.2.2. Lesion size >200 mm2
4.2.3. Lateral tongue site
4.2.4. Mucosal speckling or heterogeneous appearance
4.2.5. Excised OSCC during previous 5 years (but not within previous 6 months)
5. The patient is fully informed, has received PIS (Patient Information Sheet) & considered during a ‘cooling-off’ period, is competent to consent, and is able to comply with minimum attendance requirements
6. Aged =18 years

Previous participant inclusion criteria:
1. Recent (<12 months) histological diagnosis of confirmation of OED according to the World Health Organisation (WHO) criteria (i.e: Patients may be eligible who have a longstanding diagnosis of OED diagnosis but then would need either a recent biopsy (<12 months) or to enter the screening route to randomization)
2. Index lesion* which must be:
2.1. Accessible
2.2. Measurable
2.3. Amenable to clinical photography
2.4. Oral cavity, lip or oropharynx
2.5. Minimum lesion size: 10 mm x 10 mm, or >=100 mm2
(* other ‘non-index’ lesions in the same patient may be present and do not make the patient ineligible)
3. Treatment plan for either surgical resection, or for surveillance of the lesion by means of clinical and photographic follow-up
4. The index lesion must be considered to be deemed at high risk (i.e. estimated >20% over 5 years) of malignant transformation, i.e.:
4.1. WHO severe OED or
4.2. WHO mild or moderate OED, with at least one additional high-risk feature(s) from the list below:
4.2.1. Non-smoker (less than 100 cigarettes or equivalent over whole lifetime)
4.2.2. Lesion size >200 mm2
4.2.3. Lateral tongue site
4.2.4. Mucosal speckling or heterogeneous appearance
4.2.5. Excised OSCC during previous 5 years (but not within previous 6 months)
5. The patient is fully informed, has received PIS (Patient Information Sheet) & considered during a ‘cooling-off’ period, is competent to consent, age >=18, and is able to comply with minimum attendance requirements
Exclusion criteria: 1. Synchronous or metachronous OSCC (i.e. at time of screening or within 6 months)
2. Active malignancy outside head and neck region (with exception of non-melanoma skin cancer)
3. Inflammatory co-existing oral lesions: lichen planus, fungal (candidiasis) oral lesions, scleroderma
4. OSCC susceptible conditions e.g. Fanconi Anaemia, Bloom's syndrome, Ataxia Telangectasia, Li Fraumeni syndrome etc
5. Clinical and/or histopathological diagnosis of oral submucous fibrosis
6. Immunosupression, however, low dose i.e. < 10mg/day prednisolone, or equivalent steroids, are not considered an exclusion
7. Chronic previous or current use of Sodium Valproate
8. Diagnosed epilepsy that has chronic previous or current use of any antiepileptic therapy
9. Obesity (Body Mass Index >= 30)
10. Known relative or absolute contraindications to Sodium Valproate (as listed in British National Formulary), and specifically:
10.1. Acute porphyria
10.2. Known or suspected mitochondrial disorders
10.3. Personal or family history of severe hepatic dysfunction, current hepatic dysfunction (as evidenced by LFTs outwith reference range and prolonged prothrombin time)
10.4. Past history or current pancreatitis
10.5. Women with childbearing potential (< 2 years post menopause), pregnancy, breastfeeding. (This is iterated in more detail in SOP as per appendix 1)
10.6. Potential drug interactions (particularly antipsychotic and anticonvulsant medications, MAO inhibitors, antidepressants, benzodiazepines), specifically patients taking phenobarbital, primodone, carbopenem antibiotics (imipenem, panipenem, meropenem), cimetidine, erythromycin, lamotrigine, olanzapine, pivmecillinam, sodium oxybate, zidovudine, carbamazepine, phenytoin, rifampicin, salicylates e.g. aspirin
10.7. Patients with suicidal ideation and behaviour should be excluded from the trial. Patients should also be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered
10.8. Patients with known or suspected mitochondrial disease, systemic lupus erythematosus or hyperammonaemia

Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Oral epithelial dysplasia
Oral Health
Diseases of oral cavity, salivary glands and jaws

Intervention(s)

Current intervention as of 07/07/2022:
SAVER is a randomised (1 control [no medication]: 2 Sodium Valproate), unblinded, multi-centre placebo-controlled phase II clinical trial investigating the use of sodium valproate in patients with a High Risk Oral Epithelial Dysplasia.

Patients shall be allocated based on a 1:2 allocation ratio with the greater number of patients being allocated to the experimental arm (sodium valproate). The sequences of allocation will be centrally generated by the LCTU study statistician using the Stata package ralloc employing permutated block randomisation with variable block size of 3 and 6. The allocation will be stratified by site and therefore separate randomisation lists will be created for each site. Oral sodium valproate tablets, 1000mg/day (500mg twice daily). Intervention given for 4 months; including ‘step-up’ phase x 2 weeks, at 500mg once daily.

On 26/04/2021 a substantial amendment request was submitted with a trial re-design from double-blinded randomised trial with IMP/Placebo to unblinded randomised trial with IMP/observational control arm (no treatment).


Previous intervention as of 12/07/2021:
SAVER is a randomised (1 Placebo: 2 Sodium Valproate), double-blind, multi-centre placebo-controlled phase II clinical trial investigating the use of sodium valproate in patients with a High Risk Oral Epithelial Dysplasia.

Patients shall be allocated based on a 1:2 allocation ratio with the greater number of patients being allocated to the experimental arm (sodium valproate). The sequences of allocation will be centrally generated by the LCTU study statistician using the Stata package ralloc employing permutated block randomisation with variable block size of 3 and 6. The allocation will be stratified by site and therefore separate

Primary Outcome(s)

Clinical activity will be measured using the commonly used surrogate end point that has evolved over several MD Anderson studies in the same field. The primary endpoint itself will be measured using the definitions of Mallery and it will be derived as a composite score of changes in lesion size, changes in histological grade, and LOH definition at 4 months from the date of commencement of study drug.

Assessment of lesion size
Lesion size will be calculated based on a first assessment of clinical images with lesional size mm2 = pixels of lesional area x 100/(pixels of 1 centimeter unit on the calibration device in the same image)2. Secondary assessment of lesion size will be calculated based on the estimated elliptical area given by the longest length of the lesion and the associated perpendicular width.

Lesion size response will be then measured calculated on a 7 point scale ranging from -3 to 3 based on the change in lesion size between pre and post treatment assessment. Specifically, the relationship between score and outcome is as follows:
• 75% or more decrease = 3
• 50% to 74% decrease = 2
• 25% to 49% decrease = 1
• 0% to 24% decrease or increase = 0
• 25% to 49% increase = -1
• 50% to 74% increase = -2
• 75% or more increase = -3

Assessment of histology response score
Formally, a 0 to 8 grade scale will be used to obtain the histological score as follows:
• 0 = normal with or without hyperkeratosis
• 1 = atypia with crisply defined clinical margins
• 2 = mild dysplasia
• 3 = mild-moderate dysplasia
• 4 = moderate dysplasia
• 5 = moderate-severe dysplasia
• 6 = severe dysplasia
• 7 = carcinoma in situ
• 8 = invasive SCC

Assessment of LOH response score
A series of microsatellite markers will be selected for LOH analyses. These are 8 corresponding loci and associated genes:
• 3p14 [D3S1007 (VHL), D3S1234 (FHIT)]
• 9p21 [D9S171, D9S1748 (P16/CDKN2A), D9S1751 (P16)]
• 9p22 (IFN- a)
• 17p13 [D17S786 (P53) and TP53]
For each loci, a score of +1 is given if it is positive for LOH and 0 if it is negative for LOH.

Total responsiveness score
The total responsiveness score for each patient will be calculated as:
Response score = lesion size score + change in histological response score
(pre-treatment grade – post-treatment grade) + change in LOH response score
(pre-treatment score – post-treatment grade)
Based on the responsiveness score, patients will be classified as follows:
• Response score = -1– Disease Progression
• Response score between 1 and 1 – Stable Disease
• Response score = 1 - Response
The only exception to the criteria laid out is for patients who have a confirmed malignant transformation. These patients shall automatically be confirmed as having disease progression, irrespective of their responsiveness score.
The primary outcome for analysis is defined as the disease response rate which compares patients with response to treatment against patients with either stable disease or disease progression.

Secondary Outcome(s)

Measured at 4 months from the date of commencement of study drug:
1. Disease control rate, defined as treatment response or stable disease against patients with disease progression using the composite responsiveness score defined in Section 9.3.1 of SAVER’s protocol
2. Clinical response, as measured by assessment of lesion size as in Section 9.3.1 Section 9.3.1 of SAVER’s protocol
3. Histological response, as measured by assessment of histology response score as in Section 9.3.1 Section 9.3.1 of SAVER’s protocol
4. LOH Response score, as measured in 9.3.1 Section 9.3.1 of SAVER’s protocol
5. WHO grade of OED (or SCC) in entire whole resection specimen (where any oral resection is performed within trial period)
6. Toxicity, measured using CTCAE (Version 4) classifications

Secondary ID(s)

Nil known

2018-000197-30

CPMS: 37192

Source(s) of Monetary Support

NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 14/209/13

Ethics review

Status:
Approval date:
Contact:

Approved 22/05/2018, North West - Haydock Research Ethics Committee (3rd Floor - Barlow House, 4 Minshull Street, Manchester, M1 3DZ, UK; Tel: [phone]; Email: [e-mail]), ref: 18/NW/0180

Results

• Results available: Yes
• Date Completed: 30/09/2025