Condition category
Oral Health
Date applied
23/04/2018
Date assigned
24/04/2018
Last edited
24/04/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
People can develop patches (oral dysplasia) on the lining of the mouth which are at risk of developing into cancer. Standard treatments include surgery or close surveillance, although these treatments are not completely effective, as up to 25% of patients progress to oral cancer even after surgery. Oral cancer treatments can be curative, especially when caught early, but the side effects include damage to speech, swallowing, appearance and reduction in quality of life, which are permanent. Treatment for oral cancer also carries a high economic burden and the World Health Organisation has recommended a shift in policy towards early diagnosis and prevention. Survival rates for oral cancer have remained largely unchanged for decades, at around 50-55% overall survival by 5 years. There is therefore a need to develop and test new prevention treatments for this condition. It is thought that more effective treatment for oral dysplasia would reduce the incidence of oral cancer. The aim of this study is to investigate the effects of the drug sodium valproate as a preventative treatment for high-risk oral dysplasia, in order to inform a decision on a larger study.

Who can participate?
Patients aged 18 and over with high risk oral epithelial dysplasia

What does the study involve?
Participants are randomly allocated to take either sodium valproate or placebo (dummy drug) tablets twice daily for 4 months. Measurements, photographs and punch biopsy tissue samples are taken at the start of the study and after 4 months to assess the response to treatment.

What are the possible benefits and risks of participating?
It is hoped that the treatments will help patients. However, this cannot be guaranteed. The information from this study may help to improve the future treatment of patients who have oral dysplasia. As part of the study patients may have one extra biopsy in addition to the normal care needed. These biopsies involve removing a small, 5 millimetre, disc of tissue. They can be carried out under local anaesthetic, using a small injection to make that area numb and will usually need one or two dissolving stitches. The risks of oral biopsy include some pain which might last up to one week, and a small amount of bleeding although this is likely to be only minor. Patients will also receive blood tests on three occasions that will not normally be needed unless on the study. Sodium valproate may have side effects but at the dose used in the study side effects are not expected in most patients. Sodium valproate can cause some people to put on weight. Other side effects that are usually seen at higher doses (and should be rare in this study) include tremor, drowsiness and mental slowing. Other very rare side effects include damage to the liver and changes to blood cells but these are checked carefully during the study using blood tests. Whether in the study or not, the patients’ oral dysplasia might worsen or even change to cancer, but patients will be very carefully monitored. Being on the study will not alter treatment decisions, and if patients’ doctors feel they need a different treatment at any point, this will be offered as standard.

Where is the study run from?
1. Liverpool University Dental Hospital (UK)
2. Aintree University Hospital NHS Foundation Trust (UK)
3. Leeds Dental Institute (UK)
4. Eastman Dental Institute and Hospital (UK)
5. KCL Dental Institute (UK)
6. Charles Clifford Dental Hospital (UK)
7. St James’s Hospital (Ireland)
8. Royal Blackburn Hospital (UK)
9. Queen Victoria Hospital (UK)
10. Sunderland Royal Hospital (UK)
11. Bristol Dental Hospital (UK)
12. St George's Hospital (UK)

When is the study starting and how long is it expected to run for?
January 2018 to July 2022

Who is funding the study?
National Institute for Health Research (NIHR) (UK)

Who is the main contact?
1. Binyam Tesfaye
btesfaye@liverpool.ac.uk
2. Prof. Richard Shaw
rjshaw@liv.ac.uk

Trial website

https://www.lctu.org.uk/LCTU_NET/frontend/core/Features/trialinfo.aspx?Data=W1tkSEpwWVd4bmNtOTFjQT09XV1bTWc9PV1bW2RISnBZV3hwWkE9PV1dW016QTRdW1tiRzlqWVd4bF1dW01RPT1d

Contact information

Type

Scientific

Primary contact

Mr Binyam Tesfaye

ORCID ID

http://orcid.org/0000-0002-1374-491X

Contact details

Cancer Research UK
Liverpool Cancer Trials Unit
University of Liverpool
1st Floor
Mersey Bio
Bio and Life Science
Liverpool
L69 7ZB
United Kingdom
+44 (0)151 795 7328
btesfaye@liverpool.ac.uk

Type

Scientific

Additional contact

Prof Richard Shaw

ORCID ID

http://orcid.org/0000-0002-5157-4042

Contact details

Department of Molecular and Clinical Cancer Medicine
North West Cancer Research Centre
The University of Liverpool Cancer Research Centre
Roy Castle Building
200 London Road
Liverpool
L3 9TA
United Kingdom
+44 (0)151 794 8832
rjshaw@liv.ac.uk

Additional identifiers

EudraCT number

2018-000197-30

ClinicalTrials.gov number

Protocol/serial number

37192

Study information

Scientific title

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

Acronym

SAVER

Study hypothesis

Individuals can develop patches (oral dysplasia) on the lining of the mouth which are at risk of developing into cancer. Standard treatments include surgery or close surveillance, although these treatments are not completely effective, as up to 25% of patients progress to oral cancer even after surgery. Oral cancer treatments can be curative, especially when caught early, but the side effects include damage to speech, swallowing, appearance and reduction in quality of life, which are permanent. Additionally treatment for oral cancer carries a high economic burden and the World Health Organisation has recommended a shift in policy towards early diagnosis and prevention. Survival rates for oral cancer have remained largely unchanged for decades, at around 50-55% overall survival by 5 years. There is, therefore, a need to develop and evaluate new prevention treatments for this condition. It is thought that more effective treatment for oral dysplasia would reduce the incidence of oral cancer.

SAVER is a phase II clinical trial with embedded mechanistic and feasibility studies. It is randomized, double blind and placebo controlled with a planned recruitment of 110 patients. The randomisation is in the ratio 2 SV (73 patients) :1 placebo (37 patients). The study population includes patients with premalignant oral lesions that have a histological diagnosis of oral epithelial dysplasia (OED) and are at high risk (considered to be at least 20% over 5 years of malignant transformation).

The aim of this phase II trial is to investigate the effects of sodium valproate as epigenetic chemopreventive therapy on high risk oral dysplasia. In particular, we will establish: clinical activity, mechanismof action and, feasibility of conducting such research in the NHS, in order to inform a decision on a larger phase III trial.

The primary endpoint is a measure of clinical activity and a surrogate – it is a composite of clinical, pathology and molecular lesional changes which has been previously used, with peer review, in randomised trials, within the same field. It is derived from clinical measurement, photographs and punch biopsy tissue comparing baseline to primary endpoint (4 months). Approximately 10 research sites are to be opened to recruitment in the UK and Ireland.

Ethics approval

North West - Haydock Research Ethics Committee, ref: 18/NW/0180 - approval pending

Study design

Randomised; Interventional; Design type: Treatment, Prevention, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Specialty: Oral and Dental Health, Primary sub-specialty: Other; UKCRC code/ Disease: Oral and Gastrointestinal/ Diseases of oral cavity, salivary glands and jaws

Intervention

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 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.

Intervention type

Drug

Phase

Phase II

Drug names

Sodium valproate

Primary outcome measure

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 measures

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

Overall trial start date

01/01/2018

Overall trial end date

01/07/2022

Reason abandoned (if study stopped)

Eligibility

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: 10mm x 10mm, or >=100mm2
(* 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 >200mm2
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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 110; UK Sample Size: 110

Participant 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

Recruitment start date

01/12/2018

Recruitment end date

01/07/2021

Locations

Countries of recruitment

Ireland, United Kingdom

Trial participating centre

Liverpool University Dental Hospital (lead centre)
Department of Oral Medicine Pembroke Place
Liverpool
L3 5PS
United Kingdom

Trial participating centre

Aintree University Hospital NHS Foundation Trust
Head & Neck Oncology Clinical Trials Longmoor Lane Fazakerley
Liverpool
L9 7AL
United Kingdom

Trial participating centre

Leeds Dental Institute
Leeds Teaching Hospitals NHS Trust Oral and Maxillofacial Surgery Clarendon Way
Leeds
LS2 9LU
United Kingdom

Trial participating centre

Eastman Dental Institute and Hospital
Oral Medicine Unit UCL Eastman Dental Institute 256 Gray's Inn Road
London
WC1X 8LD
United Kingdom

Trial participating centre

KCL Dental institute
C/O Floor 22 Tower Wing Guy’s Hospital Campus Great Maze Pond
London
SE1 9RT
United Kingdom

Trial participating centre

Charles Clifford Dental Hospital (Sheffield)
Sheffield Teaching Hospitals NHS Foundation Trust 76 Wellesley Road
Sheffield
S10 2SZ
United Kingdom

Trial participating centre

St James’s Hospital (Dublin)
National Maxillofacial Unit James’s Street
Dublin
8
Ireland

Trial participating centre

Royal Blackburn Hospital
East Lancashire Hospitals NHS Trust Haslingden Road
Blackburn
BB2 3HH
United Kingdom

Trial participating centre

Queen Victoria Hospital
Holtye Road
East Grinstead
RH19 3DZ
United Kingdom

Trial participating centre

Sunderland Royal Hospital
Department Oral and Maxillofacial Surgery Kayll Road
Sunderland
SR4 7TP
United Kingdom

Trial participating centre

Bristol Dental Hospital
Bristol Royal Infirmary Upper Maudlin Street
Bristol
BS2 8HW
United Kingdom

Trial participating centre

St George's Hospital (London)
Oncology Research Clinical Research Facility Blackshaw Road St George’s University Hospitals NHS Foundation Trust
London
SW17 0QT
United Kingdom

Sponsor information

Organisation

University of Liverpool

Sponsor details

Research Support Office
Waterhouse Building
3 Brownlow Street
Liverpool
L69 3GL
United Kingdom
+44 (0)151 794 8339
sponsor@liverpool.ac.uk

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

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

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal. Additional documents will not be publicly available but requests for them will be considered upon receipt of an emailed request to the SAVER Trial Coordinator.

IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

01/07/2023

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes