| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High Risk Oral Epithelial Dysplasia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patches on the lining of mouth. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Mouth and tooth diseases [C07] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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, mechanism of action and, feasibility of conducting such research in the NHS, in order to inform a decision on a larger phase III trial.
The primary objective is Clinical activity, measured using the commonly used surrogate end point comprising a composite of changes in lesion size, histological grade and allelic imbalance. |
|
| E.2.2 | Secondary objectives of the trial |
• WHO grade of OED in trial biopsies, and also within the entire resection specimen (where any oral resection is performed within trial period)
• Histopathological evidence of malignant transformation (OSCC) in index lesion or other H&N site within the 6 month ‘on-trial’ window, and, separately,
• Histopathological evidence of malignant transformation (OSCC) in index lesion or other H&N site within the total period of time that SAVER remains open.
• Feasibility, defined by the rate of recruitment per centre, and for the trial as a whole.
• Mechanistic endpoints: i.e. define the changes in gene expression and epigenetic marks, at both tissue specific and systemic level, accompanying sodium valproate monotherapy.
• Qualitative endpoints: an embedded qualitative interview study to systematically investigate patients’ experiences of recruitment and participation in the trial |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
SAVER is a phase II clinical trial with embedded mechanistic and feasibility studies.
Mechanistic Study: Changes in gene expression and epigenetic marks will be defined, at both tissue specific and systemic level, accompanying sodium valproate monotherapy. Blood & tissue punch biopsy samples will be collected from each patient prior to and following study drug. 5mm punch biopsies will be split: half used for histology and immunohistochemistry (IHC), and half for combined DNA/RNA/protein preparation. It is important that patients remain on their allocated study drug right up to the day of their 4-month biopsy.
Qualitative Study: The SAVER trial will include an embedded qualitative interview study (the SAVER Information Study) to identify how to enhance communication with patients about the trial as it is ongoing, and to enhance the design and acceptability of any future phase III trial for patients.
|
|
| E.3 | Principal 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
(<12months) or to enter the screening route to randomization)
2. Index lesion* which must be:
a. Accessible
b. Measurable
c. Amenable to clinical photography
d. Oral cavity, lip or oropharynx
e. 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.:
a. WHO severe OED or
b. WHO mild or moderate OED, with at least one additional high risk feature(s)
from the list below:
i. non-smoker (less than 100 cigarettes or equivalent over whole lifetime)
ii. lesion size >200mm2
iii. lateral tongue site
iv. mucosal speckling or heterogeneous appearance
v. 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. |
|
| E.4 | Principal 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, Blooms 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
steroid, (as per BNF conversion table), 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:
a. Acute porphyria
b. Known or suspected mitochondrial disorders
c. Personal or family history of severe hepatic dysfunction, current hepatic
dysfunction (as evidenced by LFTs outwith reference range and prolonged
prothrombin time)
d. Past history or current pancreatitis
e. Women with child-bearing potential (<2 years post menopause), pregnancy,
breast feeding. (This is iterated in more detail in SOP as per appendix 1)
f. 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.
g. 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.
h. Patients with known or suspected mitochondrial disease, systemic lupus
erythematosus or hyperammonaemia |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Clinical activity will be measured using the commonly used surrogate end point that has evolved over several MDAnderson studies in the same field. The primary endpoint itself will be measured using the definitions of Mallery [Mallery et al., 2014] and it will be derived as a composite score of changes in lesion size, changes in histological grade, and LOH definition.
Assessment of lesion size
Lesion size will be calculated based on a firstassessment 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 eliptical 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 beused 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 responsivness 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint will be analysed following the last patient's last visit. |
|
| E.5.2 | Secondary end point(s) |
• WHO grade of OED in trial biopsies, and also within the entire resection specimen (where any oral resection is performed within trial period)
• Histopathological evidence of malignant transformation (OSCC) in index lesion or other H&N site within the 6 month ‘on-trial’ window, and, separately, within the total period of time that SAVER remains open.
• Feasibility of the trial, defined by:
o the rate of recruitment per centre,
o the rate iof recruitment for the trial as a whole,
o compliance with treatment
o drop-out
• Mechanisitc endpoints: i.e. define the changes in gene expression and epigenetic marks, at both tissue specific and systemic level, accompanying sodium valproate monotherapy.
• Qualitative endpoints: an embedded qualitative interview study to systematically investigate patients’ experiences of recruitment and participation in the trial |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoint will be analysed following the last patient's last visit. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The last visit of the last patient will define the end of the trial. This will be followed by the completion of a study report. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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