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Trial registered on ANZCTR


Registration number
ACTRN12618001099213
Ethics application status
Approved
Date submitted
26/06/2018
Date registered
2/07/2018
Date last updated
18/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
PENtoxyphylline+TOcopherol+/-CLOdronate (PENTOCLO) vs Hyperbaric oxygen (HBO): a randomised assessor blinded pilot study comparing two therapies for Osteoradionecrosis of the mandible.
Scientific title
Prospective randomised assessor blinded pilot study comparing Hyperbaric Oxygen therapy with PENTOCLO for the management of Osteoradionecrosis of the mandible.
Secondary ID [1] 295314 0
Nil known
Universal Trial Number (UTN)
U1111-1216-2862
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
osteoradionecrosis of the mandible 308506 0
Condition category
Condition code
Oral and Gastrointestinal 307478 307478 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Cancer 307531 307531 0 0
Head and neck

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Medication group – 4 weeks of “pre-treatment” therapy to reduce inflammation, infection and pain consisting of 2 grams daily of amoxicillin + clavulanic acid 875/125mg (1 gram morning and 1 gram at night), 50mg Fluconazole daily (morning), 16mg prednisolone daily (morning) taken orally by the patient. “Therapeutic phase” then commences immediately and consists of 5 days dosing of 800mg Pentoxifylline (400mg morning and night) and 1000iu Vitamin E (morning) (Mon-Fri) taken orally by the patient. If the patient deteriorates (defined as a negative change or worsening in either Notani or Lyons score at follow-up by consultant) then add Clodronate 1600mg daily (orally morning, Mon-Fri) for minimum of 6months but up to 18months if the patient has stable OsteoRadioNecrosis (ORN) and is not deteriorating further. If the patient experiences any pain or infection then 1gram Ciprofloxacin (500mg morning and night) and Prednisolone 16mg (morning) orally on the remaining 2 days (Saturday and Sunday) can be added to help resolve symptoms for as long as the patient is symptomatic, if this fails to be effective then a short course of 7days per week therapy of either the same steroid or antibiotic will be added to help alleviate symptoms, this will be recorded against the patients data for the trial.

Patients will receive their medication in Webster packs dispensed by the clinical pharmacy department and return any unused medication to the department at each follow-up visit that they have with the outpatient Oral and Maxillofacial Surgery clinic. In this way medications dispensed will be able to be tracked and any patients not adhering to protocol will be able to be identified.
Intervention code [1] 301642 0
Treatment: Drugs
Comparator / control treatment
HyperBaric Oxygen (HBO) group – 4 weeks of ‘pre-treatment’ therapy as above. “Therapeutic phase” incorporates HBO therapy prescribed for each patient based on Marx’s protocol of 30 dives at 2.4atm for 90minutes per dive, this will be prescribed by the Consultant Oral and Maxillofacial Surgeon that is treating the patient and will be the same for all patients in the HBO arm (patients will need to complete a minimum of 20 dives to be considered to have adhered to the protocol). If the patient is stable and not deteriorating after the “therapeutic phase” has ended then they will be reviewed as per the protocol time points. If the patient experiences pain or infection then appropriate medical treatment will be prescribed according to the same protocol outlined in the medication intervention but without the addition of any of: Pentoxifylline, Tocopherol or Clodronate.

Adherence to this intervention will be monitored by the specialist hyperbaric oxygen physicians and any reminders that need to be sent will be carried out by the hyperbaric oxygen unit.
Control group
Active

Outcomes
Primary outcome [1] 306452 0
Proportion of participants with an improvement of ORN of the mandible as defined by improvement in both Notani and Lyons scoring systems.
Timepoint [1] 306452 0
2,4,6,8,12 weeks after beginning the "pre-treatment" therapy then 6,9,12,18 months after beginning the "pre-treatment" therapy. Primary outcome will be assessed at all time points after the baseline examination.
Primary outcome [2] 306514 0
Proportion of participants with complete healing of ORN of the mandible as defined by both Notani and Lyons scoring.
Timepoint [2] 306514 0
2,4,6,8,12 weeks after beginning the "pre-treatment" therapy then 6,9,12,18 months after beginning the "pre-treatment" therapy. Primary outcome will be assessed at all time points after the baseline examination.
Secondary outcome [1] 348598 0
Proportion of participants with worsening of ORN as indicated by increase in severity of either Notani or Lyons scoring.
Timepoint [1] 348598 0
2,4,6,8,12 weeks, then 6,9,12 and 18months from date of first enrolment and commencing on 4 weeks of "pre-treatment" therapy. Secondary outcome will be assessed at all time points after the baseline examination.
Secondary outcome [2] 348729 0
This is a composite secondary outcome which will aim to document any complications that arise from treatment e.g. adverse drug reactions (as reported by the patient at follow-up appointments after baseline), decrease in quality of life (as reported by the patient at follow-up appointments after baseline using SF-36 health survey), increase in pain score (as reported by the patient at follow-up appointments after baseline using 100mm visual analogue scale to rate pain from 0-10), new infection developing (as detected by the Consultant Surgeon at follow-up appointments after baseline, primarily this will be though clinical examination).
Timepoint [2] 348729 0
2,4,6,8,12 weeks, then 6,9,12 and 18months from date of first enrolment and commencing on 4 weeks of "pre-treatment" therapy.

Eligibility
Key inclusion criteria
– Patients diagnosed with ORN by an Oral and Maxillofacial surgeon
- Patients or proxies that are able to give informed consent
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
– Patients that have spontaneously healing ORN
- Patients that have undergone previous treatment for ORN (PENTO, HBO or surgery).
- Patients or proxies that are unable to give informed consent
- Patients that are pregnant at the time of therapy
- Patients that have received previous anti-resorptive or anti-angiogenic medications
- Patients requiring further surgical management for their Head and Neck cancer during the study period
- Patients diagnosed with ORN requiring urgent surgery
- Patients that are unable to be randomised

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Clinical pharmacy department will hold the master unblinded list for the duration of the trial, once participants have been recruited they will be allocated a unique ID number and randomly assigned by computer to one of the two treatment groups. Clinical pharmacy will not have any physical contact with the participants until after they have been assigned.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated random numbers with participants to be stratified by grade of ORN, co-morbidities, sex, age, socio-economic status & smoking status.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
For this pilot study we will recruit a sample size of 8 patients per treatment arm. As we are not testing a hypothesis the initial results from this pilot study will be used to determine a sample size for a larger trial.

Descriptive statistics will be utilised to define the time point during follow-up at which the patient is completely healed or in the event of improvement without complete healing at 18months descriptive statistics (estimates of the mean and standard deviation for each treatment group for continuous measurements and proportions in each treatment group for categorical variables) will be used to quantify the degree of improvement for each patient within both groups. At the conclusion of the trial all participants will be included in an intention to treat analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 11240 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 23113 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 299904 0
Self funded/Unfunded
Name [1] 299904 0
presently unfunded.
Address [1] 299904 0
presently unfunded
Country [1] 299904 0
Primary sponsor type
Individual
Name
Dr Emma Lewis
Address
Department of Oral and Maxillofacial Surgery
Fiona Stanley Hospital
11 Robin Warren Drive
Murdoch
Western Australia
6150
Country
Australia
Secondary sponsor category [1] 299271 0
Individual
Name [1] 299271 0
Dr VIshal Bulsara
Address [1] 299271 0
School of Dentistry
The University of Western Australia
11 Monash Avenue
Nedlands
Western Australia
6009
Country [1] 299271 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300773 0
South Metropolitan Health Service Human Research Ethics Committee
Ethics committee address [1] 300773 0
Fiona Stanley Hospital
11 Robin Warren Drive
Murdoch
Western Australia
6150
Ethics committee country [1] 300773 0
Australia
Date submitted for ethics approval [1] 300773 0
30/07/2018
Approval date [1] 300773 0
13/09/2018
Ethics approval number [1] 300773 0

Summary
Brief summary
Introduction: Osteoradionecrosis (ORN) of the mandible is a painful and debilitating condition frequently occurring after radiotherapy to the head and neck to treat cancer. For decades Hyperbaric oxygen (HBO) has formed the mainstay of non-surgical management of ORN. Literature about the efficacy of HBO is contentious. Recently a combination of medications known as PENTOCLO has shown promising results in treating ORN. The purpose of this pilot study is to generate a hypothesis that can be tested in larger multi-centre controlled trials.

Who is it for?

You may be eligible for this study if you are an adult who has been diagnosed with osteoradionecrosis by an Oral and Maxillofacial surgeon.

Study details

For this pilot study, we will recruit 16 participants. These participants will be randomly allocated to up to 18 months of either Hyperbaric Oxygen or PENTOCLO treatment after completing 4 weeks of ‘pre-treatment’. Pre-treatment involves taking daily medications (Amoxicillin + Clavulanic acid, Fluconazole, and Prednisolone) for 4 weeks, with the overall goal of reducing inflammation, infection and pain.

Participants will have an initial appointment to take some measurements and record their medical history as well as having X-rays of their jaw taken. They will then be followed up at two weeks, four weeks, six weeks, eight weeks, twelve weeks, six months, nine months, twelve months and eighteen months and have photographs and a further assessment at each visit. Further X-rays will be taken throughout the follow-up period according to when they are needed such as if a participants condition improves or worsens. No other tests need to be performed during the study.

It is hoped that this research will help us to conduct much larger studies in the future about whether each treatment is suitable for use in Australia as well as providing international doctors and patients with meaningful information about which treatment for ORN is better. This will help to improve the lives of patients currently suffering with ORN and those who may develop the condition in the future by limiting their pain and suffering.






Ethics and dissemination: This study will be registered with the clinical trials database of the TGA in Australia as well as the Australian New Zealand Clinical Trials Registry of the NHMRC. Data generated by conducting this study will be uploaded to an open access repository in a de-identified form. Results from this study will be disseminated at national and international conferences as well as peer reviewed medical publications.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 2811 2811 0 0
Attachments [2] 2812 2812 0 0
http://www.anzctr.org.au/AnzctrAttachments/375428-PICF2018.docx (Participant information/consent)
Attachments [3] 2813 2813 0 0
Attachments [4] 2814 2814 0 0

Contacts
Principal investigator
Name 84770 0
Dr Vishal M Bulsara
Address 84770 0
School of Dentistry
The University of Western Australia
17 Monash Avenue
Nedlands
Western Australia
6009
Country 84770 0
Australia
Phone 84770 0
+61 438 899 424
Fax 84770 0
Email 84770 0
vishal.bulsara@gmail.com
Contact person for public queries
Name 84771 0
Dr Vishal M Bulsara
Address 84771 0
School of Dentistry
The University of Western Australia
17 Monash Avenue
Nedlands
Western Australia
6009
Country 84771 0
Australia
Phone 84771 0
+61 438 899 424
Fax 84771 0
Email 84771 0
vishal.bulsara@gmail.com
Contact person for scientific queries
Name 84772 0
Dr Vishal M Bulsara
Address 84772 0
School of Dentistry
The University of Western Australia
17 Monash Avenue
Nedlands
Western Australia
6009
Country 84772 0
Australia
Phone 84772 0
+61 438 899 424
Fax 84772 0
Email 84772 0
vishal.bulsara@gmail.com

No information has been provided regarding IPD availability
Summary results
No Results