1. ‘How will I manage my recommended oral dose’?

You will be sent an automatic notifications by SMS to manage your oral dose and remind you to take your study medication. It will help you to maintain a dosing schedule of the study medicine on every 4th day. Your dosage frequency would be pre-calculated from the baseline visit until the end of the study. You will be required to confirm use of study medication by completing weekly short surveys.

2. ‘How is this study funded to conduct the trial?’

The study is being sponsored by the University of Sydney and funded by a pharmaceutical company, Arthropharm Pty Ltd. The researchers involved in the study are not employees of Arthropharm and will not benefit financially from any of the findings of the study. There is no conflict of interest to be disclosed.

All the funds being paid by the pharmaceutical company to run the trial will be deposited into an account managed by the University of Sydney. No money is paid directly to individual researchers.

3. ‘What are the alternatives to participating in this study?’

If you decide not to participate in this study, and you wish to continue treatment, you will still receive the standard treatment available for your condition. It is important that you discuss the alternatives to participating in this study with your doctors.

4. ‘Are there risks to me in taking part in this study?’

All medical procedures involve some risk of injury. Also, there may be risks associated with this study that are presently unknown or unforeseeable. Possible risks are outlined below.

Pentosan Polysulfate (ELMIRON®)

Elmiron is contra-indicated (warned against) in patients with:

- A known hypersensitivity to PPS or related compounds

- Haemophilia

- An active (or recent history of) bleeding, alcoholic patients

- Concurrent heparin or oral anti-coagulant therapy

Warnings

Pregnancy – Reproduction studies performed in mice, rats and rabbits revealed no evidence of any potential for impaired fertility or harm to the foetus. An overall evaluation of these studies indicated minimal risk to the human foetus by the oral ingestion of up to 600mg Elmiron per day.

Data from studies in pregnant women undergoing abortion have indicated that PPS does not pass the placental barrier. There are, however, no well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, Elmiron should not be used during pregnancy.

Nursing Mothers – It is not known if Elmiron is secreted in milk of animals or humans. Because many drugs are known to be excreted in human milk, Elmiron should not be administered to nursing women.

Paediatric Use – Safety and efficacy in children (<18 years) has not been established.

Other considerations

Habit-forming potential – Nil. Elmiron is not addictive.

Overdosage – no known reported incidents.

Very long-term continuous daily dosing (greater than 7 years, over 1.5 kg PPS accumulated dose) has been linked with a degenerative maculopathy in 20% of patients with interstitial cystitis, however the causative mechanism is yet to be established.

Some people may experience mild effects of swelling, headache, dizziness, nausea, indigestion, or diarrhoea. If any of these occur and are bothersome, contact the research coordinator on 02 9463 1896. Other unwanted effects not listed may also occur in some patients. Tell your doctor if you notice any other effects.

Precautions

We recommend avoiding high impact sports activities that can easily result in injury. Note that you can still exercise for example walking, running, and swimming.

We recommend reducing consumption of alcohol to a minimum. Alcohol consumption above recommended levels increases the risk for major bleeding from an injury.

Minor bleeds like dental floss, electric razor, trimming your fingernails and toenails can be avoided. Seek medical help if you injure yourself.

Due to the nature of the medication uptake in our study (Study Flowchart), you will always be re-assessed after going through a 5-week medication cycle. Those visits will allow us to monitor for safety. Any side-effect will be thoroughly reviewed by the study investigator.

Blood Draws

Drawing blood from a vein may cause local pain, bruising, occasional light-headedness, fainting, and very rarely, infection at the site of the blood draw. The blood pressure cuff may cause discomfort or bruising to the upper arm. Stopping the bleeding may take slightly longer than usual.

Radiation

As part of everyday living, everyone is exposed to naturally occurring background radiation and receives a dose of about 2 millisieverts (mSv) each year. The additional effective dose participants will receive from entering this trial is approximately 0.04 mSv. At this dose level, no harmful effects of radiation have been demonstrated as any effect is too small to measure. Studies suggest any risk is minimal.

Magnetic resonance imaging (MRI)

MRI stands for magnetic resonance imaging. An MRI scanner is a machine that uses electromagnetic radiation (radio waves) in a strong magnetic field to take clear pictures of the inside of the body. Electromagnetic radiation is not the same as ionising radiation used, for example, in X-rays. The images taken by the machine are called MRI scans.

There are no proven long-term risks related to MRI scans as used in this research project. MRI is considered to be safe when performed at a centre with appropriate procedures. However, the magnetic attraction for some metal objects can pose a safety risk, so it is essential to tell your us if you have:

− implanted pacemaker or defibrillator ;

− presence of metallic bodies in the eye;

− implantable hearing aids;

− insulin pumps;

− claustrophobia (a fear of being in closed or small spaces);

5. ‘Will participating in this study affect my plans to start a family?’

The effect of the study drug on an unborn baby is unknown. It is possible that the treatment regime under this study could have serious effects on the development of a foetus.

If at any time you think that either you or your sexual partner may be pregnant, it is vital to let researchers, or your medical team know immediately.

It is crucial that you are not pregnant and do not become pregnant during this study as the study drugs and procedures may damage an unborn baby.

If you are of childbearing potential and there is any possibility that you are pregnant, the researchers will need to perform a urine pregnancy test before you start in the study. If necessary, you must use reliable contraception (such as oral or implanted contraception, an IUD or have had a tubal ligation, or use condoms) during the course of this study.

6. ‘What happens if I suffer injury or complications as a result of the study?’

If you suffer any injuries or complications as a result of this study, you should contact the study investigator as soon as possible, who will assist you in arranging appropriate medical treatment.

You are also advised to take the national emergency services by dialling “000” for any untoward medical incident which requires immediate attention.

You will be provided with a Participant Identification Card stating that you are taking part in a clinical trial, the contact details of the study coordinator, and what to do in emergencies. You will always be required to keep this card with you during the study duration so that any physician can note your involvement with the study. This may be useful in the case of any complications that may arise, related or unrelated to the study.

You may have a right to take legal action to obtain compensation for any injuries or complications resulting from the study. Compensation may be available if your injury or complication is caused by the drugs or procedures, or by the negligence of any of the parties involved in the study. If you receive compensation that includes an amount for medical expenses, you will be required to pay for your medical treatment from those compensation monies.

If you are not eligible for compensation for your injury or complication under the law but are eligible for Medicare, then you can receive any medical treatment required for your injury or complication free of charge as a public patient in any Australian public hospital.

7. ‘Will I benefit from the study?’

This study aims to further medical knowledge and may improve future treatment of knee osteoarthritis; however, it may not directly benefit you. You may or may not experience an improvement in your OA symptoms by the end of the study. We cannot guarantee or promise that you will receive any benefits from this research; however, possible benefits may include reduced knee pain and improved knee function.

8. ‘Will taking part in this study cost me anything, and will I be paid?

Aside from giving your time, we do not expect that there will be any major costs associated with taking part in this study. Visit to the study site by public transport will not be compensated. We will cover the cost of all study-related procedures and examinations.

We will also provide you meal vouchers on every visit (for Zouki Café within RNSH) and a free parking voucher for all the study visits for your parking expenses at Parking P1 and P2 within hospital. Castlereagh Imaging centres at St. Leonards and Cremorne have their independent car parking facility. You can use the parking at these centres at no further expense.

Remote travellers may be reimbursed for travel expenses such as petrol costs with a grocery/gift vouchers.

9. ‘What will happen to my tissue samples after it has been used?’

The blood and urine samples provided during the study will be tested at the NSW Health Pathology laboratory to monitor the safety of study participants. A set of blood and urine samples will be collected for the bone and collagen turnover markers testing. Some of the tests will be performed by Arthropharm Pty Ltd, and some serum samples will be sent to Duke University (USA) for proteomic biomarkers testing that have shown to predict osteoarthritis progression better than traditional research methods.

Testing for bone and collagen turnover markers or proteomic biomarkers are not routinely performed by the NSLHD pathology labs, but all samples sent for testing will be de-identified (coded by Study ID and DOB) so your personal information will remain confidential.

The remaining set of samples will be stored at -80 degrees C at Royal North Shore Hospital as a backup to address the risk of specimen transportation. For any future research exploratory biomarkers not disclosed here, an ethics amendment would be sought for future testing. If the unused samples are not utilized within 2 years of the period after study completion, all the samples will be destroyed.

10. ‘How will my confidentiality be protected?’

By signing the consent form, you consent to the Study Investigator and relevant research staff collecting and using personal information about you for the research project. Any information obtained in connection with this research project that can identify you will remain confidential and will only be used for this research project. It will only be disclosed with your permission, except as required by law.

To ensure that your personal information is kept confidential, your name and any other information that allows you to be identified directly will not be entered on any records or samples the study coordinator provides to the Sponsor or the Sponsor’s authorised representatives. Instead, you will only be identified by a code (Study ID). The code is used so that you can be re-identified if necessary. The information collected about you will be held on password protected database (REDCap).

REDCap is a secure, web-based application designed to support data capture for research studies. It is hosted at the University of Sydney servers. The hard copies of your blood test reports will be kept in locked filing cabinets within Rheumatology Department, Royal North Shore Hospital accessible by the designated study coordinators.

The Sponsor or its authorised representatives will perform some of the tests, but all samples will only be identifiable by Study ID and DOB.

Any information obtained for this research project that can identify you will be treated as confidential and securely stored in accordance with Australian privacy laws for a minimum of 15 years after the completion of the research project. It will be disclosed only with your permission, or as required by law.

Information about you may be obtained from your health records held at this and other health services for the purpose of this research. By signing the consent form, you agree to the study team accessing health records if they are relevant to your participation in this research project. Information about your participation in this research project may also be recorded in your health records.

Your health records and any information obtained during the study may be inspected (for the purposes of verifying the procedures and the data) by the Food and Drug Administration (FDA) or by the Australian Government’s Therapeutic Goods Administration (TGA) or/and by the Human Research Ethics Committee (HREC) approving this study.

By signing this consent form, you authorise the release of, or access to, this confidential information to the relevant study personnel and regulatory authorities as noted above.

In accordance with relevant Australian and/or NSW privacy and other applicable laws, you always have the right to access and rectify your data or obtain a copy of your data collected. If your personal details are inaccurate or incomplete or are not being processed in compliance with the applicable regulatory requirements, you may ask for a correction or to block your personal data. Please contact the study team member named at the end of this document if you would like to access your information. If you participate in this trial, you will not own any of the information collected or produced for the purpose of the trial.

A description of this clinical trial is available on Australian New Zealand Clinical Trial Registry https://www.anzctr.org.au (#: ACTRN12621000654853)

This web site will not include information that can identify you. At most, the web site will include a summary of the results. You can search this web site at any time.

11. ‘What happens with the results?’

If you give us your permission by signing the consent document, we plan to discuss/publish the results in journals, presentations at conferences, symposia, Congress and scientific meetings in general. No information which could lead to your identification will be included in the dissemination of results.

In any publication, information will be provided in such a way that you cannot be identified.

13. Can I tell other people about the study?

Yes, you are welcome to tell other people about the study by sharing the link sent to you.

14. ‘What happened to my treatment when the study is finished?’

You will not be supplied the study drug following completion of this study. Any decision to take PPS after the trial should be made in consultation with you and your treating doctor considering the most appropriate treatment for you at that time.

15. ‘‘What should I do if I want to discuss this study further before I decide?’

When you have read this information, the researcher coordinator will discuss it with you and any queries you may have. If you would like to know more at any stage, please do not hesitate to contact the study coordinator on 02 9463 1896.

16. ‘Who should I contact if I have concerns about the conduct of this study?’

This study has been approved by the Northern Sydney Local Health District HREC. Any person with concerns or complaints about the conduct of this study should contact the Research Office who is nominated to receive complaints from research participants.

You should contact the following:

Local Complaints Contact Person