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EME – TIPAC – Idiopathic Pulmonary Fibrosis Study

The Efficacy and Mechanism Evaluation of Treating Idiopathic Pulmonary Fibrosis with the addition of Co-trimoxazole (EME-TIPAC).

Treating pulmonary fibrosis with co-trimoxazole.

What is the purpose of the study?

Pulmonary fibrosis is a condition with limited treatments. It is thought to occur because of tiny “scars” (which we call fibrosis) that develop throughout the lungs. In a previous study, it appeared that people with pulmonary fibrosis who regularly took an antibiotic (called co-trimoxazole) were more likely to be alive after one year of the treatment than those who didn’t. However, treatments for pulmonary fibrosis are changing and we are trying to find out if co-trimoxazole effective with these medications. We want to know whether co-trimoxazole, when given alongside current treatments, improves life expectancy and/or reduces the chances of a person with pulmonary fibrosis being admitted to hospital. In addition, we would like to find out how co-trimoxazole may be working so that we can use this information to develop other better treatments.

Why have I been invited?

We are approaching people with a lung condition called Idiopathic Pulmonary Fibrosis (which we will call pulmonary fibrosis from now on) which is a specific type of lung scarring with no known cause. We are aiming to recruit 330 participants from different regions throughout the UK. All patients must have some degree of breathlessness and reduced breathing tests and not have other major health problems, particularly problems with their liver or kidneys or have experienced side effects when taking trimethoprim or sulphonamides (some types of anti-inflammatory, diabetic or water tablets) in the past.

 Do I have to take part?

No. The decision to participate is entirely up to you. We will describe the study here, and if you have further questions then you are welcome to contact us. If you are interested then we will ask you to sign a consent form before taking part in the study. If you are not interested, it will not influence in any way your future treatment.

What will happen to me if I take part?

Since at the moment we don’t know which way of treating patients is the best way, we need to compare the new way of treating you with the old way. The standard way to do this is to put people into groups and give each group the different treatment. The results are then compared to see if one is better. To try to make sure the groups of people are the same to start with, each patient is put into a group by chance (randomly). This is like tossing a coin to decide which group you will be in. You will have an equal chance of getting the co-trimoxazole treatment or the placebo. A placebo is a ‘dummy treatment’ that looks like the genuine medicine but contains no active ingredient. Neither you nor your doctor will know which treatment group you are in, this is called a double-blind study (although, if your doctor needs to find out for emergency/safety purposes he/she can do so).

Table showing visits and measurements

  Visit Time point
Procedure / Assessment Entry to the study 6 weeks 3 months 6 months 9 months 12 months every 6 months for a maximum of 42 Months End of study or first non-elective admission
Informed consent taken X
Demographic information collected X
Entry criteria checked X
Treatment allocated X
Trial Drug dispensed X X X X X
Blood tests X X X X X X X X
Blood sample taken
for DNA analysis
X              
Blood sample taken for Biomarker analysis X   X X   X   X
Questionnaires completed by patient X X X X X X
Full lung function test X X X X X X
Routine microbiology (if clinically indicated) X X x X X X X X
Adverse events
(side-effects checked)
X X X X X X X

If you are interested in taking part we will make plans to see you at your next clinic appointment.

 

Before agreeing to take part in this study you should check that any private medical insurance you have will not be affected by your participation.

 

At this first visit, we will ask you to:

1) sign a consent form saying that you are willing to take part in the study.

2) confirm the medicines you are taking and any other health problems you may have if this information is not in your medical notes

3) fill out three separate questionnaires (one with 15 questions, one with 19 questions and one with 6 questions) and answer 4 additional questions. These tick-box questionnaires will take about 15 minutes to complete in total. They aim to find out how you feel about your condition and about any cough or breathlessness you may have.

4) put a probe or peg on your finger to measure your oxygen levels. This is a harmless, painless test (it shines a light through your fingernail) which you probably have done whenever you see your doctor.

5) do some breathing tests to see how well your lungs are working. The breathing tests will be the same ones that you usually have when you attend the Respiratory Clinic, therefore no additional breathing tests will be necessary. They will include a forced breathing test when you have to breathe hard and a gentle breathing test – you may need to enter a Perspex box for this test.

6) allow us take a blood sample. We will take up to 40mls (about 8 teaspoons) of blood. The samples will be identified by a unique code and will not have your name or other details written on them. They will be kept securely.

The blood sample will be used to allow us to make sure it is safe for you to take part in the study by testing that your kidneys and liver are working normally (safety blood tests) and also by testing whether you have enough building blocks to make red blood cells (Folate and Vitamin B12). There is a rare condition which causes red blood cells (oxygen carrying cells in the blood) to break up when people take certain medications including co-trimoxazole called glucose-6-phosphatase deficiency. This condition is more common in males of African, Asian or Mediterranean decent and we will test your blood (measure glucose-6-phosphatase– G6P) to see if you are in this group to check if you have this condition. If you are shown to be positive for this condition then we will refer you to a haematologist for further information/advice.

The blood sample will be stored in a freezer so that we can analyse it for biomarkers after the study finishes, or in the future if important new biomarkers are found. This will provide further valuable information about pulmonary fibrosis. Biomarkers are chemicals or proteins in the body which are involved in the processes of keeping us healthy and can be measured to tell us if something is going wrong. We will measure biomarkers that tell us about inflammation, lung damage and scar production. These biomarkers will be kept securely and will be identified by a unique code and will not have your name or any personal details written on it. These blood samples may be kept for up to 10 years but after this time will be destroyed.

We also invite you to allow us to undertake a genetic analysis on your blood (see section below).

You will then be randomly allocated to either receive the active drug or the dummy (placebo) drug, which you will need to take as directed – usually every morning and at night (see section 6 below). As a participant in the trial you will also be prescribed with a vitamin called folic acid which you will need to take in the morning and this will help to protect your bone marrow (which produces blood cells) from a rare side-effect of co-trimoxazole that results in a reduction in the number of certain blood cells that circulate in your blood. You will take folic acid even if you are randomised to the placebo arm. It is a commonly taken as a vitamin supplement as many people do not obtain enough folic acid from their diet. If you are on the placebo arm, the extra folic acid that you will take in the trial will not harm you. We will either arrange for the medicines to be couriered to you or ask you to collect the medicines from the hospital. You will be given these tablets in addition to all your usual treatments for pulmonary fibrosis or any other medical condition that you might have.

You will then be followed up in the clinic in the normal way. We would like to see you again after 6 weeks, 3 months, 6 months, 9 months and 12 months then every 6 months until the study ends. The study will end 3½ years after the first person starts which will be about 1 year after the last person starts in the study (as we will be recruiting participants for 2½ years) so you will be involved in the study for a minimum of 1 year (5 visits) or a maximum of 3½ years (11 visits) depending on when you started in the study. When the study stops we will ask you to attend for an additional visit unless you have seen us within the last month. We anticipate that the majority, if not all, of these visits will coincide with your regular clinic visits to the hospital.

At all of the visits i.e. after 6 weeks, 3 months, 6 months, 9 months, 12 months and if you are still in the study (see above), 18 months, 24 months 30 months, 36 months and 42 months plus a final visit or if you are admitted to hospital (see above) we will ask you to:

  • tell us if there are any changes in the medicines you are taking and about any side-effects or problems you may have had since your last visit.
  • allow us take a blood sample of 10 mls (equivalent to 2 teaspoons) to make sure co-trimoxazole is not causing a problem with your kidneys or liver. This will be sent to your hospital laboratory.
  • allow us take a sputum sample or nasal swab if your doctor thinks that this will help him/her treat you

NB it may be possible for the blood tests at 6 weeks and 9 months to be done at your GPs surgery and for you to tell us if there are side effects of treatment over the phone.

In addition, after 3 months, 6 months, 12 months and if you are still in the study (see above), 18 months, 24 months 30 months, 36 m onths and 42 months plus a final visit or if you are admitted to hospital (see above) we will ask you to

  • allow us to put a probe/peg on your finger to measure your oxygen levels.
  • do the breathing tests. The breathing tests will be the same ones that you usually have when you attend the Respiratory Clinic so no additional breathing tests will be necessary.
  • fill in two of the three base line questionnaires (one with 15 questions and one with 5 questions) and answer 3 of the 4 additional questions which will take about 10 minutes to complete.

In addition, after 3 months, 6 months, 12 months and final visit or if you are admitted to hospital we will ask you to

  • allow us to take an additional 20 mls (equivalent to 4 teaspoons) i.e. 30mls or 6 teaspoons in total in order to analyse it for biomarkers which will provide information about pulmonary fibrosis (described above). It will be kept securely and will be identified only by a unique code and will not have your name or other details written on them.

In addition, after 12 months we will ask you to

  • complete all of the questionnaires you did at the baseline visit – this will take 15 minutes.

 What will I have to do?

We ask that you:

Take the study tablets as directed (described below)

Keep the study tablets at room temperature (under 25°C)

That you attend the study visits as described above

That you carry a card explaining you are in the study and show it to your doctor whenever you consult with him or her.

Ensure you do not become dehydrated.

Stop taking the study medication and contact your hospital consultant or family doctor immediately if you experience:

  • Sudden wheeziness (noisy breathing) or difficulty in breathing
  • Swelling of the eyelids, face or lips
  • Blisters with a skin rash

Take all other medicines as normal and carry on your daily activities as usual.

What is the drug that is being tested?

Co-trimoxazole is an antibiotic that commonly used to treat many infections and will prevent certain types of respiratory infections.

You will be asked to take 2 tablets of the study medication twice per day every day for the duration of the study. If you are in the co-trimoxazole treatment group you will receive 960mg (2 tablets of 480mg per day) of co-trimoxazole twice per day. If you experience side effects and are unable to continue taking the study medication we ask that you contact your doctor (details at the end of this leaflet) to discuss it. There may be an opportunity for you to reduce the dose of the study medication to 2 tablets 3 times per week which should help stop the problems you are having. If this is the recommendation then you will be taking 960mg of co-trimoxazole three times per week.

In addition we will ask you to take folic acid every day (or three times per week if you are taking the lower dose of co-trimoxazole).

 What are the alternatives to treatment?

The study medication is not an alternative to any approved treatment that you may require, it is given alongside your usual medication.

 What treatments should I avoid?

There are a number of treatments that you should not take while you are in the study and these include:  amiodarone, azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate, D-penicillamine, colchicine, clozapine, methenamine, dapsone, gamma-interferon, ciclosporin, mercaptopurine, repaglinide, pyrimethamine, and lamivudine. You should not have the typhoid vaccination but other vaccinations are fine.

What are the side effects of the study medication?

The active drug (co-trimoxazole) and the drug given with the active drug (folic acid) sometimes cause unwanted effects in some people. We have classified these into common,(occurring more than 1 in 100), less common (between 1 in 100 and 1 in 1000) and very rare (less than 1 in 10,000) to give you an idea of the chances of an unwanted effect occurring.

For co-trimoxazole the following have been reported:

Common: nausea, diarrhoea, headache, mild skin rash, thrush in the mouth, increased potassium blood levels.

Less common: vomiting

Very rare: inflammation of the tongue and mouth, lack of appetite, antibiotic associated inflammation of the gut (colitis), inflammation of the pancreas gland, kidney, bowel or heart; severe skin rash including rashes called ‘Stevens-Johnson syndrome’ and ‘toxic epidermal necrolysis’, skin sensitivity to light; liver damage (including elevation of enzymes produced by the liver and those that lead to jaundice; cough and shortness of breath, inflammation of the lungs, non-infective meningitis, depression, fits, nerve problems in fingers/toes, unsteadiness, ringing in ears, hallucinations, low blood sugar; blood disorders (including low white cells, red cells and platelets (leading to possible risk of infection and bleeding)); low blood sodium; so called auto-immune conditions including fever, allergy, swelling of mouth, pains in joints and muscles, inflammation of blood vessels.

The following undesirable effects have been reported with folic acid:

Uncommon: loss of appetite, feeling sick, swelling of the stomach, wind, allergic reactions.

The doctor and local study team at your hospital are available for you to call if you experience any unwanted side-effects. In an emergency you should contact your hospital or family doctor.

If you are receiving warfarin (a blood thinning medicine), it is likely that you will require increased monitoring of your blood clotting tests. You may need increased blood monitoring if you take digoxin or procainamide hydrochloride (heart rhythm drugs), phenytoin (drug for epilepsy), sulphonylureas (tablet for diabetes) or drugs affecting your potassium (a blood salt).

What if I forget to take the tablets?

If you forget to take a dose, take it as soon as you remember it and then take the next dose at the right time. Do not take a double dose to make up for a forgotten dose.

 What happens to my samples?

The blood sample will be split in two. Some of the blood will be sent to your hospital for testing to make sure that it is safe for you to take part or continue taking part in the study. The rest of the blood will be used exclusively for research and will be treated as a gift. It will be stored anonymously and will be labelled with a unique code i.e. not your name or personal details. Please see section Will my taking part in the study be kept confidential? below for more details. The blood will be sent to Norwich so that we can analyse the sample for chemicals that may help us understand how the pulmonary fibrosis is affecting your lungs this includes the effect of inflammatory cells in the lung, of scarring and of damage to your lungs.

If any samples remain unused at the end of this research project these will be stored, in a linked-anonymised form (as described in Will my taking part in the study be kept confidential? below), by the Norfolk and Norwich University Hospital NHS Foundation trust so that they might be used in future ethically approved research projects including by third parties. Samples will be stored in this way for up to 10 years before being destroyed.

 What are the possible disadvantages and risks of taking part?

You may not get the active treatment (co-trimoxazole) and may receive the dummy treatment (placebo) but you will be able to receive any approved treatment for pulmonary fibrosis from your doctor.

It may be necessary for you to attend the hospital on visits in addition to your routine clinic visit. If you are required to make an additional visit, we will reimburse your traveling expenses at the current accepted rate if travelling by car, or bus/train/taxi fares against receipts if using public transport.

The blood tests may cause discomfort and bruising. The questionnaires will take time to complete. The breathing tests may cause slight breathlessness, difficulty breathing or chest discomfort for a few minutes at the most.

You may experience the side-effects mentioned above.

What are the possible benefits of taking part?

It cannot be guaranteed that the study will help you but the information that we get from this study will improve our ability to treat patients with pulmonary fibrosis in the future.

What happens when the research study stops?

Co-trimoxazole is not currently used to treat patients with pulmonary fibrosis and you will stop taking the medication at the end of the study. However if we find out that you have been taking co-trimoxazole and that you have had a noticeable benefit from it, we will be able to tell your doctor and he or she may decide to prescribe this or something similar.

What if relevant new information becomes available?

Sometimes we get new information about the study treatment. If this happens, your local study doctor/team will tell you the new information that has become available and discuss what this means for you. If, once you have had time to think about what you have been told, you decide not to carry on in the study, your routine care will continue as normal. If you decide to continue in the study you may be asked to sign an updated consent form.

What will happen if I don’t want to carry on with the study?

You are free to withdraw at any time and without giving a reason and this will not affect the standard of care you receive. You can stop the study treatment but keep in contact with us to let us know your progress. Information collected may still be useful and used. If you withdraw from the study, data collected up to the point of your withdrawal will still be used.

What if there is a problem?

If you have a concern about any aspect of this study you should ask to speak to the researchers who will answer your questions (contact details are at the end of this information leaflet).  If you remain unhappy and wish to complain formally, you can do this through the NHS Complaints mechanisms (or Private Institution).  Contact details can be obtained from Customer Services on Tel: (0191) 404 1072.

If you are harmed by taking part in this research project, there are no special compensation arrangements. If you are harmed during the research due to someone’s negligence then you may have grounds for legal action for compensation against your hospital, but you may have to pay your legal costs. The normal NHS complaints mechanisms will still be available to you.

Will my taking part in the study be kept confidential?

Yes. We will follow ethical and legal practice and all information about you will be handled with the strictest confidence. All information which is collected about you during the research will be held securely in accordance with the Data Protection Act.  It will be kept for 5 years after which it will be disposed of securely. All of your data (your questionnaire information, samples and clinical details) will be labelled by a code and will not have your name or any other details about you on it. We refer to this as linked anonymised as although your sample is anonymous it can be linked to you by a code. The code will only be known by your hospital doctors and, if you agree, only certain members of the research team. It will be kept securely.

We may ask for your films from the x-ray department and images of your lung biopsy (if you had one in order to make a diagnosis of IPF) to be sent in an anonymised form to a central laboratory for review.

The statistical analysis of the study is being conducted by researchers at Norwich, and to maintain confidentiality, the statistical team will only analyse completely anonymous data.  Any reports or publications arising from the study will contain totally anonymised data so that you cannot be recognised from it.

Other third party researchers may wish to access anonymised data from this study in the future (anonymised data does not include names, addresses or dates of birth, and it is not possible to identify individual participants from anonymised data).  If this is the case, the Chief Investigator will ensure that the other researchers comply with legal, data protection and ethical guidelines.

If you join the study, the data collected for the study, together with any relevant medical records, may be looked at by authorised persons from Norwich Medical School, the Research and Development Department of your local hospital and the Regulatory Authorities to check that the study is being carried out correctly. They all will have a duty of confidentiality to you as a research participant.

With your permission, your GP will be informed of your participation in this study.

What will happen to the results of the research study?

The results of the study will be published in scientific journals and presented at scientific meetings. You will not be named or identified in any way in any report of the study. If you would like information about the results of the study please contact the Principal Investigator named below.

 PARTICIPATION IN THE GENETIC RESEARCH

If you agree to participate in the study you will also be invited to participate in the genetic part of the study. By looking at DNA (genes – the building blocks of life) in your blood researchers may be better able to understand how patients differ in the way they respond to co-trimoxazole. Approximately 10mls (about 2 teaspoons) of blood will be taken at the same time as one of the other blood tests – usually the blood test at the beginning of the study. Your sample will be given a code in the same we as for the rest of your data (as described above) so only the researchers and your doctors can link it back to you. Samples will be collected and shipped to Norwich for analysis. Analysis of these samples may be undertaken after completion of the study and following assessment of the primary study outcome.

Participation in the Genetic research is voluntary. If you decide to take part you are still free to withdraw at any time if you change your mind. If you decide not to take part or to withdraw your consent for the Genetic part of the study, you do not have to give a reason and there will be no change to your medical treatment or to your participation in this study. If you withdraw from the Genetic research, your sample will be destroyed and the sponsor will only keep any study information collected/generated up to that point. If you withdraw from the clinical study, you can choose whether to have your Genetic sample destroyed or not.

We would like to use your sample for scientific and medical research purposes, for example to test for certain proteins and other biological markers of disease and prognosis. We ask you to explicitly confirm your consent for the testing of your blood samples by putting your initials where appropriate on the consent form.

The purpose of these analyses is not to provide a diagnosis for you. Results from the genetic analyses will not be used to prove any disease-causing genes which may carry any risk of disease for you or your close relatives. The intention is to determine genetic associations related to pulmonary fibrosis or response to or side effects from treatment.

What benefits can I expect from the Genetic part of the study?

There will be no benefit to you by taking part in the Genetic part of the study but you may help researchers understand why people react differently to co-trimoxazole.

Who is organising and funding the research?

This study is being organised by the Norfolk and Norwich University Hospital NHS Foundation Trust and The University of East Anglia. The study is being co-ordinated by Norwich Clinical Trials Unit (part of the University of East Anglia). The research is being funded by the National Institute for Health Research (NIHR), Efficacy and Mechanism Evaluation (EME) programme. NIHR-EME grant number 12/206/09

 Who has reviewed the study?

All research in the NHS is looked at by independent group of people, called a Research Ethics Committee to protect your safety, rights, wellbeing and dignity. This study has been reviewed and given favourable opinion by London-Surrey Borders Research Ethics Committee.

 In addition, the study has also been reviewed and approved by the Medicines and Healthcare Products Regulatory Agency (MHRA).  The Research and Development Department of your local hospital has also reviewed and approved the study.

Contact for further information

If you have any questions or would like more information, please contact either your local researchers or the co-ordinating team (details below). You can receive general information about participating in research from your doctor.

If you are interested in taking part in this research please let us know.  You can telephone us, email us, or use the reply slip and freepost envelope.

Local Researchers Details:

Local PI Name         Dr Elizabeth Fuller

Local PI Address    South Tyneside NHS Foundation Trust

Local PI Address    South Shields

Co-ordinating Team Details:

Dr Andrew Wilson

EME-TIPAC Office

Norwich Clinical Trials Unit,

Norwich Medical School,

University of East Anglia

Norwich, NR4 7TJ

EME-TIPAC@uea.ac.uk


Thank you for taking the time to read this information

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