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Protocol for Cranberry for Cystitis Clinical TrialTITLEDetermining the efficacy of cranberry capsules in the management of acute radiation cystitisAIMSTo determine whether taking daily cranberry capsules is superior to taking daily placebo capsules in managing non-haemorrhagic radiation cystitis in prostate cancer patients, using the RTOG scale.To determine whether a novel scale is as good as a current standard scale in measuring the severity of non-haemorrhagic radiation cystitis in prostate cancer patients BACKGROUNDRadiation cystitisProstate cancer is, after skin cancer, the most common cancer among older men in developed countries. The latest reports from Cancer Statistics NZ show an increasing trend in the number of men diagnosed with prostate cancer each year, from 2484 in 2007 to 3139 in 2012 [1]. Radiation-induced cystitis is a common acute side effect of radiation therapy for prostate cancer, with up to 60% of men suffering from cystitis to some extent [2–4]. Acute symptoms occur within two to three weeks of starting radiation treatment and include urinary urgency, frequency, dysuria, haematuria and an increased risk of urinary tract infections [5]. Symptoms mostly resolve several weeks after completion of radiation therapy. However during therapy, acute radiation cystitis can compromise patient wellbeing. There is currently no effective treatment to prevent and treat radiation cystitis, with management focusing almost exclusively on symptom relief.Cranberries to manage radiation cystitisBecause radiation cystitis is caused by free radical damage to the bladder lining, therapies that decrease the number of free radicals in the bladder may decrease radiation cystitis severity [5]. Proanthocyanidins (PACs), phytochemicals found in the North American cranberry, have dose dependent radical scavenging, anti-bacterial and anti-carcinogenic properties [6–9]. The effect of cranberries on radiation cystitis has been investigated in four clinical studies. Two of these studies tested the effect of cranberry juice on cystitis severity [4,10] and found statistically non-significant decreases in cystitis symptoms. These studies were the open label Canadian RCT comparing the effects of cranberry juice and apple juice on radiation cystitis in 112 prostate cancer patients [10] and the double blinded Scottish RCT comparing the effect of cranberry juice and a similar control juice on radiation cystitis in 128 patients with bladder and cervical cancer [4]. A third Italian non-randomized study showed that standardized cranberry tablets significantly decreased radiation cystitis compared to no treatment in a cohort of 370 prostate cancer patients [11]. The fourth study was a double blinded pilot RCT, conducted by our group in New Zealand that compared the effects of highly standardized cranberry capsules with those of placebo capsules on the incidence and severity of radiation cystitis in 41 prostate cancer patients. We showed that men taking one cranberry capsule (containing 72mg PACs) daily from the start of radiation treatment till 2 weeks after completion of treatment were less likely to develop radiation cystitis than men taking placebo capsules (incidence 65% and 90% respectively; p=0.058) and that men on the cranberry arm experienced pain/burning less frequently (p= 0.045) [12]. Need for a more sensitive scaleScales commonly used to measure radiation cystitis severity (such as RTOG: Radiation Therapy Oncology group and EORTC: European Organisation for Research and Treatment of Cancer) are not very sensitive, limiting the number of possible grades to 5: grade 1: mild, grade 2: moderate, grade 3: severe; grade 4: life threatening/hospitalisation and grade 5: death (see Table 1 for grading of non-haemorrhagic cystitis). Table 1. RTOG/EORTC: Acute Radiation Morbidity Scoring Criteria: non-haemorrhagic cystitis. Modified from [13].Modified RTOG/EORT radiation-induced cystitis grades for non-haemorrhagic cystitisGrade 0Grade 1Grade 2Grade 3Painnonenot requiring medicationlocal anaesthetics(pyridium)pelvic pain bladder spasms frequent narcoticsUrgencynormalnot requiring medicationlocal anaesthetics(pyridium)pelvic pain bladder spasms frequent narcoticsDay time Frequency normal2x pre-treatment< once an houronce an hourNight time Frequency normal2x pre-treatment< once an houronce an hourNon-invasive interventions such as cranberry capsules are not expected to affect the outcome of patients with grade 4-5 cystitis but may be able to decrease the severity of symptoms of grade 1-3 cystitis. The standard scales are not sensitive enough to distinguish between small differences in severity which may be clinically relevant because they affect patient wellbeing and QoL. In this trial we will use a modified version of RTOG which pertains only to non-haemorrhagic cystitis.RICAS: Radiation-Induced Cystitis Assessment Scale for non-haemorrhagic cystitisIn our previous trial we used the urinary domain of the health related quality of life scale, EPIC. The severity and bother items of EPIC were useful indicators of the symptoms associated with cystitis, particularly those that affected day to day life. We therefore devised a new scoring system that we called RICAS roughly modelled on the RISRAS (Radiation-induced Skin Reaction Assessment Scale), which was validated against WHO and RTOG in the late 1990s [14] and by our own group [15] in 2014. Table 2 shows the new scale in detail, which consists of an “item severity score” and an “item impact score”. Item severity scoreWe have compiled nine symptoms that our patients had indicated impacted on their daily life and gave all the items identically weighted severity scores (0-3: never, mild, moderate and severe). Severity scores will be added up to a total of 0 (none of the items different from normal)-27 (all 9 items severe). Note some of these (urgency, frequency and pain are also in the RTOG scale.Item impact scoreIn addition we ask that the patients score how much of an impact each of these items has had on their life in the week preceding the questionnaire. Individual impact scores (0-3: no, small, moderate, large impact) are added up as well, giving a total score of 0 (no impact of any of the items) to 18 (large impact of all of the items on daily life). The total RICAS score would then consist of the total item severity score plus the total item impact score (total between 0 and 45), which allows for very small differences to be identified between intervention and control cohorts.Table 2. RICAS: Radiation-induced Cystitis Assessment ScaleRICAS: Radiation-induced Cystitis Assessment Scale (between 0 and 45)Item Severity Score (total scores between 0 and 27)Pain frequency when urinating0123?neveronce a week> once a weekevery dayPain severity when urinating0123?nonemildmoderateseverePelvic pain frequency0123neveronce a week> once a weekevery dayPelvic pain severity0123nonemildmoderatesevereDay time frequency0123?normal2x normalfewer than hourlymore often than hourly Night time frequency0123?normal2x normalfewer than hourlymore often than hourlyUrgency0123?nonemust go within 30 minmust go within 15 minutesmust go within 5 minControl0123?normaloccasional dribblingfrequent dribblingno control at allStrength of flow0123?normalslightly weakermoderately weakermuch weakerItem Impact Score (total scores between 0 and 18)no impactsmall impactmoderate impactlarge impactPain0123Day time frequency0123Night time frequency0123Urgency0123Control0123Strength of flow0123STUDY DESIGNThis is a stage III double blinded placebo controlled clinical trialHYPOTHESES AND OBJECTIVESHypothesesCranberry capsules are better than placebo capsules in decreasing RICAS and RTOG scores of radiation cystitis.RICAS is better than RTOG/EORTC in measuring small differences in severity of non-haemorrhagic cystitis between prostate cancer patients taking daily cranberry capsules and those taking daily placebo capsules.ObjectivesPrimary Objective: To determine if cranberry capsules decrease the severity of non-haemorrhagic cystitis compared with placebo capsulesSecondary Objective: To determine if RICAS is better than RTOG in measuring small differences in the severity of non-haemorrhagic cystitis in patients of the same cohort (cranberry or placebo) and between cohortsPARTICIPANTSEligibility: All men receiving radiation therapy for prostate cancer and whose CT planning scan shows at least 100cc of bladder is in the radiation field.Exclusion criteria*: previous RT to the pelvis systemic disease allergy to cranberries history of kidney stones anticoagulant usageRADIATION THERAPY TREATMENT: AS PER INSTITUTIONAL PROTOCOL. TRIAL TREATMENT REGIMENPatients will receive information about the trial verbally from the radiation oncologist and research assistant and in the form of the participant information sheet (Appendix B). If they elect to participate in the trial, they will give written informed consent before randomization (Appendix C). Consented participants will be randomized to either the cranberry arm or the placebo arm. Each participant will be given a numbered bottle (patient 01 will have bottle 01 etc.) containing either 140 cranberry or 140 placebo capsules at the start of their RT treatment. The participants will take two capsules a day during breakfast from the first day of treatment and continue until all the capsules have been taken (10 weeks).Participants are not allowed to take foods, drinks or supplements containing cranberries, blueberries or blackberries and limit consumption of grapes and wine.Schematic diagram INTERVENTIONAL PRODUCTS Test Drug: Cranberry capsules Naturo Pharm is a New Zealand company that will provide the unmarked bottles with cranberry capsules (containing 36 mg PACs) each. The clinical material is a solid drug product and is packaged in high-density polyethylene (HDPE) bottles. The tablets should be stored in original bottle at20°C to 25°C (68°F to 77°F); excursions from 15°C to 30°C (59°F to 86°F) are parative Drug: Placebo capsulesThe placebo capsules containing colloidal silica, magnesium stearate, cellulose and gelatin. The capsules will be opaque, making them indistinguishable from the cranberry capsules. The clinical material is a solid drug product and is packaged in HDPE bottles with child-resistant closures. The tablets should be stored in original bottle at 20°C to 25°C (68°Fto 77°F); excursions from 15°C to 30°C (59°F to 86°F) are permitted.Packaging and LabelingAll medication used in this study will be prepared, packaged, and labeled under theresponsibility of qualified staff. Standard operating procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, International Conference on Harmonisation (ICH) Good ClinicalPractice (GCP) guidelines, and applicable local laws/regulations will be followed. Each bottle will bear a label conforming to regulatory guidelines, GMP and local laws and regulations, which identifies the contents as investigational drug. A qualified person will perform the final release of the medication.The study centers will be provided with bottles containing Cranberry capsules 36 mg capsules and bottles containing capsules of matching placebo. The capsules will be opaque, making them indistinguishable from the cranberry capsules.Study Drug HandlingCurrent ICH GCP Guidelines require the Investigator to ensure that study drug deliveries from the Company are received by the Investigator/or designee and thatdeliveries are recorded;study drug is handled and stored according to labeled storage conditions;study drug with appropriate expiry/retest only is dispensed to study subjects in accordance with the protocol, any unused study drug is returned to the primary investigatordrug inventory and accountability records for the study drugs will be kept by the investigator, or designee. MEASUREMENTS: CYSTITIS ASSESSMENTRTOG/EORC and RICAS (see above).The men will be asked to fill in the RTOG/EORTC and RICAS scores before they start radiation treatment to obtain baseline data and once a week after that for the next 10 weeks. For the first 8 weeks this will happen in the department when the men come for their radiation treatment. The questionnaires will be collected by the research assistant. After completion of treatment, each participant will be rung up once a week for the next 2 weeks by the research assistant who will note down their scores over the phone.BLINDING AND RANDOMISATIONThis is a double-blind study. Subjects will be randomized to receive Cranberry capsules or placeboin a double-blind fashion such that neither the Investigator, study management team, clinical staff, nor the subject will know which agent is being administered. The randomization number will be assigned based on information obtained from the study statistician.Blinding MethodFor the purpose of this study, the efficacy and safety of Cranberry capsules and placebo will be compared in a double-blind manner. Cranberry capsules and placebo will be indistinguishable from one another in appearance, and packaging for each treatment group will also be indistinguishable from one another in appearance.UnblindingUnblinding will occur after all data have been collected at the end of the trial, followed by an in depth data analysis by the PI and the biostatistician. The randomization list and study medication blind will be maintained by the academic PI and the IRT system. Breaking the Treatment Code for EmergencyThe treatment code for each randomized subject will be provided by the IRT in the event of a medical emergency requiring knowledge of the treatment assigned to the subject. The time, date, subject number and reason for obtaining any of these codes, and therefore breaking the blind, must be documented in the study file. They must only be requested by the Investigator or other persons designated as sub-investigators. No subjects or other study personnel will be made aware of the treatment given to any subject unless a medical emergency necessitates such disclosure.Any unblinding by the investigational staff must be reported immediately to the academic PI and clinical PI and must include an explanation of why the study medication was unblinded.Assignment and AllocationSubjects will be entered into the IRT system at screening and assigned a subject number.Randomisation will be performed in a 1:1 ratio to cranberry capsules or placebo capsules by the academic PI based on computer-generated numbers provided by the study’s statistician.TRIAL OVERSIGHTThere will be a trial management committee (TMC) which will oversee adherence to protocol, any adverse events etc. The TMC will mmeet when necessary to discuss chenges to protocol or any adverse events. The TMC will be made up of:Independent Chair: Dr Chris JacksonAcademic PI: Dr HerstClinical PI; Dr CostelloCharge RT: Alison Aumata/ Noelle BennettStatistician: Gordon PurdieADVERSE EVENTS AND OTHER SAFETY ASPECTSBoth cranberry and control capsules should be well tolerated by patients. However, if a patient experiences an unexpected adverse event, the trial will terminate for him at that point. 10.1 Adverse EventAn AE is: any untoward medical occurrence in a subject or clinical investigation participants administered a medicinal product, which does not necessarily have to have a causal relationship with this treatment (the investigational product).An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of the investigational product, whether or not considered related to the investigational product.10.2 Serious Adverse Event (SAE)A SAE is any untoward medical occurrence that at any dose:Results in death,Is life-threatening, NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.Requires inpatient hospitalisation or prolongation of existing hospitalisation,Results in persistent or significant disability/incapacity,Is a congenital anomaly/birth defect,Other important medical events. NOTE: Other events that may not result in death, are not life threatening, or do not require hospitalisation, may be considered a SAE when, based upon appropriate medical judgement, the event may jeopardise the subject and may require medical or surgical intervention to prevent one of the outcomes listed above.To ensure no confusion or misunderstanding of the difference between the terms "serious" and "severe", which are not synonymous, the following note of clarification is provided:The term "severe" is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as severe headache). This is not the same as "serious," which is based on subject/event outcome or action criteria usually associated with events that pose a threat to a subject's life or functioning as defined in the bullet points above. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.10.3CausalityThe relationship of each AE to the investigational product must be determined by a medically qualified individual according to the following definitions:Not Related: in the opinion of the investigator, the AE is probably produced by the subject’s clinical state or by other modes of therapy administered to the subject.Unlikely related: no temporal association, or the cause of the event has been identified, or the investigational product cannot be implicated based on available information;Possibly related: temporal association, but other etiologies are likely to be the cause; however, involvement of the investigational product cannot be excluded based on available information;Probably related: temporal association, other etiologies are possible, but unlikely based on available information.10.4 Procedures for Recording Adverse EventsAll AEs occurring during the study observed by the investigator or reported by the subject, whether or not attributed to the investigational product, will be recorded on the CRF.The following information will be recorded: description, date of onset and end date, severity, assessment of relatedness to the investigational product, other suspect drug or device and action taken. Follow-up information should be provided as necessary.AEs considered related to the investigational product as judged by a medically qualified investigator or the sponsor will be followed until resolution or the event is considered stable. All related AEs that result in a subject’s withdrawal from the study or are present at the end of the study, should be followed up until a satisfactory resolution occurs.It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient severity to require the subject’s removal from treatment. A subject may also voluntarily withdraw from treatment due to what he or she perceives as an intolerable AE. If either of these occurs, the subject must undergo an end of study assessment and be given appropriate care under medical supervision until symptoms cease or the condition becomes stable.The severity of events will be assessed on the following scale: 1 = mild, 2 = moderate, 3 = severe.The relationship of AEs to the investigational product will be assessed by a medically qualified investigator.10.5 Reporting Procedures for Serious Adverse EventsAll SAEs must be reported to the sponsor within one working day of discovery or notification of the event. The sponsor will perform an initial check of the report, request any additional information and ensure the SAE is reviewed on a weekly basis. The sponsor must notify the ethics committee of a SAE in writing within 1 week of discovery or notification of the event.Procedure in Case of PregnancyThe effects on Cranberry on pregnancy are unknown. Study participants are recommended to take precautions to avoid pregnancy whilst on treatment. These could include abstinence or other contraceptive measures as discussed with the investigator. Any pregnancy occurring during the clinical study and the outcome of the pregnancy, should be recorded.DISCONTINUATION/ WITHDRAWAL OF PARTICIPANTS FROM STUDY TREATMENTEach subject has the right to withdraw from the study at any time. In addition, the investigator may discontinue a subject from the study at any time if the investigator considers it necessary for any reason including:Significant protocol deviation (in the opinion of the investigator)Significant non-compliance with treatment regimen or study requirements An AE which requires discontinuation of the investigational product or results in inability to continue to comply with study proceduresDisease progression which requires discontinuation of the investigational product or results in inability to continue to comply with study proceduresConsent withdrawnLost to follow upThe reason for withdrawal will be recorded in the CRF. If the subject is withdrawn due to an AE resolved or stabilised. In the case of early withdrawal, the investigator will attempt to conduct the end of study assessments. If any information becomes available during the study that may be relevant to participants’ continued participation, they will be informed by phone or at the next study visit at the discretion of the investigator.STATISTICAL ANALYSISParticipant numbersBased on our previous pilot study, we aim to recruit 100 patients, 50 in the cranberry arm and 50 in the placebo arm. Trial is powered to 80% to detect a statistically significant difference between cranberry and placebo arms (p<0.05) of cystitis incidence and RICAS impact items of pain, nocturia and strength of stream.Baseline Statistics and General MethodsBaseline characteristics by treatment arm will be summarised in frequency tables and by the use of descriptive statistics for quantitative variables. Summary tables will be prepared giving numbers of patients by treatment arm and by randomisation irregularities, treatment compliance, eligibility infringements, and losses to follow-up (as per CONSORT guidelines). All available data will be used where possible. There will be no imputation of missing data.The safety analysis set (SAF) will include all patients who receive at least one dose of investigational product or placebo. Patients will be analysed according to the treatment actually taken. All safety analysis will use the SAF population.The full analysis set (FAS) will include all randomised patients who received at least one dose of investigational product or placebo and for whom baseline and end-of-treatment score are available. The FAS will be used for the primary analysis of the primary variable. Patients will be analysed for the primary efficacy variable in the FAS population according to their randomized treatment even if they did not receive the designated randomized treatment allocated.The intention to treat (ITT) analysis set is a subset of the FAS and includes those who have at least one post-baseline assessment other than an end-of-treatment score. Patients will be summarised according to the treatment they were randomised to. All other efficacy endpoints will use the ITT population.Primary objective. The severity of non-haemorrhagic cystitis in cranberry and placebo groups will be compared with Wilcoxon rank-sum tests for both the RTOG/EORTC and RICAS scoring systems.Secondary objective . The difference between cranberry and placebo for the average severity of cystitis using RTOG/EORTC will be compared to the difference between cranberry and placebo for average RICAS by comparing the Wilcoxon rank-sum test statistics for the two comparisons.References1. New Zealand Cancer Registry (NZCR), Ministry of Health – Manatū Hauora, 2013 [Internet]. Available from: . McCammon R, Rusthoven KE, Kavanagh B, Newell S, Newman F, Raben D. Toxicity assessment of pelvic intensity-modulated radiotherapy with hypofractionated simultaneous integrated boost to prostate for intermediate- and high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2009;75(2):413–20. 3. Pervez N, Small C, MacKenzie M, Yee D, Parliament M, Ghosh S, et al. Acute toxicity in high-risk prostate cancer patients treated with androgen suppression and hypofractionated intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2010;76(1):57–64. 4. Cowan CC, Hutchison C, Cole T, Barry SJE, Paul J, Reed NS, et al. A randomised double-blind placebo-controlled trial to determine the effect of cranberry juice on decreasing the incidence of urinary symptoms and urinary tract infections in patients undergoing radiotherapy for cancer of the bladder or cervix. Clin Oncol [Internet]. Elsevier Ltd; 2012 Mar [cited 2013 Sep 7];24(2):e31–8. Available from: . Antonakopoulos GN, Hicks RM, Berry RJ. The subcellular basis of damage to the human urinary bladder induced by irradiation. J Pathol [Internet]. 1984 Jun;143(2):103–16. Available from: . C?té J, Caillet S, Doyon G, Sylvain J, Lacroix M. Bioactive compounds in cranberries and their biological properties. Crit Rev Food Sci Nutr. 2010;50(7):666–79. 7. Brown P, Turi C, Shipley P, Murch S. Comparisons of large (Vaccinium macrocarpon Ait.) and small (Vaccinium oxycoccos L., Vaccinium vitis-idaea L.) cranberry in British Columbia by phytochemical determination, antioxidant potential, and metabolomic profiling with chemometric analysis. Planta Med 2012 Apr;78(6)630-40. 2012;78(6):630–40. 8. Cesonien? L, Daubaras R, Jasutien? I, Venclovien? J, Miliauskien? I. Evaluation of the biochemical components and chromatic properties of the juice of Vaccinium macrocarpon Aiton and Vaccinium oxycoccos L. Plant Foods Hum Nutr. 2011;66(3):238–44. 9. Viskelis P, Rubinskiene M, Jasutiene I, Sarkinas A, Daubaras R, Cesoniene L. Anthocyanins, antioxidative, and antimicrobial properties of American cranberry (Vaccinium macrocarpon Ait.) and their press cakes. J Food Sci 2009. 2009;74(2):C157–61. 10. Campbell G, Pickles T, D’yachkova Y. A Randomised Trial of Cranberry Versus Apple Juice in the Management of Urinary Symptoms During External Beam Radiation Therapy for Prostate Cancer. Clin Oncol [Internet]. 2003 Sep [cited 2013 Sep 4];15(6):322–8. Available from: . Bonetta A, Di Pierro F. Enteric-coated, highly standardized cranberry extract reduces risk of UTIs and urinary symptoms during radiotherapy for prostate carcinoma. Cancer Manag Res [Internet]. 2012 Jan;4:281–6. Available from: . Hamilton K, Bennett NC, Purdie G, Herst PM. Standardized cranberry capsules for radiation cystitis in prostate cancer patients in New Zealand: a randomized double blinded, placebo controlled pilot study. Support Care Cancer [Internet]. 2015 Jan [cited 2015 Sep 20];23(1):95–102. Available from: . Cox J, Stetz J, Pajak T. Toxicity criteria of the radiation therapy oncology group (RTOG) and the European organization for research and treatment of cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31(5):1341–6. 14. Noble-Adams R. Radiation-induced skin reactions 3: Evaluating the RISRAS. Br J Nurs. 1999;8(19):1305–12. 15. Herst P, Bennet N, Sutherland A, Peszynski R, Paterson D, Jasperse M. Prophylactic use of Mepitel Film completely prevents radiation-induced moist desquamation in an intra-patient controlled RCT of 78 breast cancer patients in New Zealand. Radiother Oncol. 2014;110(1):137–43. ................
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