Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Cooper BA, Branley P, Bulfone L, et al. A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med 2010;363: DOI: /NEJMoa

2 Study Protocol Contacts: Professor Carol Pollock Royal North Shore Hospital, Sydney Phone: (02) A/Professor David Harris Westmead Hospital, Sydney Phone: (02) Dr. Bruce Cooper Royal North Shore Hospital, Sydney Phone: (02) Joan Kesselhut & Anne Jackson CNS Nurse Coordinators. Royal North Shore Hospital, Sydney. Phone No Fax No

3 TABLE OF CONTENTS COMMITTEES...4 EXECUTIVE SUMMARY...6 BACKGROUND...7 STUDY OBJECTIVES...9 OVERALL STUDY DESIGN...10 Flow Sheet Patient identification Consenting and Registration Baseline assessment Randomisation Treatment Ongoing Assessment Adverse Events Outcomes Trial end points:...21 A-Primary Outcome:...21 B-Secondary Outcome Factors:...21 OTHER DEFINITIONS...22 Early commencement of dialysis in the patients randomised to the late start group Late commencement of dialysis in the early start group Discontinuation of the trial Transplantation METHODS...24 A- Power calculations and statistics Baseline survival for dialysis patients...24 Estimated survival effect of intervention...24 Number of subjects required for this study...24 Interim analysis...25 Anticipated drop-outs...26 Data analysis...26 B- Equations to be used: C- Standardisation of methods for collections DATA MANAGEMENT...33 BUDGET...34 FUNDING...34 Appendix A...36 PATIENT INFORMATION SHEET PATIENT INFORMATION SHEET optional tests Appendix B

4 Consent Form No. 1 (Sample) Consent Form No. 2 (Sample) Appendix C...42 Data collection sheets (see separate document) Appendix D...42 New York Heart Association Functional Classification NYHA REFERENCES...43 Appendix E...45 Nutritional Study Sub-Group Background...45 Study Objectives...45 Patient Identification...45 Nutritional Assessment...46 Methods...48 References (nutritional):...51 Appendix F...53 Cardiac Echo Sub-Group Background...53 Study Objectives...53 Patient Identification...53 Cardiac Assessment...53 Methods

5 COMMITTEES Management committee: The management committee consists of the following personnel: Chairpersons: David Harris Carol Pollock Members: Pauline Branley John Collins Bruce Cooper Jonathan Craig Alex Disney Margaret Fraenkel David Johnson John Knight Grant Luxton David Tiller 4

6 Safety and data monitoring committee: This committee consists of the following personnel: Professor John McNeil (chair) Professor Andrew Tonkin Dr John Dawborn The ʻTerms of Referenceʼ for this committee have been defined and are available from the study Coordinators on request Outcomes or End Point Committee: This committee consists of the following personnel: Professor Henry Krum (chair) Professor Peter Kerr Professor Aubrey Pitt The ʻTerms of Referenceʼ for this committee have been defined and are available from the study Coordinators on request 5

7 EXECUTIVE SUMMARY Why is this study needed? One of the most important dialysis related questions at present is "When is the best time to start dialysis"? The question has not been addressed adequately by any previous study, and as far as we are aware, there are no randomised control trials planned or in process to examine the question. What is the design of this study? This is a multi-centre Australian and New Zealand randomised controlled study, over 5 years. It will compare outcome in patients commencing dialysis with a GFR of ml/min/1.73m 2 versus a GFR of 5-7mls/min/1.73m 2. Between patients will be randomised into each group. To qualify for entry a patient must have a GFR not less than 10mls/min/1.73m 2. However, our preference is to enrol the patient when their GFR is between 15-20mls/min/1.73m 2. Randomisation will occur when each patient's GFR is first less than 15mls/min/1.73m 2. Following commencement of the study it is planned to have a median patient follow up of 3 years. The objectives are to determine which level of GFR at initiation of dialysis in patients with end-stage renal failure (ESRF) is associated with the best outcome in terms of mortality (primary outcome), and in terms of morbidity, hospitalisation, Quality of life and total treatment costs (secondary outcomes). 6

8 BACKGROUND The optimal time to commence maintenance dialysis for end-stage renal failure (ESRF), be it haemodialysis or peritoneal dialysis, is not clear. This uncertainty has been recognised by nephrologists internationally as perhaps the most important dialysis-related question to be addressed in the next decade. A number of groups have tried to resolve this issue of when to commence dialysis using a cohort design or with case control studies (1-6), which are both subject to potential biases. The biases, which have confounded these latter studies, include referral-time and lead-time bias, patient age, co-morbidity and compliance, and as a result no firm conclusion has been reached about the optimal time to start dialysis. There have been no randomised controlled clinical trials examining the question. Nevertheless, despite a lack of firm supporting data, guidelines have been issued by one national and two international expert panels recommending the initiation of dialysis at a level of renal function much higher than is current usual practice. Adoption of these guidelines will have enormous implications in terms of finance and infrastructure of dialysis services in Australia and New Zealand. The Dialysis Outcomes and Quality Initiatives (DOQI) of the National Kidney Foundation of USA (7) has recommended that dialysis be commenced at a GFR of approximately 10.5 ml/min/1.73m 2, a level based on the minimum target level of total (residual renal and dialysis) clearance for peritoneal dialysis. The Canadian Society of Nephrology (8) has recommended that dialysis be commenced at a GFR <12ml/min, or lower if there is no evidence of uraemia or malnutrition. Guidelines developed under the auspices of the Australian & New Zealand Society of Nephrology and Australian Kidney Foundation as part of the CARI (Caring for Australians with Renal Impairment) initiative (9) recommended commencement of dialysis at a GFR of 10 ml/min/1.73m 2 in patients with evidence of uraemia or malnutrition, or lower without uraemia or malnutrition. Despite the lack of firm evidence to support these recommendations, they are already having an effect on attitudes and practice of nephrologists in Australia and New Zealand and elsewhere. The argument for commencing dialysis at a GFR of >10ml/min/1.73m 2 is based mainly on extrapolation from the CANUSA study in which morbidity / mortality for PD patients was less in those with a total weekly 7

9 Kt/V >2.0 (1). Balanced against this is the mortality (15% annually in Australia and New Zealand in 1998) and morbidity of dialysis. There was marked lack of uniformity in the responses of 100 individual Australian and New Zealand nephrologists to questions posed in October 1999 at the Dialysis and Transplant Workshop about when they initiate dialysis in their patients, be they otherwise well, or malnourished. Patients Patients GFR* Otherwise well Malnourished > <5 3 0 Donʼt rely on GFR * ml/min/1.73m 2 This accords well with data from the 6 month period of April to September 1998 in which 21% of Australian patients commencing HD and 23% commencing PD did so at a creatinine clearance of greater than 10 ml/min (10). In contrast, creatinine clearance at initiation was <5mls/min in 15 and 17% respectively. GFR at initiation was higher amongst diabetics (35%) than non-diabetics, patients of age versus 65-74, and males versus females. There was some interstate variability. 8

10 STUDY OBJECTIVES To determine whether early or late initiation of dialysis in patients with ESRF -! Primary: Reduces (all cause) mortality! Secondary: Reduces morbidity Improves quality of life Reduces overall treatment costs Reduces total days of hospitalisation Alters loss of residual renal function Improves nutritional state (sub study) 9

11 OVERALL STUDY DESIGN Multi-centre randomised controlled trial of dialysis start time. Patients will be enrolled from renal units throughout Australia and New Zealand. Patients will be randomised to commence dialysis at: GFR of ml/min/1.73m 2 versus GFR of 5-7 ml/min/1.73m 2. Flow Sheet PATIENT IDENTIFICATION GFR=15-20ml/min/1.73m 2 Consent and enrol into trial (Form A + Z) * If GFR < 10 at first review then patient ineligible for trial If GFR between at first review then patient still eligible for trial 3 monthly assessment (Pre-randomisation: Form B) ** Consider access creation Consent and enrol patient ASAP (Form A + Z) ** and then proceed straight to full baseline assessment When GFR is first between 10-15ml/min/1.73m 2 Full baseline assessment (Form C) and RANDOMISATION THESE CHECKS WILL OCCUR AT THE TIMES INDICATED * GFR calculated to ensure it meets the study criteria Estimate of serum creatinine for a GFR=15ml/min/1.73m 2 ** GFR calculated and flagged if <=15ml/min/1.73m 2 *** GFR calculated and flagged if <=7ml/min/1.73m 2 (late start patients only) Commence dialysis within 6 weeks (Form D) EARLY START Commence Ongoing assessment every 3 months (Forms E - P)*** QOL assessment every 12 months (Form Q) Record adverse events (Form X) LATE START of dialysis When GFR first reaches 7ml/min/1.73m 2 Commence dialysis END POINT (Form S) 10

12 Patient identification Identify patients who have an estimated GFR between 15-20ml/min/1.73m 2 by the Cockcroft and Gault equation with body surface area correction (see Methods B - Equations to be used) and whose renal function will fall below 15 ml/min/1.73m 2 within the next 2 years. Patients with a GFR between 10-15ml/min/1.73m 2 when first identified can also be entered into the study although they must be registered and randomised immediately. A-Patient population Patients will be drawn from all adult (>18 years) patients commencing maintenance dialysis in Australian and New Zealand renal units participating in the study. B- Inclusion criteria Age " 18 years Progressive chronic renal failure with GFR ml/min/1.73m 2 at time of baseline assessment. Revised inclusion criteria for patients with failing transplant. (April 2001) This has been expanded on. The protocol states ʻProgressive chronic renal failureʼ as one of the inclusion criteria and, as patients with failing renal transplant also have progressive chronic renal failure, these patients may now be considered for the trial. Stratification of these patients at the randomisation process will be based only on the pre-existing variables (centre, diabetes and planned modality). Note: The preferred GFR at registration should be between 15-20ml/min/1.73m 2. Written, informed consent (see patient information form - Appendix A) C-Exclusion criteria Age < 18 years GFR <10 ml/min/1.73m 2 at time of initial assessment Inability to provide written, informed consent Planned transplantation from live donor within the next 12 months Malignancy (other than skin) See next page 11

13 Revised inclusion criteria for patients with previous malignancy. (April 2001) Originally, patients with a history of cancer were excluded from the trial. This criterion has now been changed to include patients who have a previous diagnosis of cancer but are now disease free or who have localised prostate cancer that is not contributing to their renal impairment through obstruction. The amended guidelines (Adapted from the NZ guideline for selection of patients for transplantation), to determine eligibility for the entry into the trial of patients with a prior cancer, are as follows: Patients with previous cancers should be excluded from the IDEAL trial unless the following is/are true: Patients with solid organ tumours who demonstrate a disease free interval of at least two years - with the following exceptions: Breast and colon: Melanoma: Other skin cancer: disease free interval - 5 years disease free interval - 5 years disease free interval - at the discretion of the renal physician Renal carcinoma associated with acquired cystic disease: No disease free interval is required, provided there has been complete histological removal. Regarding Ca prostate, these patients may be included if: The malignancy is limited to the prostate and, It is not contributing to the renal failure as a result of obstruction to the urinary tree. Rationale: Most solid organ tumours will recur within 2 years if metastatic. Exceptions are breast and colon where there is a higher recurrence rate between 2-5 years follow up. Melanoma is similar. Localised cancer of the prostate is common with increasing age and tends to have a limited effect on mortality. There needs to be some flexibility in the approach to cancer as carcinoma in situ and less aggressive forms of cancer will require a shorter disease free interval. Please seek advice from surgical and oncological colleagues. 12

14 Consenting and Registration Information in regards to the details of this trial will be given to the patient (Appendix A) and, if they are willing to participate, they will be asked to sign a consent form (Appendix B). The original consent form should be kept in the patient's trial folder, a photocopy should be given to the patient and a copy placed in the patient's medical records. Patients who are willing to participate in the Nutrition sub-study should also sign consent form 2 (Appendix B) at this time. Patients will be registered for the trial at this point recording their identifying details as well as information on their planned dialysis modality, demographic information, primary renal disease, baseline morbidity, residual renal function and medication usage. At this point in time the patients will be allocated a trial ID number that should be used on all future forms. Routine surveillance will continue, and will include assessment of renal function on a 3 monthly basis until the patient's GFR is first 15 ml/min/1.73m 2. Full baseline assessment and randomisation will occur at this point (see next section). Note: Patients may be first entered into the trial with a GFR between 10-15ml/min/1.73m 2 however, randomisation at 15ml/min/1.73m 2 is preferred. If patients are entered into the study at this point in time then they should be randomised immediately. 13

15 Baseline assessment When the patient's estimated GFR is first 15ml/min/1.73m 2 (Cockcroft and Gault with BSA correction) and not <10ml/min/1.73m 2 and providing he/she is still willing to proceed further, full baseline assessment will be performed. The tests will include: 1. Blood parameters:! Electrolytes, Ca, PO4, glucose, cholesterol, triglycerides, LFTs Calculate GFR (Cockcroft and Gault with BSA correction). (Serum albumin should be measured using the bromocresol green method of analysis where possible.)! Full blood count, ESR! CRP, PTH 2. Twenty four hour urine collection: To be used to calculate the following parameters (The calculations will be performed centrally, see Methods B - Equations to be used):! Protein catabolic rate (PCR)! Protein equivalent of nitrogen appearance (PNA) normalised to actual and ideal body weights (npcr)! Kt/V! Urea / creatinine clearance 3. Quality of Life assessment- SF 36 Health Survey 4. Optional Nutrition assessment for those participating in nutrition sub-study at own site or at Royal North Shore Hospital (see Appendix E). 6. Optional Cardiac Echo to be performed prior to commencement of dialysis (see Appendix F). 14

16 Complete registration forms (consent forms already completed). Registration:! Inclusion criteria met! No exclusion criteria! Planned dialysis modality recorded Once these details have been collected and recorded centrally, the patient's ongoing treatment will be determined by central randomisation (see next section). 15

17 Randomisation Once the patient has been registered and consented, and the GFR has first reached a value of 15 ml/min/1.73m 2 (but 10ml/min/1.73m 2 ), he/she will be randomised centrally to either:! Commence dialysis, at a GFR of ml/min/1.73m 2, or! Continue routine care and commence dialysis when GFR falls to 5-7 ml/min/1.73m 2. The randomisation procedure will be carried out at: IDEAL Data Coordinating Centre Clinical Trials Research Unit, University of Auckland To access Phone, Fax or Internet for randomisation see the Data Collection Forms Patients will be stratified based on: a) Dialysis centre b) Planned dialysis modality c) Presence or not of diabetes mellitus The dialysis modality should have been determined prior to the randomisation process. Patients who are randomised to the early start arm of the trial should commence dialysis as soon as practicable, and preferably within 6 weeks. Early creation of access is preferable to avoid delay in randomised start time. The type of dialysis and dialytic regimen remain the choice of the primary physician. Dialysis dose should be maintained above currently accepted targets for total weekly Kt/V, namely: -! Above 2.0 in patients receiving peritoneal dialysis (2.2 if on APD) and;! Above 3.6 if on HD. The use of incremental or full dialysis remains the choice of the treating physician. (This may have subsequent advantages in sub-analysis looking at higher targets and residual renal function (RRF) versus dialytic clearances as there are divided opinions regarding the utility of incremental dialysis). 16

18 Treatment When a patient reaches his/her allocated start time, determined by GFR, dialysis should be commenced as soon as practicable, and preferably within 6 weeks. The following tests should be performed as near as possible to the dialysis start date. Blood parameters:! Electrolytes To be used to calculate GFR (Cockcroft and Gault with BSA correction) 24 hr urine collection: To be used to calculate the follow parameters (this will be done centrally, see Methods B - Equations to be used)! Protein catabolic rate (PCR)! Protein equivalent of nitrogen appearance (PNA) normalised to actual and ideal body weights (npcr)! Kt/V! Urea / creatinine clearance All patients will receive regular dietary advice and support as per the usual protocol in their units. 17

19 Ongoing Assessment Following randomisation and the initiation of the given therapy all the patients will then be followed for the next three years as outlined below. The following time intervals are considered optimal but usual unit protocol may be followed: Every 3 months the following data will be collected and recorded:! Electrolytes, Ca, PO4, glucose, cholesterol, triglycerides, LFTs! Full blood count, ESR! CRP, PTH! Residual renal function (arithmetic mean of urea and creatinine clearance, and if not on dialysis Cockcroft and Gault estimate with BSA correction)! Dialysis adequacy (Kt/V; creatinine clearance (PD only); urea reduction ratio (HD only))! Assessment of protein intake using PCR! Dialysis modality! Dialysis dose! Medication change Every 12 months:! Quality of life assessment (SF-36) should be completed by the patient.! Nutrition assessment of those in optional nutritional sub-study.! Optional cardiac echo (please retain report in the Case Record Folder for future analysis). When an adverse event, transplantation or end point occurs this should be recorded and notified as soon as possible on the appropriate data collection forms (for further details see next section) 18

20 Adverse Events After randomisation, the following events should be reported using the Adverse Event Form (Form X): New cardiac event! Angina:- chest pain (CP) associated with ECG changes without evidence of myocardial damage (normal cardiac enzymes)! Acute myocardial infarction:- CP + ECG + cardiac enzyme rise! NYHA classifications see Appendix D! Coronary artery bypass grafting! Arrhythmia: - Newly documented AF, SVT, VF or VT. Cerebrovascular event! Transient ischaemic attack: - Onset of new neurological symptoms or signs that last for less than 24hrs without residual sequelae.! Stroke: - Onset of new neurological symptoms or signs which last for greater than 24hrs and may be associated with long lasting sequelae. Other disease onset:! Respiratory! Osteoporosis! Renal osteodystrophy! Neuropathy The number of days of hospitalisation required for the above events will be recorded. Randomised 'late' but started dialysis prior to the GFR falling to 7ml/min/1.73m 2, recording:! Modality of dialysis used! Reason for early start! Hospitalisation (number of days required to start dialysis) Randomised ʻearlyʼ, but the access is insufficiently mature to commence dialysis by 10ml/min/1.73m 2. The patient will remain in the early start group for the analysis on an intention to treat basis. 19

21 Dialysis complication: (including pre dialysis) Peritoneal dialysis complication:! Peritonitis! Exit site/tunnel infection! Mechanical catheter problem! Catheter removal or replacement! The necessity to insert a vascath Haemodialysis complication (Access)! Blocked / stenosed! Infected! Revision / replacement! The necessity to insert a vascath Significant fluid overloading! If symptomatic fluid overloading requiring hospitalisation and/or additional dialysis therapy. Significant electrolyte imbalance! If symptomatic electrolyte imbalance requiring hospitalisation and/or additional dialysis therapy. Number of days of hospitalisation required for dialysis-related complication. Transplantation is not an adverse event (see section entitled Other definitions of this manual). 20

22 Outcomes Trial end points: Death from all causes (Cause should be documented where known.) After three years from the date of randomisation A-Primary Outcome: Survival assessed by life table analysis at 3 years B-Secondary Outcome Factors: Disease complications! Myocardial infarction, cerebrovascular event, infection, gangrene etc. Dialysis complications! Peritonitis, vascular access occlusion, complications secondary to access placement, dialysis modality change, required vascath insertion etc. Quality of life Economic analysis Hospitalisation Residual renal function rate of decline! pre -dialysis! on dialysis Nutrition (subset) Left ventricular hypertrophy and function (subset) - assessed by cardiac echo 21

23 OTHER DEFINITIONS Early commencement of dialysis in the patients randomised to the late start group If a patient has been randomised to commence dialysis late but the treating nephrologist feels that the patient should commence dialysis prior to reaching a GFR of 5-7ml/min/1.73m 2 then he/she should do so. Data collection should be performed as outlined in the section entitled Ongoing assessment. An Adverse Event form (Form X) should be completed, the reason for the early commencement of dialysis specified and the patient's RRF at this point in time recorded. Should this occur, the patient would remain in the trial, as the analysis will be performed on the basis of intention to treat. Late commencement of dialysis in the early start group If randomised to early start, but the access is insufficiently mature to commence dialysis by 10ml/min/1.73m 2. The patient remains in the early start group on an intention to treat basis and an adverse event is recorded Discontinuation of the trial Patients may withdraw from the trial at any stage if they wish. Alternatively patients may be withdrawn from the trial if their nephrologist feels it is in their best interests. Future trial end point data should be collected where possible. Transplantation Patients may join the cadaveric transplant waiting list from the time of randomisation i.e. patients randomised to the late start group can be on the transplant list prior to the commencement of dialysis. There will be no waiting time advantage for patients until dialysis is commenced. The length of time on dialysis is one small component that is normally considered as part of the algorithm for renal transplant allocation. Hence, this could potentially disadvantage patients in the late start group. Therefore, in the interests of equity, the Renal Transplant Advisory Committee agreed that patients who have been randomised to the early start arm of the trial would have their actual dialysis start date modified, for the 22

24 allocation algorithm, to a date six months ahead. Similarly, late start patients would have their actual dialysis start date modified, for the allocation algorithm, to a date two months before the actual start date. Tissue Typing laboratories have been notified of this change and should be informed that the patient is enrolled in the trial. The timing of initiation of dialysis may continue to impact on events that occur after subsequent transplantation (eg. vascular events). Thus transplantation and adverse events that follow transplantation should be reported using the Notification of Transplant (Form T) and the Transplant patient 3 month assessment and adverse event form (Form E (T)). 23

25 METHODS A- Power calculations and statistics Baseline survival for dialysis patients The three-year dialysis survival rate censored for transplantation and loss to follow up was obtained from ANZDATA. The three-year survival rate was calculated over 1988 to 1998 using life table methods and was 63.5% survival at three years; at four years the survival was 52%. This was used for the power calculations below. Estimated survival effect of intervention Few data are available on this subject, as no prospective randomised trial has yet been undertaken. However, Bonomini et al suggest in a 12 year observational study that the difference in mortality may be as high as 25% (KI, 1995). This study however had numerous problems and was not prospectively randomised. It is impossible to estimate the likely difference in mortality over 3 years, but a clinically significant effect of 10% or more over the three years would be of interest. Number of subjects required for this study Method 1 (Jonathan Craig, Senior Lecturer, Clinical Epidemiology, Department of Public Health, University of Sydney and Staff Specialist in Nephrology, New Childrenʼs Hospital, Sydney) Control group rate 0.64 Intervention group rate 0.73 Follow up 3 yrs Accrual time 2 yrs Significance 0.05 (2-sided) Power 0.80 Number of subjects required 970 Control group rate 0.64 Intervention group rate

26 Follow up 3 yrs Accrual time 3 yrs Significance 0.05 (2-sided) Power 0.80 Number of subjects required 880 Method 2 (Pauline Branley, Senior Lecturer, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne) Control group rate 0.64 Intervention group rate 0.73 Follow up 1 yr Accrual time 2 yrs Significance 0.05 (2-sided) Power 0.80 Number of subjects required 1190 Control group rate 0.52 Intervention group rate 0.63 Follow up 1 yr Accrual time 3 yrs Significance 0.05 (2-sided) Power 0.80 Total number of subjects required 921 Hence we plan to recruit patients. In 1997 there were approximately 1500 Australian and 300 New Zealand patients accepted for ESRF treatment (10). Interim analysis It is anticipated that the study may need to have a follow up period of greater that three years in order to detect any difference between the randomised groups. However, an interim analysis at three years is planned in order to detect any definite trend towards improved patient survival in either randomised group. Such a result would enable the study to be halted at three years. The significance level for the interim 25

27 analysis will be p< This additional analysis required a small increase in the number of patients in the study (i.e. 951 instead of 921 on the second calculation of Pauline Branley, see below). Control group rate 0.52 Intervention group rate 0.63 Follow up 1 yr Accrual time 3 yrs Significance 0.05 (2-sided) Power 0.80 Total number of subjects required 951 Anticipated drop-outs It is anticipated that there will be some patients who initially agree to participate but who decide to withdraw after randomisation to early-start treatment as they are feeling well and do not want to start treatment. As this will reflect real life where patients refuse treatment, analysis of such subjects will be according to intention to treat. We have no idea if this will be a large number of patients, however if it were, the power of the study to detect a real effect will be reduced. Hence, a secondary analysis according to actual treatment received will also be undertaken. As the ANZDATA registry follows all patients on dialysis in Australia and New Zealand, true loss to follow up should be minimal (1-2%). Data analysis The primary outcome variable of survival will be assessed by life-table analysis at 3 years. Secondary outcome variables include co-morbid events, quality of life, total cost of treatment, hospitalisation, decline of residual function and effects on nutrition. Primary and secondary outcome variables will be assessed on an intention to treat analysis for all patients. Subsequently, outcome will be reanalysed according to actual GFR at initiation of dialysis. Outcome will also be stratified for patient age, aetiology of ESRF, referral time, co-morbidity score at 26

28 randomisation, rate of loss of residual renal function, and modality and regimen (incremental versus full) of dialysis. 27

29 B- Equations to be used: Units Actual Body Weight (abwt) Current body weight expressed to 1 decimal place kg Note that peritoneal dialysis patients should be weighed with the abdomen drained of fluid. Ideal Body Weight (IBW) Ideal body weight is based on BMI 22.5 kg/m 2 IBW = 22.5 x Height 2 kg Body Mass Index (BMI) BMI= Weight (kg) kg/m 2 Height 2 (m) Body Surface Area (Dubois & Dubois, 1916) BSA = abwt Ht m 2 Where Ht is expressed in centimetres (cm). Cockcroft and Gault equation (to calculate glomerular filtration rate with BSA correction): GFR = (140 - age) x wt (kg) x 1.73 (x 0.85 for women) ml/min/1.73m 2 Scr (mmol/l) x 814 BSA Clearance assessment Arithmetic mean of urea and creatinine clearance= (Residual Urea Clearance + Residual Creatinine Clearance) ml/min/1.73m

30 Equations to be used continued Units Residual Urea Clearance = urine urea conc. (mmol/l) x urine volume (L) x 24 x 1.73 ml/min/1.73m 2 serum urea conc. (mmol/l) X 1440 hours of collection BSA Residual Creatinine Clearance = urine creatinine conc. (mmol/l) x urine vol. (L) x 24 x 1.73 ml/min/1.73m 2 serum creatinine conc. (mmol/l) X 1440 hours of collection BSA Kt/V: Residual renal function Kt/V Kt/V r = urine urea conc. (mmol/l) x Urine volume (L) x 7 serum urea conc. (mmol/l) x TBW Peritoneal dialysis Kt/V Kt/Vpd = dialysate urea conc. (mmol/l) x dialysate volume out (L)) x 7 serum urea conc. (mmol/l) x TBW Haemodialysis Kt/V Kt/Vhd = ln (pre-dialysis urea conc.) (post-dialysis urea conc.) Kt/Vdaug= -ln((post urea conc./ pre urea conc.) x HD duration (hrs)) + (4 - (3.5 x (post urea / pre urea)) x (pre wt - post wt) / post wt Urea reduction ratio URR= (pre urea - post urea) x 100 % pre urea 29

31 Equations to be used continued Units Randerson npcr (SI UNITS) npcr = 5.02 x ((Urea Generation Rate (mmol/min) x 60.06) ) Weight (kg) mmol/min/kg Urea Generation Rate UGRpd= (urine urea conc. (mmol/l) x urine vol. (L)) + (Dialysate urea conc. (mmol/l) x Dialysate vol. (L)) mmol/day UGRhd= - (0.58 x post wt x post urea conc x pre wt x pre urea) + urinary urea loss (mmol/day) inter-dialytic time (days) mmol/day Urinary urea loss HD= urine volume x urine urea conc. inter-dialytic time (days) mmol/day Protein Equivalent of Total Nitrogen Appearance PNApd= 6.49 x UGR x x TBW + urine protein conc. X urine volume + dialysate protein conc. X dialysate volume g/day PNAhd= 6.49 x UGR x x TBW + ((urine protein conc. X urine volume) / inter-dialytic time (days)) g/day 30

32 C- Standardisation of methods for collections Peritoneal dialysis 24hr adequacy collections: CAPD (either of the following methods may be used) METHOD 1 (single sample to lab) i) Discard the first drainage bag of the day ii) Collect drainage bags for 24hrs and store at room temperature iii) Weigh each drained dialysis bag and draw off 1% iv) Note the total volume of drained dialysate v) Mix the samples from each bag and draw a final sample from the mixed 24hr collection.! Send for laboratory analysis of creatinine and urea. METHOD 2 (multiple samples to lab) i) Weigh each drained dialysis bag and record weight on laboratory request form. ii) Draw a sample from each bag! Send for laboratory analysis of creatinine and urea. APD Use a dialysate effluent bag to collect the overnight sample. The effluent bag should hold 15L; if more is required connect a second bag and mix thoroughly together. For high dose CCPD (OCCPD) the day exchanges should drain into the same effluent bag to facilitate sampling. If manual day exchanges are used, I% of the overnight effluent and 1% of each day drain should be mixed to obtain the final sample. Mix the dialysate thoroughly. Be aware of the risk of dilution with unspent fluid when a different glucose solution is used for the last fill. If the exact volumes cannot be used a manual last fill is the safest option. Urine collections: The patient should collect all urine after they have first emptied their bladder. All urine passed within the collection period should be obtained. At the end of the collection period the patient should empty their bladder and include this amount with the sample. 31

33 In patients prior to commencing dialysis urine collections should be performed as a 24-hour collection. In patients on peritoneal dialysis, urine collections should be performed as a 24-hour collection in the period concurrent with the dialysate collections. In haemodialysis patients, urine collections should be performed as an inter-dialytic collection. (All urine is collected from the end of the dialysis to the beginning of the next dialysis). 32

34 DATA MANAGEMENT Data will be stored and analysed by the Auckland Clinical Trials Research Unit. The Clinical Trials Research Unit will perform the central stratification and randomisation of patients entered into the study. It will also coordinate the storage, security and analysis of all data collected. 33

35 Appendix A PATIENT INFORMATION SHEET 1. Background You have been invited to take part in an Australian and New Zealand trial, which will answer the question of the appropriate time to commence dialysis. Many patients and their nephrologists like to delay dialysis until symptoms have developed. However, recent studies suggest (but have not proven) that it might be better to start dialysis earlier before symptoms have commenced, to improve nutrition and perhaps even survival. 2. What does the trial involve? If you agree to take part in the trial then you will be randomly assigned to commence dialysis early (when your remaining kidney function is still 10-14% of normal) or to delay dialysis until your kidney function is 5-7% of normal. At present in Australia and New Zealand more than 20% of patients commence their dialysis when the remaining kidney function is more than 10%, and an equal number delay it until it is less than 5%; the remainder commence dialysis at between 5% and 10%. Thus, whichever group you are randomised into, your treatment will be no different to current practice for a large number of patients in Australia and New Zealand. For several months before and during the trial you will have blood tests performed every three months. For the majority of patients in the trial these blood tests will be no different to those currently performed for routine clinical care; in a small number of patients extra tests will be performed (this is explained below). Every three months you will also need to perform a 24-hour collection of your urine; this is current practice in a number of but not all renal units, and this represents the major imposition of the trial. The trial will last for three years from the time you are randomised to one treatment or the other. 36

36 3. What about transplantation? Your likelihood of transplantation will not be altered by the trial. If your nephrologist feels that you are healthy enough to receive a renal transplant, then you can be placed on the Transplant Waiting List from the time of randomisation. So, if you are in the late initiation group then you could receive a transplant even before you commence dialysis. There are a number of different criteria that determine whether transplants are offered to patients, including the compatibility of their tissue type with the donor, their age and the amount of time they have been on the Waiting List. Waiting time is usually determined from the time that dialysis commences, and so if this criteria is left unchanged then this would result in a small advantage (in terms of waiting time) for early rather than late commencement of dialysis. Hence to correct for this difference the Renal Transplant Advisory Committee.(the committee in charge of transplantation allocation) have decided to generate an adjusted waiting time to ensure equality. Even if you receive a kidney transplant, your participation in the trial will still continue. 4. Do I have to take part in the trial? The trial is voluntary. Your usual care will continue and will not be affected if you decide not to take part in the trial. If your nephrologist feels that it is not in your best interest to take part in the trial, then he or she will advise you to decline. 5. Can I withdraw from the trial? You can withdraw from the trial at any stage. If your nephrologist feels that it is in your best interest to withdraw, then he or she will advise you to do so. If you withdraw, you will continue to receive full medical care, and this care wonʼt be prejudiced by your decision to withdraw. 37

37 6. What are the likely benefits of this trial? The majority of nephrologists in Australia and New Zealand, and around the world, think this is a very important trial. Based on the results of the trial, nephrologists will be able to advise patients about the best timing to commence dialysis. At present, such advice is based purely on opinion, and not on fact. So, the benefits of the trial will not necessarily be to you as an individual, but rather to all of the patients with endstage renal failure who come after you. PATIENT INFORMATION SHEET optional tests 7. What about the extra tests? If you are willing to participate, some extra tests can be done to measure your nutritional status. These tests can be done at your own Renal Unit. These tests would occur every twelve months during the trial; these are simple measurements of body fat and muscle that involve no pain. In addition you will be questioned about various symptoms, and how you are feeling, and coping with daily activities. In patients who are willing to provide extra blood samples and/or to attend Royal North Shore Hospital for half a day every twelve months, extra testing will be performed to measure nutritional state. You can take part in the main trial described above without having these additional tests; they are voluntary. If your nephrologist feels that it is not in your best interest to take part in this additional testing, then he or she will advise you against this. Your medical care will not be influenced by your decision to undergo these additional measurements or not. The additional tests involve the following: Your nutrition will be measured by a 15-minute body scan, which exposes you to as much radiation as a chest X-ray. A second method involves measuring your bodyʼs resistance to a tiny electrical current (you are not aware of the current). A third method of nutritional assessment will be performed which involves measurement of muscle and skin fold thicknesses of the trunk and arms. The food 38

38 reserves that are being utilised by your body will also be measured by a urine collection and by measuring the amount of oxygen that you breathe in and the amount of carbon dioxide that you breathe out. 8. What about my other treatment? This trial only involves a change in the time at which you commence dialysis. No other aspects of your other treatment will be altered. The type of dialysis that you receive, and whether you need to change that form of dialysis or not, will not be influenced at all by the trial. Similarly, all your drug and dietary treatment will not be altered by the trial. 39

39 Appendix B Consent Form No. 1 (Sample) IDEAL Study 1. Approval has been given for this trial by the Human Research Ethics Committee of [Insert your own of Area Health authority here]. 2. The aim of the trial is to determine the best time to commence dialysis. 3. The results obtained from the trial may not be of direct benefit to my medical management, but will be of benefit to future dialysis patients. 4. The three-year trial involves measurements of my kidney function and nutrition by three monthly blood and urine tests. 5. No adverse effects are expected as a result of participation in this study. 6. Should I develop a problem which I suspect may have resulted from my participation in the trial, or have any complaint related to the conduct of the trial, then I may contact [Co investigators name] on [Phone No.] Should I have any problems or queries about the way in which the trial was conducted I am aware that I may contact the Patient Representative who is an independent person within the hospital on [Insert Phone Number] 7. I can refuse to take part in the trial, or withdraw from it at any time, without affecting my medical care. 8. Participation in this trial will not result in any extra hospital or medical cost to me. 9. The results of any published information regarding my medical history will not be published in a way that reveals my identity. After considering these points I accept the invitation to participate in this trial. Patientʼs Name: Signature: Date: Copy and give to patient Copy and place in patient's medical records Original in trial folder 40

40 Consent Form No. 2 (Sample) IDEAL Study Nutritional Assessment Study 1. Approval has been given for this trial by the Human Research Ethics Committee of [Insert your Area Health Authority]. 2. The aim of the trial is to determine the best time to commence dialysis by assessing nutritional status. 3. The results obtained from the trial may not be of direct benefit to my medical management, but will be of benefit to future dialysis patients. 4. This part of the trial will involve additional testing at the commencement of the trial and every 12 months. The amount of protein in my body will be measured, as will be the type of energy source that my body is using. These additional tests will involve approximately one half day. 5. No adverse effects are expected as a result of participation in this study. 6. Should I develop a problem which I suspect may have resulted from my participation in the trial, or have any complaint related to the conduct of the trial, then I may contact [Insert Co investigators name and phone Number] Should I have any problems or queries about the way in which the trial was conducted I am aware that I may contact the Patient Representative who is an independent person within the hospital on [Insert phone Number]. I can refuse to take part in the trial, or withdraw from it at any time, without affecting my medical care. 7. Participation in this trial will not result in any extra hospital or medical cost to me. 8. The results of any published information regarding my medical history will not be published in a way that reveals my identity. After considering these points I accept the invitation to participate in this trial. Patientʼs Name: Signature: Date: Copy and give to patient Copy and place in patient's medical records Original in trial folder 41

41 Appendix C Data collection sheets (see separate document) Appendix D New York Heart Association Functional Classification NYHA Class Definition I. No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, or dyspnoea. II. Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, or dyspnoea. III. Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, or dyspnoea. IV. Unable to carry on any physical activity without symptoms. Symptoms are present even at rest. If any physical activity is undertaken, symptoms are increased. Reference: Diseases of the Heart and Blood Vessels - Nomenclature and Criteria for Diagnosis, 6th edition, Boston, Little Brown and Company,

42 REFERENCES. 1. McKusker FX, Teehan BP, Thorpe KE, Keshaviah PR, Churchill DN, the CANUSA Peritoneal Dialysis Study Group: How much peritoneal dialysis is required for maintenance of a good nutritional state. Kidney Int 50:S56-S61, 1996 (suppl 56). 2. Tattersall J, Greenwood R, Farrington K: Urea kinetics and when to commence dialysis. Am J Nephrol 15: , Bonomini V, Vangelista A, Stefoni S: Early dialysis in renal substitutive programs. Kidney Int 13:S112-S116, 1978 (suppl 8). 4. Bonomini V, Feletti C, Stefoni S, Vangelista A: Early dialysis and renal transplantation. Nephron 44: , Jungers P, Zingraff J, Albouze G, Chaveau P, Page B, Hannedouche T, Man NK: Late referral to maintenance dialysis. Detrimental consequences. Nephrol Dial Transplant 8: ; Sesso R, Belasco AG: Late diagnosis of chronic renal failure and mortality on maintenance dialysis. Nephrol Dial Transplant 11: , National Kidney Foundation, Dialysis Outcome Quality Initiative (DOQI). Peritoneal Dialysis; 1 Initiation of Dialysis 8. Clinical Practice Guidelines of the Canadian Society of Nephrology for Treatment of Patients with Chronic Renal Failure. J Am Soc Nephrol 1999:10 (Suppl 13), S289-S

43 9. The CARI Guidelines: Caring for Australians with Renal Impairment. Acceptance onto Dialysis: 6. Level of renal function at which to initiate dialysis. 10. ANZDATA Registry Report Schuster J. CRC Handbook for Clinical Trials, 1943 pp Kopple JB, Jones MR, Keshaviah PR, Bergstrom J, Lindsay RM, Moran J, Nolph KD Teehan BP. A proposed glossary for dialysis kinetics. Am J Kidney Dis 26: ,

44 Appendix E Nutritional Study Sub-Group Background Patients with renal disease and protein caloric malnutrition have a significantly reduced life expectancy. The origin of this malnourished state is often multi-factorial. One factor, which appears to be important in determining nutritional state, is the timing of the initiation of dialysis. In observational studies, patients who commence dialysis late have a worse nutritional state. Patients who are on dialysis can also develop protein malnutrition due to increased protein losses. What is not known is whether malnutrition will be prevented or exacerbated the by the earlier initiation of dialysis. Study Objectives To determine whether the timing of the initiation of dialysis in patients with ESRF- Influences patients nutritional state Patient Identification Patients should be identified and consented to enter the nutritional sub-study at the same time they are entered into the main trial. Inclusion criteria (for the nutritional sub-study) Patients who are to also be entered into the main trial Patients able to undergo any of the nutritional sub-tests Written, informed consent (see patient information and consent form Appendix A and B) Exclusion criteria (for the nutritional sub-study) Inability to provide written, informed consent 45

45 Nutritional Assessment In the sub-set of patients involved in the nutritional study the following measurements will be carried out at the baseline assessment (randomisation) and then on a 12 monthly basis. These tests include: 1. Subjective global assessment 2. Anthropometric measurements: Height Weight Mid upper arm circumference (MUAC) Skin-fold thickness - biceps, triceps and subscapular. The above measurements will be used to calculate the following parameters: Body mass index Percent ideal body weight Percent body fat Fat-free mass 3. Bioelectrical impedance analysis to assess total body water and fat-free mass 4. Blood parameters: Serum albumin (which is to be collected as part of the main trial) Interleukin-1, interleukin-6, tumour necrosis factor IGF-1 and IGFBP-3 Homocysteine 5. Indirect calorimetry to measure respiratory quotient 6. Total body nitrogen assessment Some or all of the above tests can be performed at the patients own dialysis centre if equipment and resources are available. 46

46 Alternatively for those patients who are willing and physically able to attend, all of the tests may be performed at Royal North Shore Hospital. Tests 1 to 6 will take approximately a half-day to perform. Every 12 months after randomisation, the above mentioned tests will be repeated on each patient throughout the duration of the trial. 47

47 Methods 1. Subjective global assessment (SGA) will be performed using the clinical assessment as adapted by Detsky [1]. This involves taking a medical history of weight change, dietary intake, gastrointestinal symptoms and functional impairment. A physical examination is also required to assess subcutaneous fat, muscle stores and the presence or absence of oedema. Patients will then classified as being well nourished (score A), mild-moderately malnourished (score B) or severely malnourished (score C). A more detailed description (manual and training video) of the technique can be obtained on request if required (contact Renal Research Dietitian Royal North Shore Hospital ). 2. Anthropometric measurements will be performed with the patient wearing only light clothing without shoes using the following methods:! Height should be measured using a wall-mounted standometre with the measurement recorded to the nearest 0.1cm.! Weight should be measured using a calibrated scientific electronic scale with the weight recorded to the closest 0.1kg. Weight should be measured in CAPD patients with the peritoneum empty. For haemodialysis patients the weight should be taken post haemodialysis.! Mid upper arm circumference (MUAC) and skin fold thickness will be performed in a standardised manner (see Manual of Operations). The above measurements will be used to calculate several body parameters using the following calculations:! Dry weight will equal the patientʼs weight in kg's at which they have no clinical or symptomatic evidence of fluid overloading or hypovolaemia.! Body mass index will be calculated using the following equation: BMI= Dry weight (kg)/(height (m))^2 48