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Standardised Outcomes in Nephrology – Glomerulonephritis (SONG-GN) Project Plan for KDIGO

BACKGROUND AND CONTEXT KDIGO are currently updating clinical practice guidelines on glomerulonephritis. The evidence review team will be involved in updating all 11 relevant Cochrane Kidney and Transplant systematic reviews, and perform additional searches and screening of the literature. We propose to launch a new SONG stream – SONG-GN concurrently with the update of the Cochrane Systematic Reviews and KDIGO GN Guidelines (August 2018).

This will help to ensure that patient priorities for outcomes are incorporated into the KDIGO GN guidelines in a transparent, rigorous, and systematic way. SONG-GN may be co-badged with KDIGO.

SUMMARY OF AIMS AND PROJECTS The overall aim of the SONG-GN is to develop a core outcome set for trials in glomerulonephritis. The specific objectives and phases are outlined in the following: 1. To assess the scope and consistency of outcomes across trials in patients with glomerulonephritis We will

conduct a systematic review of the scope and consistency of outcomes and outcome measures reported in trials in GN. This will include source trials from the systematic reviews that will be used for the KDIGO guidelines. For feasibility, we may apply a 5 ot 10 year time frame for feasibility.

2. To identify and prioritise outcomes that are important to patients and caregivers with glomerulonephritis We will conduct approximately 12 focus groups with nominal group technique with 120 patients with GN and their caregivers. The proposed sites will be across Australia (6 groups); United States (2 groups), Canada (2 groups), and the United Kingdom (2 groups). Participants will identify and rank outcomes that they believe are important and relevant to them, and to discuss reasons for their choices.

3. To describe stakeholder beliefs, attitudes, and perspectives on outcomes in glomerulonephritis Semi-structured key informant interviews will be conducted with at least 50 international health professionals.

4. To generate a consensus-based prioritised list of core outcomes among stakeholders, including patients/caregivers and health professionals An international Delphi Survey (target n>1000 participants from over 70 countries) will be conducted.

5. Achieve consensus on the implementation of outcomes among key stakeholders We will convene an international workshop with patients/caregivers to establish the core outcomes.

DETAILED PROJECT PLAN

The detailed project plan is provided in this section, which covers Phases 1-5. We will conduct phase (1) and (2) to identify outcomes that are important to patients and family members to inform the selection of outcomes to include in the CKT systematic reviews and the KDIGO Guideline Update – prior to the KDIGO GN Meeting in August 2018. Please note, this project is focussed on adults with GN (as SONG-Kids has identified important outcomes for children/family members with chronic kidney disease – including GN)

Status: We have identified two Co-Chairs for SONG-GN – Dr Liz Lighstone, Dr Dan Cattran. Dr Simon Carter (pediatric nephrologist), has been appointed as the project coordinator and has commenced the systematic review. Due to the time frame (with the KDIGO GN Meeting scheduled in August 2018), we have identified potential investigators and sites for the focus groups (Phase 2) to ensure that these can be completed prior to the KDIGO GN Meeting.

Our methodological framework is adapted from OMERACT/COMET, which is recognised by the World Health Organisation (WHO) as a valid approach for developing core outcomes. These are also the recommended approaches for involving patients and caregivers in a transparent, systematic and meaningful way.

PHASE 1 | Systematic review of outcomes reported in trials in GN (Q1-Q2, 2018)

We will conduct a systematic review to identify and assess the scope and consistency of outcomes reported in randomised controlled trials (RCTs) of interventions for adults with GN. A comprehensive search of Cochrane Kidney and Transplant Specialised Register, and trial registries (e.g. ClinicalTrials.gov) will be conducted to identify all RCTs that enrolled patients with GN aged 18 years or older; without date or language restrictions. Any intervention used in adult patients with GN will be included, and may include pharmacological, surgical, lifestyle, psychosocial, and health service interventions. Two reviewers will independently extract trial

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characteristics including: first author, publication date, country, participant characteristics (age, gender), trial duration, name and type of intervention (e.g. pharmacological, psychosocial, lifestyle), primary or secondary outcomes as reported in the trial (including definitions, measurement instruments, thresholds, measurement time points or time frames, changes in level or percentage, scores). We will group similar outcomes into appropriate outcome domains (e.g. kidney function, kidney/cyst volume, blood pressure, pain). We will identify the number of trials that reported each outcome domain. For each outcome domain, we will assess the number of different measures and the number of trials that reported each outcome.

We will identify outcomes reported in trials in GN. These outcomes will inform Phase 2.

PHASE 2 | Focus groups with nominal group technique with patients and caregivers (Q1-Q3, 2018)

Patients with GN and their caregivers/family members will identify and rank outcomes that they consider are important to include in trials and will discuss reasons for their choices. The nominal group technique is highly recommended as a transparent, equitable, and systematic approach to generate ideas and consensus on priorities in health, and allows each participant to raise their views and suggestions without direct rejection or criticism from others in the group. Our research team has extensive experience in conducting nominal groups.

Participants and recruitment: Patients with GN aged 18 years and older and their caregivers will be eligible to participate. We will convene 18 nominal groups (involving 10 participants per session; total N=180) will be convened. Based on our previous work, this sample size is estimated to be required to achieve data saturation, i.e. when no new outcomes or concepts are being identified in subsequent groups. Participants will be recruited from the sites listed below. We will use purposive sampling to obtain maximum diversity in demographics (age, gender, socioeconomic status, ethnicity, and education) and clinical characteristics (stages of CKD: i.e. patients not on renal replacement therapy, CKD Stage 1-5; patients on dialysis, 5D; and patients with a kidney transplant, 5T; time since diagnosis, comorbidities, and complications). As recommended by guidelines on consumer involvement in research, a $50 reimbursement will be provided to participants.

Table 1. Proposed Focus/nominal groups sites (*TBC)

City Sites No. of groups

Language/s Investigators (tbc)

Australia

Sydney Westmead Hospital 3 English David Harris

Melbourne Monash Medical Centre 3 English Peter Kerr, Jess Ryan, Richard Kitching

Brisbane Princess Alexandra Hospital 3 English Yeoungjee Cho, Andrea Viecelli

United States

Los Angeles UCLA 3 English, Spanish Jenny Shen

United Kingdom

Sheffield University of Sheffield 2 English Martin Wilkie London Imperial College London 2 English Liz Lightstone

Canada

Montreal TBC 2 French TBC (via Amelie Bernier-Jean)

Hong Kong

TBC TBC TBC TBC Angela Wang (tbc)

Data collection: Each focus/nominal group will be two hours in duration and held at a centrally located venue external to the hospital to encourage open discussion and minimise censoring of conversation among participants, which may occur in a clinical setting. The focus groups will be conducted in the participants’ native language (English, Spanish, French) and facilitated by trained moderators. The question guide will adapted from those we have designed and used to successfully elicit patient-prioritised outcomes in kidney transplantation and haemodialysis, and includes:

i. Focus group discussion (50 minutes) – Participants will deliberate and discuss experiences of GN, perceived benefits, harms and complications of GN and GN-related interventions.

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ii. Nominal group technique (70 minutes) – Participants will individually identify outcomes they believe are important and relevant. These outcomes will be written on the flipchart/board then augmented with outcomes identified from the systematic review (phase 1) and in previous nominal groups. The list of outcomes will be discussed and clarified. A copy of the consolidated list will be printed for participants to individually rank the outcomes in order of perceived importance (from 1=most important to 10=least important). Similarities and differences in ranking will be discussed among the group.

Data analysis: Quantitative analysis (scores): Individual rankings will be used to calculate scores for each outcome. The highest ranked outcome for each respondent will be assigned a value of 10, through to the least important (value=1). Outcomes not ranked in the top 10 will be assigned a value of zero. We will sum the ranking scores and divide this by the maximum possible ranking score for that item to obtain a mean priority score for each outcome across all groups. The maximum possible ranking score for a given outcome will be calculated by multiplying the number of participants who considered the outcome by 10 (the maximum rank). If all participants who ranked an outcome scored it as the most important, the priority score is 100%. A score of 0% means that all participants did not score it in the top 10. This approach has been used in previous studies to provide a rank and an estimate of the relative importance of the group items. Mean priority scores and number of times an outcome was voted in the top 10 will be calculated for all participants, and will also be calculated separately for demographic and clinical characteristics and differences in mean scores will be assessed using analysis of variance. This will generate a prioritised list of outcomes.

Qualitative analysis: The transcripts will be imported into HyperRESEARCH software for qualitative data analysis. Using thematic analysis, the transcripts will be reviewed line by line to identify concepts, themes, and compared within and across groups, to be developed into a coding scheme. This will be conducted by the moderators to retain cultural and linguistic nuances in the analysis. The preliminary themes will be discussed among the three investigators to ensure that it captures the full range and depth of data (investigator triangulation). Through constant comparisons between individuals and groups, analytical themes will be developed. The final themes will reflect the beliefs, values, and reasons underpinning the participants’ choices and ranking of outcomes.

This will generate a list of outcomes identified and prioritised by patients with GN and their caregivers, to inform the selection of outcomes in CKT systematic reviews and KDIGO GN Guidelines.

PHASE 3 | Stakeholder key informant interviews (Q4, 2018 – Q3, 2019)

A suite of qualitative semi-structured interviews will be conducted to elicit a range and depth of individual values, beliefs and attitudes on a research topic; not to quantify frequency of opinion. Results from Phase 1-2 will inform the design of the interview guide. We will conduct 45 min face-to-face interviews unless video conference/telephone interviews are preferred by the participants, or when an in-person interview is not feasible. Participants will discuss their perspectives on: i) the benefits and harms of treatment in GN; ii) treatment decision-making; iii) outcomes believed to be important to include in GN trials and why, iv) reactions to the outcomes reported in current trials (phase 2) and those identified as important by patients/caregivers (phase 3), and v) suggestions for implementing core outcomes in research in GN. At least 60 key informant interviews with be conducted with patients/caregivers (n=20), Clinicians (n=20), and policy makers/regulators (n=20). The transcripts will be imported in to HyperRESEARCH software to facilitate qualitative data analysis. We will extract all outcomes suggested by the participants, and use thematic analysis to inductively identify themes that reflect the reasons for their choice of outcomes. The transcripts will be reviewed line-by-line to identify concepts/themes, and compared within and across stakeholder groups. Through a process of constant comparisons between individuals and groups, analytical themes will be developed. The preliminary themes will be discussed with the two other investigators (investigator triangulation), and sent to the participants for feedback (member-checking), to ensure that it captures the full range and depth of data. We will generate a comprehensive list of outcomes that stakeholders consider are important, supported with compelling narrative explanations to understand the rationale and context for their priorities.

PHASE 4 | Delphi survey (Q4, 2018 – Q2, 2019)

We will conduct an international online Delphi survey to gain consensus on the outcome domains that are critically important to all stakeholder groups for trials in GN. The Delphi survey has been successfully used to reach consensus on core outcome sets for various health conditions or treatment, including in haemodialysis and kidney transplantation. The Delphi technique usually involves three rounds of surveys completed sequentially and anonymously by a panel of experts with experience or expertise on the topic of interest. Respondents contribute their individual perspectives (for example, rating the importance of an outcome) and in subsequent rounds, participants can view their previous scores and the results of the group, reflect on the group results, and have the

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option of revising their opinion. This process results in equitable contribution from all participants as it allows individual respondents to express independent thought and minimizes direct confrontation.

Participants and recruitment: Our minimum target sample size will be 1000 with at least 500 patients with GN and their caregivers, to ensure a balance between patients/caregivers and health professionals. We will also aim to include participants from more than 70 countries. Broad and comprehensive recruitment strategies will be applied to obtain maximum variation in the demographics, clinical characteristics (patients), and professional experiences and roles (health professionals); and snowballing strategies (where participants can nominate other relevant stakeholders to participate) will be used. Patients/family members will be recruited through participating hospital/university institutions and patient organisations. Health professionals will be recruited via the collegial networks of the investigators and professional transplantation and nephrology societies. In additional, invitations will be sent to patients/caregivers and health professionals registered on the SONG Initiative database – which has over 3500 members.

Data collection: All participants will register their name and email address via the SONG Initiative website. The surveys will be custom programmed and completed online (via Qualtrics). Each round will be 3 weeks in duration, one month apart. Three reminders will be sent each Round in an attempt to retain at least a 70% response rate across all three rounds. Participants will be asked to rate the importance of each outcome (approx. 40) using the GRADE 9-point Likert scale. Rankings of 7-9 indicate outcomes of critical importance, rankings of 4-6 indicate outcomes that are important but not critical, and rankings of 1-3 indicate outcomes of limited importance. Participants can suggest additional outcomes and provide reasons for their rankings. We will review the distribution of scores across all outcomes for each stakeholder group i.e. patients/caregivers and health professionals. Any outcomes with a median and mean of more than 7 will be retained for Round 2. Any new outcomes suggested by more than 10% of the participants will also be included in the next round. This is based on criteria established for previous SONG Delphi surveys. In Round 2, participants will be shown their previous score for each outcome (highlighted in the rating scale), and a column graph of the distribution of scores for: all participants (equally weighted by stakeholder group), patients/caregivers, and health professionals. Participants will be asked to re-rate the outcomes on the same GRADE 9-point Likert scale. A text box will be provided for optional comments such as reasons for their ratings. This process is repeated in Round 3.

Data analysis: For all three rounds, we will summarise the distribution of scores and calculate the mean, median and proportion for ratings and rankings of each outcome.

PHASE 5 | Consensus workshop (Q3-Q4, 2019)

A face-to-face stakeholder consensus workshop will be convened to obtain feedback and discuss the proposed core outcomes for trials in GN as identified from Phase 1-4. The meeting will be chaired and facilitated by members of the SONG-GN Steering Group, and held in conjunction with an international nephrology conference (American Society of Nephrology) to maximize participation. We will invite approximately 60 participants, including at least 30 patients with GN and their caregivers. Health professionals (nephrologists, surgeons, geneticists, nursing, allied health professionals, researchers, policy makers, and industry) with a range of clinical and research experience in GN, including in clinical trials; or who have leadership or advisory roles in major research, funding, and regulatory agencies, will be invited to attend. All breakout and plenary discussion will be audiotaped and transcribed verbatim. We will summarise the discussion with input from other investigators to ensure that the summary is comprehensive and captures all the points raised in the discussion. A draft plain language report will be circulated to the workshop attendees and collaborators for feedback within a two-week timeframe. Additional comments will be integrated into the final report.

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KDIGO GN Meeting 26-28 August 2018 Final guideline (tbc)

TIMELINE

Year, Quarter 2018 2019 Phase Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q3 1. Systematic review 2. Focus group with nominal group technique 3. Stakeholder interviews 4. Delphi Survey 5. Consensus workshop

BUDGET (USD, 2 years)

Currently, we have internal funding to conduct focus groups in Australia where the SONG team are currently based. With contribution from KDIGO, we will be able to conduct and additional 9 focus/nominal groups with 90 patients/caregivers across four sites in three countries – United States, United Kingdom, and Canada. The contribution and support of KDIGO will be acknowledge in all manuscripts and presentations arising from this work.

Item Description KDIGO contribution

Total (USD)

1.0FTE Project officer Simon Carter, Nephrologist, PhD -

Facilitators Simon Carter, Talia Gutman, Charlotte Logeman, Allison Tong

-

Focus groups (Australia)

Venue hire ($750 x 9 groups = $6750); participant reimbursement ($50 x 90 participants = $4500); transcription ($300 x 9 groups = $2700)

- 13950

Focus groups (USA, UK, Canada)

Venue hire ($750 x 9 groups = $6750); participant reimbursement ($50 x 90 participants = $4500); transcription ($300 x 9 groups = $2700)

13950 13950

Translation and interpretation of focus groups and transcripts 1000 2000

Internal travel only for 2 facilitators (Flights, hotel, transport) 5000 10000

Stakeholder interviews Travel and transcription 50 interviews - 6000

Delphi Programming - 10000

Consensus workshop Venue, participant reimbursement (Co-badged as SONG-GN and KDIGO)

3000 10000

TOTAL 21770 OUTPUT AND IMPLEMENTATION IN KDIGO GUIDLINES

The SONG-GN process involves patients and caregivers in a transparent, meaningful, and systematic way; to identify a prioritised list of outcomes for GN trials. The outcomes identified from Phase 2 SONG-GN will directly inform the selection of outcomes in the CKR Systematic Reviews and the KDIGO Guidelines. Thus, SONG-GN provides a robust and rigorous mechanism for KDIGO to involve patients and caregivers in the selection of outcomes for the GN Guideline Update.