Platform
1.1 Does a domain need to be complete before a subsequent domain is started?
No, participants can be enrolled into a new domain at any time.
1.2 Can a patient participate in more than one domain at the same time?
Yes. There is no limit on the number of domains a participant can participate in, as long as they meet the eligibility criteria for each domain.
1.3 How can new staff members at sites be trained on trial procedures?
New staff can review Site Initiation Visit slides and study documentation. Regional Coordinating Centres can provide training, including refresher training, upon request.
2.1 Can participants be recruited if they do not tolerate ACEi/ARBs?
Yes, participants can be recruited as long as all standard of care therapies appropriate to their region have been offered to them.
2.2 Can participants be recruited if they are not on an SGLT2i?
SGLT2i are considered standard of care for chronic kidney disease. Participants are eligible for the trial if they have a documented reason for not being on an SGLT2i. Potential reasons for not using a SGLT2i include intolerance (including allergy or absolute contraindication), cost or inaccessibility (including unavailability), participant refusal or physician decision.
Participants can be recruited as long as all standard of care therapies appropriate to their region have been offered to them. If SGLT2i are not available or accessible to participants in the region where they reside, they can be recruited to the trial.
2.3 Is current kidney transplant an exclusion criterion for the study?
While current kidney transplant is not an exclusion criterion for the platform, it is for the MRA and GLP-1 RA domains. The exclusion criteria for the platform and individual domains are kept separate in the study.
2.4 Can people receiving immunosuppressive therapy be recruited into the trial?
Yes, participants receiving immunosuppressive therapy can be recruited.
2.5 Can people with high eGFR, for example eGFR > 85 ml/min/1.73m², be recruited into the trial?
Yes, they can be recruited. There is no upper cut off limit for eGFR.
2.6 Can the Screening visit and Randomisation visit be held on the same day?
The Screening visit and Randomisation visit can occur on same day provided that blood test and urinalysis test results are from different days. This requires the use of prior, standard of care pathology results (dated up to -31 days before randomisation) for the Screening visit. Blood and urinalysis tests for the Randomisation visit must occur on same day as randomisation. This is important as baseline eGFR and uACR is the average of 2 values from the screening and randomisation visits.
2.7. If uACR indicates eligibility ( > 200mg/g) but uPCR done on the same does not (< 300mg/g) can the uACR value be used to randomise participant, or do both uACR and uPCR values need to indicate eligibility?
In case of significant differences between uACR and uPCR (for sites that is standard of care to collect both) the value that meets eligibility can be used to satisfy inclusion criteria.
3.1 Are blood tests and urinalysis performed at local labs?
All pathology is performed at local labs and there are no central labs. Routine clinical tests can be used if they fall within visit windows. For the randomisation visit, pathology will likely need to be performed for the trial as it is unlikely a test result is available from routine clinical care.
3.2 Can a participant remain in the trial if standard of care (SOC) treatment changes; for example, if the participant stops ACEi/ARB?
Yes, the participant can remain in the trial even if their SOC treatment changes.
3.3 Can a participant remain in the trial if standard of care (SOC) treatment guidelines change; for example, if a new treatment is considered SOC?
Yes, the participant can remain in the trial even if SOC changes. We will collect data on what treatments a participant is receiving at all visits.
3.4 Should the study intervention be stopped if the participant commences dialysis or has a kidney transplant?
Yes, the study intervention should be stopped if a participant starts dialysis or has a kidney transplant. This is a study end point.
3.5 Can a participant start IMP for another domain while still dose escalating in an existing domain?
Yes, participants in the MRA domain do not need to wait until they have reached a stable finerenone/placebo dose before commencing IMP in a new domain. For example, a participant may still be undergoing dose escalation at their Week 4 MRA visit and can start IMP for the GLP-1-RA or ERA domain at that time. The same principle applies to participants who are dose escalating within the GLP-1-RA domain and are eligible to commence IMP in another domain.
4.1 How will passive follow up be conducted?
We plan to follow participants every 5 years using medical records. Sites will be asked to check participant medical records to assess survival (dead or alive) and kidney (receiving dialysis or transplant) status. Data linkage may replace review of medical records in jurisdictions where it is available.
4.2 How are unknown dates entered into the eCRF?
If the exact day is not known, enter ‘15’ for day. If the month is not known, enter ‘June’.
4.3. If a participant did not meet the eligibility criteria at pre-screening, can they be re-screened at a later date? If so, should they be entered in the database as a new participant?
Whether a participant can be re-screened depends on the reason they were ineligible. If the participant was ineligible because their potassium level was ≥5.0 mmol/L at screening, a new potassium level may be collected in accordance with the protocol and eligibility reassessed. If the participant was ineligible because they had not been on a stable dose of an SGLT2 inhibitor for at least 4 weeks, eligibility may be reassessed once this requirement has been met. The participant does not need to be entered in the database as a new participant; the same screening eCRF can be used. New consent is not required, provided the consent form version has not changed.
5.1 What is the primary outcome for CAPTIVATE and how was this selected?
The primary outcome for CAPTIVATE is chronic eGFR slope.
Chronic eGFR slope measures the rate of eGFR decline while on treatment. The duration of time over which chronic eGFR slope is computed can vary by domain. Domain-specific appendices will specify the duration of time over which chronic eGFR slope is computed for the individual domain.
Large trial data show that eGFR slope is a valid surrogate endpoint in phase 3 randomised controlled trials in chronic kidney disease (CKD) (Levey et al. AJKD 2020). This allows for smaller sample sizes and shorter trial durations compared to traditional “hard” kidney outcomes such as kidney failure. Several therapeutic agents that may potentially improve kidney outcomes in CKD and will be tested in CAPTIVATE produce initial haemodynamic effects, resulting in an acute “dip” in eGFR which typically occurs within the first 4 weeks. To mitigate the risks of type 1 errors, one approach is to utilise chronic eGFR slope, i.e. exclude the values during the acute period. Another method is to use eGFR values from randomisation to the end of a washout period to evaluate total “off-treatment” slope. Extensive expert discussions, statistical analyses, and trial simulations have been conducted to reach this final decision to use chronic eGFR slope as the CAPTIVATE primary outcome and the reasons are as follows:
- The use of chronic eGFR slope ensures consistency between the primary outcome and interim analyses, as off-treatment washout values are not available for those undergoing interim analyses.
- Excluding values during the acute eGFR dip will reduce statistical complexities and risk for error as additional domains are added and combination therapies are studied.
- The required sample size for assessment chronic eGFR slope is smaller than that for total eGFR slope.
- Importantly, chronic eGFR slope has been demonstrated to be a stronger predictor of kidney outcomes.
- For additional sensitivity analyses, we have included total eGFR slope measured from week 0 (randomisation) to week 108 (end of washout) as a secondary outcome.
Reference: Levey AS, Gansevoort RT, Coresh J, Inker LA, Heerspink HL, … Levin A, Perkovic V, Zhang L, Willis K. Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency. Am J Kidney Dis. 2020 Jan;75(1):84-104. doi: 10.1053/j.ajkd.2019.06.009.
5.2 The KDIGO definition for AKI is very strict, and participants are unlikely to have the frequency of pathology tests required to meet the KDIGO AKI definition. Can we use the clinical discretion to diagnose AKI?
Yes, AKI is defined ‘as per the KDIGO definition or at discretion of the investigator’.
6.1 Which staff members can sign-off eCRFs and emergency unblind?
Any personnel with the Investigator role in the database can sign-off eCRFs and emergency unblind. The site can choose which Principal Investigator and Sub-Investigators have Investigator role(s) in database.
7.1 How can a site access specific study visit eCRFs and logs in the database?
The table below is a guide on how to access study visit eCRFs and logs from the Participant Summary Page:
7.2 How can a site access the ‘Consent & Eligibility’ eCRF for participant that was previously pre-screened?
To access the ‘Consent & Eligibility’ eCRF for participant who was previously pre-screened, go to the participant’s pre-screening record and click on ‘Continue’. The ‘Start Eligibility’ button will appear if the participant is deemed eligible at pre-screening.
7.3 How can study staff opt-in or opt-out to receive automated email notifications?
To opt-in or opt-out to receive automated email notifications, go to ‘My Details’ under your account and click on ‘Emails’. Select ‘√’ to receive email alerts or ‘X’ to opt-out.
7.4 How can a site view the bottle/kit number dispensed at an active follow-up visit?
The list of bottle/kit numbers along with the dose dispensed at any active follow-up visit can be viewed by clicking on the Active follow-up eCRF specific to a study visit timepoint. The Investigational Product Dispensed section will appear at the top of the eCRF.
7.5 Can changes be made to Screening visit eCRFs after the participant is randomised?
Once the data entered in the Screening Visit eCRFs (Consent and Eligibility, MRA DSA Incl/Excl, GLP-1 DSA Incl/Excl, ERA DSA Incl/Excl Screening, Con Meds, BP & Pathology) is saved and the participant is randomised, the forms are locked and changes cannot be made by sites. If changes to these forms are required, please email captivate@georgeinstitute.org.au and cc RCC/study monitor.
Note: Only Screening and Week -4 BP and Pathology forms can be unlocked for editing post-randomisation
MRA Domain
1.1 What are the inclusion and exclusion criteria for the MRA domain?
Please see MRA DSA synopsis here.
1.2 If a participant with hyperkalaemia is started on a potassium lowering agent to reduce serum potassium to below 5 mmol/L, is this participant excluded from recruitment into the MRA domain?
Provided potassium is <5 mmol/L at most recent blood test during screening period, the participant is eligible for recruitment even if they are on a potassium lowering agent.
1.3 Is the use of a potassium binder an exclusion criteria for the MRA domain?
No, use of a potassium binder is not an exclusion criteria.
1.4 Bloods are taken on the day the participant is due to start IMP (week 0), but test results come out later in the day (after the visit for randomisation or week 0). If the potassium level is >5.5 mmol/L, does participant need to hold off commencing study medication and do another blood test in 1 week?
Yes. They should employ some potassium lowering strategies before the next blood test in a week. The finerenone guidance document contains more information about this.
2.1 What dose of finerenone should my participant be on?
Finerenone starting dose is based on eGFR.
Table 1: Finerenone starting dose
Most recent eGFR (mL/min/1.73m2) | Starting Dose |
K+ < 5.0 | |
≥ 60 | 20mg once daily |
25-59 | 10mg once daily |
After 4 weeks the dose of finerenone should be adjusted (in most cases up-titrated) based on the participant’s potassium level.
Table 2: Finerenone dose adjustment*
Starting Dose | Dose at 4 weeks and thereafter Dependent on serum potassium levels (K+, mmol/L)α | ||
K+ < 5.0 | K+ 5.0-5.5 | K+ >5.5 | |
20mg once daily | 20mg once daily | 20mg once daily | Suspend Restart at 10 mg once daily if serum potassium ≤5.0 mmol/L |
10mg once daily | Increase the dose to 20mg once daily if eGFR decrease is ≤ 30% lower than the eGFR value at the previous visit | 10mg once daily | Suspend Restart at 10 mg once daily if serum potassium ≤5.0 mmol/L |
* CYP34A Inhibitors: If the participant is receiving strong CYP3A4 inhibitors (e.g. (oral) ketoconazole, itraconazole, ritonavir, or clarithromycin), finerenone should be withheld while the participant is receiving these medications. If the participant is receiving less potent CYP3A4 inhibitors (e.g. erythromycin, amiodarone, diltiazem, verapamil, or fluconazole), the serum potassium should be monitored especially during initiation of or changes to dosing of finerenone or the CYP3A4 inhibitor
α Up-titration or maintenance of the starting dose at 4 weeks should only occur if the eGFR reduction is ≤ 30% lower than the baseline eGFR value. A reduction in eGFR of >30% is beyond the expected haemodynamic effects of finerenone.
2.2 Are there any limits on the time period between pausing and allowing restart of study medication in the MRA domain?
Participants should be restarted on active study drug as soon as it is safe to do so. The aim is to achieve the maximum dose possible for as long as possible while maintaining participant safety. However, there are no hard timelines or limits on when study medication can be re-started.
2.3 If finerenone/placebo is suspended due to K+ >5.5 mmol/L and then later restarted, should the drug be titrated up after re-starting?
Yes, finerenone/placebo should be titrated up after re-start if it is safe to do so. The aim is to achieve the maximum dose possible for as long as possible while maintaining participant safety. Finerenone/placebo can be up-titrated at any time if the participant meets the criteria for up-titration.
4.1 What is the primary outcome for the MRA domain?
Chronic eGFR slope estimated from all available eGFR values from week 4 to the end of treatment.
6.1 What washout period is required if a participant has been on a strong CYP3A4 inhibitor and it has been discontinued, particularly regarding when the study medication can be initiated or restarted?
Strong CYP3A4 inhibitors have a washout period of 1 week. Finerenone/placebo can be initiated or re-started 1 week after the CYP3A4 inhibitor has been discontinued.
6.2 Can the site select the number of bottles that are dispensed to supply the participant until the next visit?
The database will recommend the number of bottles, but the site can change this number.
6.3 Do tablet counts have to be exact?
No. Approximate tablet counts are acceptable based on weight or visual inspection.
6.4 Will the database be allocating the correct drug bottles and will sites need to check the expiry date of drug selected?
The database should dispense the correct bottles. Sites should also double-check the expiry date on the bottles.
6.5 Can open bottles of IMP/matched placebo be returned to the same participant after tablet counts?
Opened bottles can be returned to same participant if the dose does not change and where this is permitted by local regulations.
7.1 Does the IP log need to be updated if the IMP dose has not changed?
No. If the IMP dose is unchanged, the IP log entry can remain as “Ongoing”.
7.2 How can IMP be dispensed at Wk 12 visit if the dose has not changed and only 2 bottles of IMP were dispensed at Wk 4?
If the dose of IMP remains the same at the Wk 12 visit, the “Unscheduled Dispense” function must be used 3 times to dispense 3 bottles of IMP.
GLP-1 RA Domain
1.1 Inclusion and exclusion criteria for GLP-1 RA domain
Please see GLP-1RA DSA synopsis here.
2.1 What dose of semaglutide should my participant be on?
Semaglutide dose is based on body mass index (BMI).
Table 1. Semaglutide dosage and dose adjustment*
Baseline BMI | Week | |||||||||
0 | 4 | 8 | 12 | 16 | 20 | 24 | 52 | 78 | 104 | |
Dose / mg weekly | ||||||||||
BMI < 27 kg/m2 | 0.25 | 0.50 | 1.0 | Dose maintenance | ||||||
BMI ≥ 27 kg/m2 | 0.25 | 0.50 | 1.0 | 1.7 | 2.4 | Dose maintenance | ||||
* If dose increases lead to unacceptable adverse effects, the dose-escalation intervals can be extended, treatment can be paused, or maintenance doses below the weekly target dose can be used.
For those in the lower BMI group, they will be randomised to a maximum target dose of 1.0mg. For those in the higher BMI group, they will be randomised to a maximum target dose of 2.4mg.
2.2 Can participants change the dose group they are allocated to?
No, participants cannot change dose groups. Once they are allocated to a BMI group and the corresponding dose group, they will not be able to change to the other dose group, even if there has been a significant weight loss or gain. Participants stay on the target dose they are randomised to at the beginning on the trial.
2.3 Are there any limits on the time period between pausing and allowing restart of study medication in the GLP-1 RA domain?
Participants should be restarted on active study drug as soon as it is safe to do so. The aim is to achieve the maximum dose possible for as long as possible while maintaining participant safety. However, there are no hard timelines or limits on when study medication can be re-started.
2.4 What dose of study medication should be restarted?
If treatment is ceased, and it is clinically reasonable to re-start the study medication after, e.g. gastrointestinal symptom improvement, participants may re-start the study medication following these guidelines:
- If ≤ 2 doses missed/weeks treatment cessation, participant may re-start on most recent tolerated dose.
- If 3-4 doses missed/weeks treatment cessation, participant may re-start 1 dose level below most recent tolerated dose and then proceed with up-titration.
- If ≥ 5 doses missed/weeks treatment cessation, the participant must re-start up-titration process from initial starting dose (e.g. 0.25mg weekly).
A longer period between up-titration of dose may be considered at the investigator’s discretion.
4.1 What is the primary outcome for the GLP-1 RA domain?
Chronic eGFR slope estimated from all available eGFR values from week 0 to the end of treatment
6.1 Can the site select the number of kits that are dispensed to supply the participant until the next visit?
Yes, but number of kits to be dispensed depends on use and availability of stock. For the GLP-1 RA domain, the kit contains 5 pens and can last over multiple visits. To manage short expiry dates, the database may allow for only one kit to be dispensed at a time.
6.2 How are expiry dates managed if they are short?
The database may limit one kit to be dispensed at a time. In addition, sites should double-check the expiry date on the kits and pens allocated before dispensing it. Participants should be educated to look at the expiry date before administering the pen. Direction is provided in the Pharmacy Manual of Operations. If there are any issues with expiry date, please contact the Regional Coordinating Centre immediately.
6.3 Can the site dispense individual pens?
No, individual pens cannot be dispensed. Each kit contains 5 pens and only a kit can be dispensed.
6.4 How do we review the completion of the pens, does the count have to be exact?
Sites will be asked to record if pens are used (empty), unused (full) or partially used (some solution remaining). There is no way to determine the exact amount of the solution remaining, so an approximation based on visual inspection is acceptable. The participant diary will be the primary source to assess adherence.
6.5 Can open kits of IMP/matched placebo be returned to the same participant after pen volume counts?
Unused pens can be returned to the same participant if permitted by local regulations and if there have been no temperature excursions. Used pens must be safely discarded.
6.6 Are participants provided with temperature control devices and safe needle disposing bins?
Participants are not provided with temperature control devices for transporting the kits/pens from the hospital to home. Safe needle disposable bins are provided to participants for safe needle disposing.
6.7 Are sites provided with refrigerators for temperature controlled study medication?
No, sites are not provided with refrigerators if they do not have the resources available at site. If your site requires this, please speak to the Regional Coordinating Centre.
7.1 Does the IP log need to be updated if the IMP dose has not changed?
No. If the IMP dose is unchanged, the IP log entry can remain as “Ongoing”.
7.2 How can IMP be dispensed at Wk 12 visit if the dose has not changed and only 2 bottles of IMP were dispensed at Wk 4?
If the dose of IMP remains the same at the Wk 12 visit, the “Unscheduled Dispense” function must be used 3 times to dispense 3 bottles of IMP.