A #NephTrials Chat
Friday March 10th
9 AM Eastern, 3 PM Central European, 7:30 PM Indian Standard Time
In the last edition of Nephtrials we highlighted some of the problems and barriers in evidence generation in many clinical trials as well as the increasing need for reducing complexity and inefficiencies. In a bold and provocative 2015 paper “A Brave New World Of Clinical Cancer Research” Dr. Berry calls clinical trials the final links in the chains of knowledge; and unfortunately, in an important sense the weakest links as well (Berry, Mol Onc 2015). He points out the irony in using the same clinical trial approach to evaluate all manner of potentially amazing transformative experiential therapies and yet neglecting to experiment with the design of the clinical trial itself. Fortunately, the tide is turning and the remarkable advances in genomic technology and tumor biology have thrust the field of cancer research, in particular, to embrace non-traditional trial designs. Nephrology is playing catch-up.
Innovative trial designs in CKD are the need of the hour
Renin-angiotensin-system (RAS) inhibitors have been a cornerstone therapy for delaying progression of diabetic kidney disease disease (DKD) and it has been decades since these drugs arrived that a new class of medicines was introduced to delay disease progression. A 2018 review article made a call to the nephrology community to reimagine the research approach, and develop a new paradigm for clinical trials in DKD for the 21st century (Heerspink et al, Diabetes Obes Metab 2018). Fast forward in 2022, we are now living in the era of SGLT2 inhibitors, aka flozins, which have transformed management of not only DKD but a wide range of chronic kidney diseases (CKD) as well as heart failure.
Despite improving the prognosis of a large chunk of the CKD population, not every patient will benefit from or tolerate flozin therapy, and a substantial number of patients remain at risk for progressive decline in kidney function. Flozin trials performed thus far have excluded patients with an eGFR below 20-25 mL/min/1.73m2 at inclusion, prevalent dialysis patients, and kidney transplant recipients. Innovative new approaches are needed to test flozins in these groups and to test other new agents to prevent CKD progression in a rapid and efficient manner.
Phase 3 clinical trials in slowing CKD progression, especially DKD, are long and expensive. This is due observation periods that are long enough to show separation of eGFR curves between study arms, to have adequate event rates for progression to kidney failure or death, and to allow a large number of patients to be recruited for the trial to be sufficiently powered. Hundreds of other components such as lab tests, packaging, storage, shipping drugs, infrastructure for tracking and allocation, quality control etc. and thousands of person hours in research organization, recruitment, data handling to name a few, exponentially add operational inefficiencies to the timeline. Novel trial designs using a master protocol are one of the innovations that might improve the current clinical trials framework in terms of time and costs.
What are master trial protocols?
In the oncology world, master trial protocols were first used in response to rapid progress in the areas of genomics, tumor biology, and drug discovery. Master protocols allow a framework in which a centralized screening platform and a common protocol format allows multiple parallel studies. Master protocols may involve one or more interventions in multiple diseases, or a single disease with multiple interventions, each targeting a particular biomarker-defined population or disease subtype. Basket, umbrella, and platform trials are all types of master protocols. Multiple substudies under an over-arching master protocol are designed with an aim to achieve better coordination. This can be done by sharing key design elements as well as study materials such as patient data, and removing redundancies of stand alone traditional trials each requiring their own infrastructure.
Table from Heerspink et al, Diabetes Obes Metab. 2018
What are Basket trials?
A basket trial involves one intervention that is studied across multiple diseases which can be defined by stage of histology, genetic, biomarker or other demographic characteristics. Each substudy may have different objectives or end points.
Figure from Woodcock et al, NEJM 2017.
What are Umbrella trials?
Unlike a basket trial which studies one drug across multiple diseases, umbrella trials test multiple interventions for a single disease.
Figure from Woodcock et al, NEJM 2017
What are Platform trials?
Platform trials test multiple interventions against a common control group and can run in perpetuity. The trial generally comprises a platform to which therapies can be added or dropped off seamlessly to reduce overall sample size and improve trial efficiency compared to an equivalent set of two arm trials.
Figure from Woodcock et al, NEJM 2017
Availability of multiple interventions in a platform allows successive testing of biomarker response to a treatment at which point they would be randomized to that treatment or placebo plus standard of care. This approach offers the possibility to implement personalized medicine in the trial design and future clinical practice. Bayesian decision rules are used to determine if therapies with low probabilities of success or side effects should be discontinued and therapies with high probabilities of future success should advance for further study. Platform trials have really taken off with COVID - RECOVERY and REMAP-CAP are examples.
What are some of the advantages of master protocols?
Benefits for sponsors/investigators:
Streamlined higher quality recruitment process yielding fewer screening failures and shorter recruitment times.
Single centralized governing bodies such as steering committees, IRBs, and data monitoring committees use fewer resources and enable uniform decisions about trial conduct, thereby improving quality control and oversight.
Central labs and imaging and adjudication committees etc. enhance data quality through coordinated efforts. Quality improvements that are identified for one trial can be applied to all.
Benefits for patients:
More opportunities to participate in investigational research and earlier access to potential beneficial therapies.
Common screening platform allows coordinated screening and gives the advantage of more efficient use of patients and resources.
What are some of the examples of Master protocols?
AFFINITY, a phase 2 trial was designed as a basket trial to study safety and efficacy of Atrasentan in patients with proteinuric glomerular diseases at risk of progressive kidney function loss. Approximately 80 patients with 20 patients each in four cohorts for IgAN, FSGS, Alports and DKD received Atrasentan for 52 weeks evaluating proteinuria reduction and change of eGFR from baseline at week 56. The ongoing RECOVERY trial for hospitalized patients with COVID-19 is one of the largest platform trials to test a range of possible treatments compared to usual care. Eligible patients were randomly allocated between various treatment arms like dexamethasone and tocilizumab - each treatment to be given in addition to standard care with a common placebo arm. Since the beginning of this trial, several therapies such as dexamethasone, tocilizumab, Baricitinib, hydroxychloroquine, lopinavir-ritonavir, azithromycin, convalescent plasma etc entered the platform out of which a few such as dexa and tocilizumab were found effective and the other ineffective arms such as HCQ and azithromycin arms have been closed to recruitment. More ongoing examples are the TOGETHER trial and the PROTECT-V trial. Such nimbleness of adding and removing treatment arms and a common placebo arm has led to rapid evaluation and further approval of effective treatments against COVID-19, reduced trial costs and improved efficiency. We hope to discuss some of these in future NephTrials (and subsequently NephJC) editions.
What are the challenges in implementation of master protocols?
Master protocols are not widely used as yet in nephrology likely due to the lack of a global cohort of trial ready patients which is essential for most platform trials. The International Society of Nephrology (ISN) has led an initiative to develop a network of patients with kidney disease willing to participate in clinical research projects, accessible through a single global CKD platform called Global Kidney Patients Trial Network (GKPTN). The aim of GKPTN is to accelerate the development of new treatments for kidney disease, by finding participants who are suitable for and willing to participate in clinical studies.
Table from Kotwal et al AJKD 2022.
What are some of the important differences between traditional trials and platform trials?
What are some of the limitations or challenges in the use of master protocols?
Upfront increased cost in time and resources to establish the needed trial infrastructure.
Increased upfront planning and coordination to bring a larger number of groups into agreement on trial design, operations, and governance than a stand-alone trial requires can add to the complexity of design.
Bias occurs when randomization ratios between trial groups are allowed to change over time, when some sites that have different mortality rates restrict randomization to a specific subset of trial agents, when some sites do not allow randomization to the control group, or when administered concomitant treatments are different between trial treatment groups.
In a platform trial, it may be difficult or burdensome to blind patients to every possible arm due different modes of administration or dosing
In this edition of #Nephtrials we discuss the RENAL LIFECYCLE trial as an example of an ongoing basket trial.
Visual Abstract of the RENAL LIFECYCLES trial by Denisse Arellano and the ISN Social Media Team
The RENAL LIFECYCLE Trial: Not just another FLOZIN trial
SGLT2 inhibitors aka “flozins” have revolutionized the management of CKD and heart failure, irrespective of the underlying diabetes or proteinuria status. CREDENCE included patients with type 2 DM with moderately increased albuminuria, but patients with eGFR <30ml/min/1.73m2 were excluded. Subsequently, the DAPA-CKD trial was done with about a third of its cohort without DM and eGFR criteria of 25-75ml/min/1.73m2 with required albuminuria of at least 200mg/g. After the success of DAPA-CKD trial, eGFR cutoff for initiation of flozins was lowered to 25ml/min/1.73m2. The EMPA-KIDNEY trial further expanded on the results of DAPA-CKD with inclusion of patients without DM and with eGFR as low as 20ml/min/1.73m2 along with normo-albuminuria. These 3 trials have covered the spectrum of CKD down to eGFR of 20ml/min/1.73m2 with and without albuminuria.
Figure from Krishnan et al Kidney Medicine 2023
However, the efficacy of flozins in patients with CKD G4/5, on dialysis, or living with a kidney transplant remains unknown. As the indications for this class of drugs expand, there is a sound rationale to study the long-term reno- and cardioprotective efficacy and safety of flozination in patients with eGFR less than 20 ml/min/1.73m2, as well as those on dialysis or with kidney transplant. These patients are nearly always excluded from flozin clinical trials while they are at very high risk of adverse cardiovascular outcomes.
The RENAL LIFECYCLE trial is a pragmatic, randomized, controlled, clinical trial with a basket design. It plans to enroll 1500 participants, consisting of a screening period and a double blind treatment period with two arms. Participants will be randomly assigned in a 1:1 ratio to double blind treatment with dapagliflozin 10 mg/d or matching placebo.
The study population will include patients with or without diabetes mellitus and
Pre-dialysis patients with advanced CKD, i.e. an eGFR <25 mL/min*1.73m2 or
Patients on dialysis with a residual diuresis >500 mL/24h at least 3 months after dialysis initiation or
Patients with a kidney transplant and an eGFR ≤45 mL/min/1.73m2 at least 6 months after transplantation
Patients with type 1 diabetes or patients with a life-expectancy less than 6 months in the opinion of the treating clinician or a scheduled start of dialysis within 6 months or kidney transplantation within 6 months will be excluded.
Patients afflicted with kidney disease can go through a long and arduous journey from acute and chronic kidney failure to dialysis and transplant; sometimes failed transplant and re-transplant! It is not uncommon for one nephrologist to care for a patient through all these different stages. Kudos to the investigators of RENAL LIFECYCLE trial for such a brilliant name epitomizing the very essence of what it really comes down to for patients with kidney disease- its all about their renal lifecycle.
Primary outcome measure is combined endpoint of all-cause mortality, kidney failure, and hospitalization for heart failure in the overall study population
Secondary outcomes
Incidence in the overall study population of:
All-cause mortality
Kidney failure requiring kidney replacement therapy (chronic dialysis, kidney transplantation, or death due to kidney failure)
Hospitalization for heart failure
Incidence of the composite outcome in:
Patients with eGFR <25 mL/min/1.73m2 (not on dialysis and not living with a kidney transplant)
Patients on dialysis with a residual diuresis >500 mL/24h
Patients with a kidney transplant and an eGFR ≤45 mL/min/1.73m2
Exploratory outcomes include among others quality of life as measured with the EQ-5D and SF-12, and cost-effectiveness of SGLT2-inhibition in the overall study population as well as in the three subpopulations.
Safety objectives include
Serious adverse events
Adverse events leading to drug discontinuation
Adverse events of special interest
clinically significant hypoglycemia (as defined as glucose concentration <3.0
mmol/L, i.e. 54 mg/dL)
diabetic ketoacidosis
urinary tract infections
genital infections
What are the Novel aspects of RENAL LIFECYCLE trial?
A unique patient population with severe CKD at very high risk of adverse outcomes for whom very few proven effective therapies exist. The initiation and efficacy of SGLT2 inhibitors has not been studied before in this population in any of the prior FLOZIN trials
When patients reach a renal endpoint, e.g. start of chronic dialysis or receiving a kidney transplantation, study medication will not be stopped as customary in many other trials in nephrology, but continued in the new phase of their “renal lifecycle”, hence the name of the trial.
This basket trial will include 450 to 525 patients with CKD stages G4/5, 400 to 475 patients on dialysis, and 550 to 650 patients with a kidney transplant. In case the maximum patient number of a subgroup is reached, inclusion of patients will be stopped for this subgroup, with a total number of patients to be included being 1500. Of note, when pre-dialysis patients start dialysis or are transplanted, they will continue in the trial, and this will not be a reason for study discontinuation. Likewise when dialysis patients are transplanted, they will also continue in the trial.
“The young physician starts life with 20 drugs for each disease, and the old physician ends life with one drug for 20 diseases.” -Sir William Osler
The RENAL LIFECYCLE trial is set to do exactly that. With the culmination of this trial the indications for use of dapagliflozin, and hopefully other flozins, will go where no flozin has ever gone before and improve prognosis for CKD 4/5, dialysis, and transplant patients.