Protocol and rationale for a randomized controlled SGLT2 inhibitor trial in paediatric and young adult populations with chronic kidney disease: DOUBLE PRO-TECT Alport

ABSTRACT

Background

Clinical trials have demonstrated positive cardiovascular and kidney outcomes of sodium–glucose co-transporter 2 (SGLT2) inhibitors in adult patients with diabetic and other chronic kidney diseases (CKDs). Whether benefits extend to children, teenagers and young adults with early-stage CKD is unknown. For this reason, the DOUBLE PRO-TECT Alport trial (NCT05944016) will study the progression of albuminuria in young patients with Alport syndrome (AS), the most common hereditary CKD, to assess the safety and efficacy of the SGLT2 inhibitor dapagliflozin. Patients living with AS and chronically elevated albuminuria have a high risk of kidney failure before the age of 50 years.

Methods

DOUBLE PRO-TECT Alport is a multicentre, randomized, double-blind, placebo-controlled trial. Participants (ages 10–39 years) must have a diagnosis of AS by genetic testing or kidney biopsy, be on a stable (>3 months) maximum tolerated dose of a renin–angiotensin system inhibitor and have a urinary albumin:creatinine ratio (UACR) of >300 mg/g (paediatric) or >500 mg/g (adult).

Eligible participants will be randomly assigned at a 2:1 ratio to 48 weeks of treatment with dapaglifozin 10 mg/day or matched placebo. Most participants are expected to be children with a normal estimated glomerular filtration rate (eGFR). In addition to safety, the primary (change in UACR from baseline to week 48) and key secondary (eGFR change from baseline to week 52) efficacy outcomes will be analysed with a mixed model repeated measures approach. Efficacy analyses will be performed primarily in the full analysis set according to the intention-to-treat principle. A sensitivity analysis will be performed using reference-based multiple imputation.

Conclusion

DOUBLE PRO-TECT Alport will assess whether SGLT2 inhibitors can safely reduce the UACR change from baseline as a marker for progression of CKD in young patients living with AS.

Graphical Abstract

Graphical Abstract.

KEY LEARNING POINTS.

What was known:

• Recent trials demonstrated positive renal outcomes of sodium–glucose co-transporter 2 (SGLT2) inhibitors in adults with CKD.

• Participants in the DAPA-CKD and EMPA-Kidney trials had a mean age >60 years and chronic kidney disease (CKD) stages 3/4.

• The trials included <0.3% of patients <40 years of age with an estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m² and no children.

This study adds:

• DOUBLE PRO-TECT Alport aims to demonstrate superiority of the SGLT2 inhibitor dapagliflozin in delaying the change in UACR in children and young adults in the early stages of CKD.

• The population of children with CKD has been excluded so far from clinical development of SGLT2 inhibitors. This trial will close this knowledge gap.

Potential impact:

• DOUBLE PRO-TECT Alport will assess whether SGLT2 inhibitors can safely reduce the UACR change from baseline (and eGFR as a key secondary endpoint) in children and young adults with Alport syndrome in the early stages of CKD.

• Children and young adults with any other kind of CKD might benefit from the trial results.

INTRODUCTION

Recent trials have demonstrated positive renal outcomes with sodium–glucose co-transporter 2 (SGLT2) inhibitors in adult patients with diabetic chronic kidney disease (CKD) and other causes of CKD [1–5]. SGLT2 inhibitors such as dapagliflozin provide control of diabetes (without causing hypoglycaemia), weight loss, blood pressure reduction, reduced risks of cardiovascular disease and cardiovascular mortality, lower uric acid levels, slower CKD progression and reduced albuminuria [1–5], making them the standard of care in patients with heart failure and CKD. Participants in the DAPA-CKD (NCT03036150) and EMPA-Kidney (NCT03594110) trials, which led to the approval of dapagliflozin and empagliflozin for treatment of CKD, had a mean age of 60–65 years and most of them were in CKD stages 3 or 4 [4, 5]. These trials included <0.3% of patients <40 years of age with CKD stages 1 or 2 and a preserved kidney function [defined as an estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m²], no young adult patients with Alport syndrome (AS) and no children.

Preclinical and clinical studies have demonstrated that SGLT2 inhibitors are nephroprotective for the non-diabetic kidney: in patients independent of glycaemic control, nephroprotection constituted a reduction in glomerular hyperfiltration and albuminuria and a stabilization of renal function [1–5]. Preclinical studies have shown SGLT2 inhibitors limit mesangial expansion, matrix accumulation, interstitial fibrosis and albuminuria via the haemodynamic mechanisms described, in addition to inhibition of renal inflammation and oxidative stress [6, 7].

Hyperfiltration is a harmful haemodynamic abnormality of glomerular disease and is a consequence of increased intraglomerular pressure and/or nephron loss. This destructive process results in loss of the permselective properties of the glomerular barrier to proteins that results in progressive albuminuria and subsequent kidney failure, a mechanism that was reported >50 years ago by physiologist K.W. Thurau in Göttingen [8, 9].

The glomerular basement membrane (GBM) in patients living with AS is mechanically vulnerable due to a type IV collagen defect. The GBM filters glucose, which then reaches the lumen of the proximal tubule and is reabsorbed transcellularly via SGLT2 (with sodium). The capacity of both transporters, SGLT2 and SGLT1, can be saturated by elevated filtrate glucose levels in the tubular lumen, leading to glycosuria. As a result of hyperglycosuria-induced activation of SGLT transporters, decreased sodium delivery to the distal tubules is sensed by the macula densa. As a consequence, the macula densa triggers renin release and renin–angiotensin–aldosterone system activation, resulting in afferent vasodilation and efferent vasoconstriction (tubuloglomerular feedback). SGLT2 inhibitors reverse these effects by inducing greater sodium delivery to the distal tubules, thereby inhibiting renin release [10–15]. It is hypothesized that this reduction in glomerular hyperfiltration leads to decreased albuminuria and decreased damage to the fragile GBM (and slower progression of CKD) in AS [10].

The clinical research question related to SGLT2 inhibitors is whether these drugs, by mechanistically acting on glomerular filtration pressure, are effective not only in adult patients with CKD stages 3 and 4 with severely impaired kidney function, but also in other patient groups at risk of progressive CKD, such as children and young adults with early stages of CKD, including patients living with AS [10, 16, 17]. AS is the most common hereditary kidney disease [18, 19]. Angiotensin-converting enzyme (ACE) inhibition has been established as the standard of care for children with AS in several observational studies [20–24] and in expert guidelines for the treatment of AS [25–27]. A previous randomized controlled trial (RCT) in children ≥2 years of age and living with AS [EARLY PRO-TECT Alport (NCT01485978)] and published standards for clinical trials in AS facilitated the planning of this RCT [28, 29].

Dapagliflozin and empaglifozin are approved in the European Union (EU) for the treatment of CKD (which includes AS) in adults, but not for children with CKD, as they have not been tested in children with CKD. Dapagliflozin and empaglifozin have a marketing authorization for the treatment of heart failure in adults, but not for children with heart failure, as they have not been tested in children with heart failure. Dapagliflozin is the first SGLT2 inhibitor that has a marketing authorization for the treatment of type 2 diabetes mellitus (T2DM) in children ≥10 years of age [30].

The hypothesis is that the SGLT2 inhibitor dapagliflozin is superior to standard-of-care treatment in delaying progression of albuminuria (as a marker of progression of CKD) in young patients with AS who have a high risk of advancing to kidney failure due to their advanced albuminuria [10].

The DOUBLE PRO-TECT Alport trial is supported by the Study Group of the German Society of Pediatric Nephrology (GPN), thus all participants in Germany (or from outside Germany who are willing to travel to Germany) will be assessed for eligibility. Recruitment will be supported by the German and other national Alport patients’ advocacy groups.

MATERIALS AND METHODS

Design and rationale

The DOUBLE PRO-TECT Alport trial is a phase 3, multicentre, randomized, placebo-controlled, double-blind (patient, investigator and trial team) clinical trial conducted in Germany according to the German Medicines Act (Arzneimittelgesetz). The trial includes participants living with AS in the early stages of CKD with a high UACR, which indicates a high risk of CKD progression. The expected baseline characteristics are shown in Fig. 1: most participants will be children with a normal eGFR but high UACR. In contrast, the adult patients (mean age 60–65 years) in the DAPA-CKD (yellow numbers in Fig. 1) and EMPA-Kidney (blue numbers in Fig. 1) trials had much lower eGFRs at baseline and lower UACRs and a very high risk of progressive kidney failure [4, 5].

Figure 1:

Trial rationale of DOUBLE PRO-TECT Alport versus DAPA-KD and EMPA-Kidney. Green: (expected) baseline characteristics of DOUBLE PRO-TECT Alport with a much younger population (>50% adolescents, high UACR, normal eGFR) but an extreme high risk of progression of CKD; blue: EMPA-Kidney baseline characteristics of participants with a mean age 60–65 years, with lower UACR, much lower eGFR and very high (but not 100%) risk of kidney failure; orange: DAPA-CKD baseline characteristics of participants with a mean age 60–65 years, with lower UACR, much lower eGFR and very high (but not 100%) risk of kidney failure.

The design of the DOUBLE PRO-TECT Alport trial is based on observational data from the European Alport Therapy Registry (NCT02378805). This multicentre, observational, retrospective, and in parts prospective, registry in participants living with AS showed a less pronounced long-term response to SGLT2 inhibitors in terms of a decrease in UACR than the DAPA-CKD trial [4]. In the European Alport Therapy Registry, participants were younger than the participants without diabetes in the EMPA-Kidney trial, had a lower body mass index (BMI), lower blood pressure (BP), a much higher eGFR and a higher UACR [5, 31]. While the data did not allow recommendation of SGLT2 inhibitors in patients living with AS with early stages of CKD (stages 1 or 2) and in children [31], it did provide the rationale that early initiation of SGLT2 inhibitors in young patients with AS may be beneficial.

DOUBLE PRO-TECT Alport will enrol participants ages 10–39 years who are on standard-of-care medication for AS [25, 26], i.e. a stable, maximum tolerated dose of ACE inhibitor (and/or angiotensin II receptor type 1 antagonist) (Fig. 2). The use of non-steroidal anti-inflammatory drugs is limited to 1 week in a row. Systemic immunosuppression such as higher doses of steroids or calcineurin inhibitors are excluded.

Figure 2:

Trial flow of DOUBLE PRO-TECT Alport.

The rationale for including children ≥10 years of age is based on the approval of dapagliflozin for children ≥10 years of age with T2DM [30]. In addition, UACR increases in most children in this age group with classical forms of AS despite renin–angiotensin system (RAS) blockade, indicating a stage of disease progression that might benefit from additional therapies.

Enrolled participants will be randomized at a 2:1 ratio to receive dapagliflozin 10 mg/day or matched placebo for 48 weeks. Dapagliflozin was chosen as the SGLT2 inhibitor because it is the first SGLT2 inhibitor approved for children ≥10 years of age with T2DM, including data for pharmacokinetics and pharmacodynamics in children [30].

The treatment intervention in the DOUBLE PRO-TECT Alport trial mimics the intervention scheme of the DAPA-CKD and EMPA-KIDNEY [4, 5] trials with the same dosing of dapagliflozin/placebo 10 mg by mouth once a day. This similarity is important, because it allows later extrapolation of the results from the DOUBLE PRO-TECT Alport trial to the results from the larger DAPA-CKD and EMPA-KIDNEY trials.

Participants

The full list of patient eligibility criteria is provided in Table 1. This trial includes children 10–17 years of age with a UACR >300 mg/g and young adults 18–39 years of age with early stages of CKD (eGFR >60 ml/min/1.73 m²) and a UACR >500 mg/g.

Table 1:

Inclusion and exclusion criteria.

Inclusion criteria

To be eligible for participation in this trial, patients must meet all of the following criteria:

1. Definitive diagnosis of Alport syndrome by kidney biopsy (in patient or other affected family members) and/or genetic testing positive for any AS gene variant (heterozygous, homozygous, hemizygous or compound heterozygous) in the COL4A3, COL4A4 and/or COL4A5 gene.

2. Age ≥10–<18 years with albuminuria (UACR ≥300 mg/g)

OR

Age ≥18–<40 years with albuminuria (UACR ≥500 mg/g) AND eGFR ≥60 ml/min/1.73 m2.

3. Stable RAS blockade [single RAS blockade with ACE inhibitor OR angiotensin receptor blocker (ARB) OR double RAS blockade with ACE inhibitor plus ARB] as standard-of-care background therapy (defined as no adjustment to dose in the last 3 months prior the baseline visit).

4. In adolescent patients: have understood the nature, meaning and consequences of the clinical trial (including age-appropriate information) and have given assent and their parent(s)/legal guardian has given written informed consent approved by the sponsor and the ethical review board governing the site.

5. In adult patients: written informed consent obtained according to international guidelines and local laws. Ability to understand the nature of the trial and the trial-related procedures and to comply with them.

6. Reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures. Ability to understand the nature of the trial and the trial-related procedures and to comply with them.

Exclusion criteria

To be eligible for participation in this trial, patients must not meet any of the following criteria:

1. Inability to take trial treatments.

2. Current treatment with any SGLT2 inhibitor or prior treatment with any SGLT2 inhibitor within 4 weeks prior to visit 1.

3. eGFR <60 ml/min/1.73 m2 (Chronic Kidney Disease Epidemiology Collaboration equation) in adult patients OR requiring dialysis OR after kidney transplantation.

4. Uncontrolled arterial hypertension defined as blood pressure >145/95 mmHg in adults OR uncontrolled arterial hypertension according to the treating paediatric nephrologist's assessment in adolescents.

5. Type 1 diabetes or type 2 diabetes with a previous history of diabetic ketoacidosis.

6. Current foot ulceration or previous amputation.

7. Known hypersensitivity or allergy to the investigational product (contains lactose).

8. Known severe hepatic impairment (Child–Pugh class C).

9. Any previous or current alcohol or drug abuse.

10. Participation in any other interventional clinical trial within the last 30 days before the start of this trial or five half times the half-life of the insulin-like growth factor 2 messenger RNA–binding proteins /metabolites (whichever is longer); simultaneous participation in registry and diagnostic trials is allowed.

11. Mental condition (not age) that renders the patient unable to understand the nature, scope and possible consequences of the study.

12. Investigator site personnel directly affiliated with this study and their immediate families or subjects who are in any state of dependency to the sponsor or the investigators. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.

13. Unlikely to comply with the protocol, e.g. display an uncooperative attitude, are unable to return for study-specific and follow-up visits and are unlikely to comply with the study-specific restrictions/requirements.

14. Any other condition that, in the opinion of the investigator, would preclude participation in the study.

15. Current or planned pregnancy or nursing period.

16. For all female patients: failure to use highly effective methods of contraception that can achieve a failure rate of <1% per year when used consistently and correctly.

Intervention

Over the treatment period of 48 weeks, randomized participants receive the standard dose of 10 mg once daily of dapagliflozin or matched placebo. The study medication is blinded by repackaging two 5 mg tablets into capsules. No dose adjustment is planned for adolescents. The 48-week treatment period is followed by a 4-week treatment-free period with a final follow-up visit at week 52. Adult participants can restart open-label SGLT2 inhibitor treatment thereafter.

Sample size and trial duration

AS is a rare disease with a prevalence of 1 in 1000 to 1 in 5000 in Europe [20–24, 32]. The sample size of 68 participants in the treatment group and 34 participants in the placebo group yields a power of 80% at a two-sided significance level of 5%, given a standardized mean difference (Cohen's d) of 0.63. This moderate to substantial effect size is justified by the efficient repeated measures model, observational studies and a recent case series [20, 21, 31, 33]. Accounting for ≈10% premature study or treatment discontinuations (dropout), which is supported by previous experiences in AS [29], the trial aims to randomize 102 participants. The sample size calculation was carried out using nQuery 9 (version 9.2.0.0; Dotmatics, Boston, MA, USA). The trial will monitor nuisance parameters (such as discontinuation rates) in a blinded fashion and adapt the sample size should this be necessary.

The expected recruitment phase is 18 months. The trial treatment phase is 12 months per participant (Fig. 2).

Outcome measures

Primary and key secondary efficacy endpoints are the change from baseline UACR after 48 weeks of study treatment and the change from baseline eGFR after 52 weeks, respectively. For the primary endpoint, UACR, the treatment period of 48 weeks is sufficient (see DAPA-CKD data [4]), as is the off-therapy follow-up period of 4 weeks until week 52. The delta of eGFR after 48 weeks, eGFR slope and off-medication eGFR at follow-up week 52 [34] will be used to compare the eGFR data of the DOUBLE PRO-TECT Alport trial with the eGFR data of the larger DAPA-CKD and EMPA-Kidney trials [4, 5] (Fig. 3).

Figure 3:

Trial schedule and visits of DOUBLE PRO-TECT Alport.

Safety assessments include adverse events, serious adverse events, physical examination, growth, vital signs and change from baseline in laboratory parameters. Adverse events of special interest include ketoacidosis or symptomatic hypoglycaemic event, hyperkalaemia, decrease in eGFR ≥30% from baseline, symptomatic dehydration, bone fractures, urinary tract infection and genital infection.

Exploratory endpoints focus on audiometry, ocular changes (both related to AS), safety, BP, serum albumin, dyslipoproteinaemia, potassium level, serum phosphate, weight, growth (height), BMI, obesity, diet, AS genotype, RAS blockade, smoking status, increase (decrease) in UACR by 20% (40%) from baseline and eGFR in relation to response to treatment. Most exploratory endpoints have already been established in the previous trial EARLY PRO-TECT Alport trial [29] (Fig. 3).

The burden of disease and patient-related outcome will be assessed by the 36-item Short Form Health Survey (SF-36) for young adults (18–39 years of age) and by the Pediatric Quality of Life Inventory (PedsQL) for adolescents (10–17 years of age).

Statistical analysis

The primary outcome change in (the logarithm of) UACR from baseline to week 48 will be analysed by a mixed models repeated measures (MMRM) approach, i.e. a Gaussian linear model with intervention (verum versus placebo), centre, age group (adolescents versus adults), time (week 4, 16, 32 and 48) and intervention-by-time interaction as factors and baseline (log) UACR as a covariate. The error terms are assumed to follow a multivariate normal distribution with unstructured covariance. Least squares mean changes from baseline will be reported for both groups with 95% confidence intervals (CIs) as well as the difference between the least squares treatment group means with 95% CIs and P-value testing the null hypothesis of no treatment effect. Although the model described above is robust to some extent to missing data, sensitivity analyses will be performed including reference-based multiple imputation, in particular if study discontinuations should turn out to be more frequent than expected. The analysis of the key secondary outcome, change from baseline eGFR after 52 weeks, and the analysis of the secondary outcome (SF-36 or PedsQL) will follow the same lines as the analysis of the primary outcome. The primary analysis population will follow the intention-to-treat principle. All details of the statistical analysis, including definitions of the analysis sets and the procedure to control the type I error rate across the primary and important secondary endpoints, will be specified in a statistical analysis plan, which will be finalized prior to database lock and unblinding. Adverse events will be reported as frequencies and percentages by treatment group. Additionally, descriptive analyses will be performed for hearing and eye tests. No interim analyses are planned. Subgroup analyses by age group (adolescents versus adults), sex and genotype will be carried out.

Patient involvement

This study offers a hope for better therapy of CKD in AS families (see the Bundesministerium für Bildung und Forschung video portrait about the EARLY PRO-TECT Alport study (https://www.gesundheitsforschung-bmbf.de/de/videoportrait-hilfe-fur-nierenkranke-kinder-14890.php). The steering committee includes one patient expert representative of the US Alport patient group (https://alportsyndrome.org/) [28] and two members of the German patient group (www.alport-selbsthilfe.de), which represents >300 families in German-speaking countries. Patient representatives are actively involved, including in investigator meetings. Criteria for supporting public involvement (e.g. INVOLVE; www.invo.org.uk/) will be followed. The international Alport Alliance includes global patient representatives from all over the world. This patient involvement will not only help us with recruiting, but also by comparison with ‘real-world’ observational data from patients living with AS from other countries who may have received off-label treatment with SGLT2 inhibitors [31].

Ethics basis, legislation and guidelines and notification of the authorities

This study complies with applicable laws and regulations, e.g. EU Regulation 536/2014 [Clinical Trials Regulation (CTR)], EU Regulation 679/2016 [General Data Protection Regulation (GDPR)], the Medicinal Products Act (AMG) as well as the guidelines for the International Council for Harmonization Good Clinical Practice and the Declaration of Helsinki.

According to the CTR, the submission, assessment and supervision for clinical trials in the EU is processed through the Clinical Trials Information System (CTIS). Through this system, the necessary positive vote of the responsible ethics committee and the given competent authorities [here, the Federal Institute for Drugs and Medical Devices) has been achieved. Each patient will be informed about the study (including data protection issues) and will need to give consent before inclusion in the study.

The intervention seems ethically acceptable, as side effects of dapagliflozin are well known and tolerable with regard to risk:benefit ratio in AS. The European Medicines Agency (EMA) has approved dapagliflozin in children ≥10 years of age with T2DM [30]. The DOUBLE PRO-TECT Alport trial focusses on early stages of AS and on safety, which is extremely relevant in the paediatric population [20, 28, 32]. The DOUBLE PRO-TECT Alport trial in children and young adults at early stages of CKD—in terms of generalizability and representativeness—could also improve evidence of early therapy with SGLT2 inhibitors for other patients, especially children, with other causes of CKD. AS was underrepresented in DAPA-CKD, with only 6 patients living with AS included out of 4304 adult participants [4]. For that reason, DAPA-CKD had no chance to detect any (specific) side effects occurring in patients with AS. In fact, it might be unethical to treat children with CKD with SGLT2 inhibitors without an adequate evidence base for efficacy and safety in this vulnerable population. Therefore, DOUBLE PRO-TECT Alport could also have an impact on improving care for children with other causes of CKD (Fig. 4).

Figure 4:

DOUBLE PRO-TECT Alport trial rationale and expected outcome. The target population for the trial (green line, estimated disease progression, from Gross et al. [20, 29]) are adolescents and young adults with higher albuminuria, indicating the high risk for fast progression of their kidney disease. Red line indicates the ‘natural’ course of disease in untreated patients [20]. If the trial is successful, the later target population (blue line, speculative course of disease progression), which will benefit most from add-on SGLT2 inhibition, will be those patients with a coincidence of early diagnosis and less severe missense variants.

Data quality assurance and dissemination

Clinical data will be recorded digitally using electronic case report forms and stored pseudonymized in a secuTrial database (interActive Systems, Berlin, Germany), a web-based database solution that meets all technical good clinical practice requirements. Plausibility checks and checks for missing values will be carried out continuously over the course of the clinical trial by data managers in order to promote data quality. The secuTrial software is installed on servers of the Gesellschaft für wissenschaftliche Datenverarbeitung Göttingen and is managed following the standard operating procedures of the Department of Medical Informatics, University Medical Center Göttingen.

The trial results will be published as open access and results will be presented for discussion at national and international meetings, educational sessions and international Alport workshops (see https://www.alportsyndromealliance.org/). Results will also be published in lay language.

In compliance with reporting guidelines (EQUATOR Network), the sponsor will follow the CONSORT guidelines for randomized controlled trials (see Gross et al. [29] as a reference for the previous EARLY PRO-TECT Alport trial). Scientific institutions will have access upon request to the full pseudonymized dataset.

DISCUSSION AND CONCLUSION

The vulnerable population of children with CKD and young adults with early stages of CKD (stages 1 and 2, eGFR >60 ml/min/1.73 m²), but at high risk for progressive CKD, has not been included in clinical trials with SGLT2 inhibitors despite a high unmet medical need for safe and better therapies. The DOUBLE PRO-TECT Alport trial aims to close this knowledge gap.

Dose selection is based on the standard fixed dose of 10 mg/day of dapagliflozin by mouth being approved for CKD in adults and for children ≥10 years of age with T2DM [4, 30]. In the latter trial in children, the mean BMI was >35 kg/m², which will be different in the DOUBLE PRO-TECT Alport trial (BMI estimated at 20 kg/m² in the paediatric participants) [30]. BMI and height/growth are secondary endpoints of this trial.

In 2012, the increasing off-label use of ACE inhibitors in AS without adequate evidence for safety and efficacy was the rationale for the EARLY PRO-TECT Alport trial with ramipril [29]. Twelve years later, the paediatric nephrology community faces the same problem with SGLT2 inhibitors and their increasing off-label use in children with CKD. DOUBLE PRO-TECT Alport provides the opportunity to generate evidence in a paediatric CKD population in which, due to the urgent medical need, it is very likely that off-label use of SGLT2 inhibitors will increase. Soon, increasing off-label use of SGLT2 inhibitors in children with CKD will eliminate the unique opportunity to create the high-level evidence that young patients deserve.

Similar to the EARLY PRO-TECT Alport trial [29], safety, patient-related outcomes and burden of disease are key endpoints of the DOUBLE PRO-TECT Alport trial. The early interventional character explains the adverse events of special interest, such as severe ketoacidosis, that would counteract the potential benefit of SGLT2 inhibitors [35]. A recent report of a suspected unexpected severe adverse event in a patient living with AS (without diabetes) could put the benefits of SGLT2 inhibitors into perspective [36], highlighting safety despite the clear long-term benefit in risk for kidney failure, cardiovascular events and impaired life expectancy [20, 37, 38].

The primary endpoint, UACR change from baseline at 48 weeks, and the key secondary endpoint, eGFR change from baseline at 52 weeks, adapt to the design of the much larger EMPA-Kidney and DAPA-CKD trials to allow extrapolation of the results [4, 5]. The focus on UACR as the primary endpoint is a limitation of our trial, which we can explain by our limited resources and by possible recruitment problems if we have tried to implement a treatment phase that was too long in a placebo-controlled paediatric RCT. Observational data from >100 adult patients living with AS contribute to the calculation of the primary endpoint [31, 33]. Of note, all participants in the DOUBLE PRO-TECT Alport trial must be on RAS blockade. ACE inhibitors play a different role in renal haemodynamics than SGLT2 inhibitors [10, 39]. Thus the key secondary eGFR endpoint after 4 weeks off therapy reaches very exciting new territory: can SGLT2 inhibitors preserve kidney function beyond decreasing filtration pressure, e.g. by protecting the podocyte or the tubulointerstitial area [7, 40]? In the target population of our trial, i.e. young patients with preserved kidney function, the known potential of SGLT2 inhibitors in reducing filtration pressure might become less important: effects on cell metabolism or on the heart could also come to the fore [7, 40].

Fig. 4 summarizes the goals and chances of the first RCT with SGLT2 inhibitors in children and young adults living with AS and with CKD: if dapagliflozin is safe and can reduce the UACR change from baseline (and eGFR as a key secondary endpoint), this can be interpreted as a predictor for a significant delay of kidney failure and—possibly—substantial preservation of kidney architecture with a positive safety profile. If successful, DOUBLE PRO-TECT Alport could change the treatment recommendations for children with CKD due to AS and could possibly also benefit young patients with other forms of CKD.

This study will be the first paediatric SGLT2 inhibitor RCT in CKD and will be funded independently from the pharmaceutical industry. This independence can be seen as a limitation: our limited resources led to the decision to focus on a single primary diagnosis. The strict financial plan results in a tight budget for the trial sites and does not allow significant compensation for travelling costs for the families. Both factors have been identified as major risks for slow recruitment and will be addressed by the passion of the trial sites and the motivation of the participants.

Our academia-driven investigator-initiated trial would be happy to receive help from the US Food and Drug Administration and EMA with this important study [41–43]: the non-commercial DOUBLE PRO-TECT Alport trial is breaking new ground in pre-emptive kidney protection in children and young adults with CKD (see Gross et al. [44]).

FUNDING

DOUBLE PRO-TECT Alport (EU trial no. 2023-508502-18-00, ClinicalTrials no. NCT05944016) is supported by the German Research Foundation (GR 1852/7-1 to O.G., project 508779211). No industry support was received for this study.

AUTHORS’ CONTRIBUTIONS

O.G. and T.F. were responsible for the initial trial rationale and design. O.G. was responsible for funding acquisition and wrote the initial draft. O.G., J.B., T.F., T.A., R.T., J.H., U.D., R.A. and C.G. wrote the initial trial protocol and informed consents. L.T.W., H.J.L.H. and J.F.S. critically reviewed the trial protocol. All authors contributed to and approved the final version of the manuscript.

DATA AVAILABILITY STATEMENT

Data supporting reported results can be requested from the corresponding author.

CONFLICT OF INTEREST STATEMENT

O.G. received advisory fees from AstraZeneca and his employer received advisory fees from Boehringer Ingelheim. Employees of Boehringer Ingelheim and O.G. are co-inventors for the patent application EP3826642 (Empagliflozin for use in treating Alport syndrome). H.J.L.H. received advisory fees from AstraZeneca. The remaining authors report no conflicts of interest related to this publication.