Chronotherapy for Pediatric Chronic Kidney Disease

Recruiting in Palo Alto (17 mi)

Overseen by Christine Bakhoum

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Yale University

Must be taking: Antihypertensives

Must not be taking: Diuretics

Disqualifiers: Organ transplant, Oncological disease, Dialysis, others

No Placebo Group

Approved in 6 Jurisdictions

Trial Summary

What is the purpose of this trial?

This is a pilot, crossover trial in which the investigator will determine if retiming of one anti-hypertensive medication from morning to evening can effectuate normal blood pressure dipping patterns in children and adolescents with chronic kidney disease.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it requires that you have been on a stable dose of anti-hypertensive medication for at least 3 months. If you are currently taking diuretic medications, you cannot participate in the trial.

What data supports the effectiveness of the drug for treating pediatric chronic kidney disease?

The research highlights that hypertension (high blood pressure) is a common issue in children with chronic kidney disease and is linked to worsening kidney function and increased cardiovascular risk. While the studies emphasize the importance of controlling blood pressure, they also indicate that current treatments, including antihypertensive drugs, are not fully effective, as many children still have uncontrolled hypertension.

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Is chronotherapy for pediatric chronic kidney disease safe for children?

The safety of blood pressure medications, which are often used in treating children with chronic kidney disease, is generally supported by their widespread use in managing hypertension (high blood pressure) in both children and adults. These medications, including thiazide diuretics, ACE inhibitors, and beta-blockers, are considered effective and safe for children when dosages are carefully adjusted based on weight.

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How does the timing of blood pressure medication affect children with chronic kidney disease?

This treatment is unique because it focuses on the timing of taking blood pressure medication, known as chronotherapy, which aims to align medication administration with the body's natural rhythms to improve blood pressure control and potentially reduce kidney damage in children with chronic kidney disease.

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Eligibility Criteria

This trial is for children and adolescents up to 18 years old with chronic kidney disease (CKD) and high blood pressure, who have been on a stable dose of anti-hypertensive medication for at least three months. They must show abnormal blood pressure patterns overnight and have an eGFR between 30-90 ml/min/1.73 m2. Kids under six or those unable to complete necessary tests, on diuretics, with a history of organ transplant, cancer, or dialysis are excluded.

Inclusion Criteria

I am under 18 and have chronic kidney disease.

Your blood pressure does not decrease during sleep, as shown by a special test called ABPM.

I have been on the same blood pressure medication for at least 3 months.

Exclusion Criteria

I have had an organ transplant, cancer, or been on dialysis.

I am older than 6 years.

I am currently taking water pills.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to either remain on their current regimen or switch to nighttime dosing of one anti-hypertensive medication. ABPM is obtained after 1 week and at 1 month.

1 month

2 visits (in-person)

Washout

A 2-week washout period during which all subjects will be on their usual anti-hypertensive regimen. A repeat ABPM will be obtained after the washout period.

2 weeks

1 visit (in-person)

Crossover Treatment

Participants crossover to the opposite arm and an ABPM is obtained after 1 week and at 1 month.

1 month

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Participant Groups

The study is testing if changing the time when one anti-hypertensive drug is taken from morning to evening can help normalize blood pressure during sleep in kids with CKD. It's a pilot crossover trial meaning each participant will receive both treatments in sequence over different periods.

Group I: nighttime dosing of one anti-hypertensive medication Experimental Treatment 1 Intervention

13 participants will be randomized to nighttime dosing of one anti-hypertensive medication. After 1 week, a repeat ABPM will be obtained. At 1 month from randomization, another ABPM will be obtained. Following this, there will be a 2-week washout period, during which all subjects will be on their usual anti-hypertensive regimen. A repeat ABPM will be obtained after the washout period. Next, the subjects will crossover to the opposite arm and an ABPM will be obtained after 1 week. A final ABPM will be obtained at 1 month after crossover.

Group II: remain on their current regimen Active Control 1 Intervention

13 participants will be randomized to remain on their current regimen. After 1 week, a repeat ABPM will be obtained. At 1 month from randomization, another ABPM will be obtained. Following this, there will be a 2-week washout period, during which all subjects will be on their usual anti-hypertensive regimen. A repeat ABPM will be obtained after the washout period. Next, the subjects will crossover to the opposite arm and an ABPM will be obtained after 1 week. A final ABPM will be obtained at 1 month after crossover.

Re-timing of anti-hypertensive drug is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

🇪🇺 Approved in European Union as Antihypertensive agents for:

• Hypertension
• Chronic kidney disease

🇺🇸 Approved in United States as Blood pressure medications for:

• Hypertension
• Chronic kidney disease
• Heart failure

🇨🇦 Approved in Canada as Antihypertensive agents for:

• Hypertension
• Chronic kidney disease

🇯🇵 Approved in Japan as Antihypertensive agents for:

• Hypertension
• Chronic kidney disease

🇨🇳 Approved in China as Antihypertensive agents for:

• Hypertension
• Chronic kidney disease

🇨🇭 Approved in Switzerland as Antihypertensive agents for:

• Hypertension
• Chronic kidney disease

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Yale New Haven Children's Hospital/Yale New Haven Health New Haven, CT

Who Is Running the Clinical Trial?

Yale University Lead Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Collaborator

American Heart Association Collaborator

References

1. Serbia pubmed.ncbi.nlm.nih.gov

[Continuous blood pressure monitoring over a 24-hour period in children with terminal renal failure treated with hemodialysis]. [2009] Recent evidence suggests that circadian blood pressure changes are common in patients with impaired renal function and has excellent correlation with end-organ damage. The aim of this paper was to: 1) evaluate if children with end-stage renal failure have altered circadian blood pressure rhythm; 2) assess whether pre- or postdialytic blood pressure is representative for the average interdialytic blood pressure; 3) assess whether pre- or postdialytic blood pressure is representative for the average interdialytic blood pressure; 3) determine influence of pre-, post and interdialytic blood pressure. Ambulatory blood pressure monitoring was performed in two groups of patients: group A-13 children with end-stage renal failure, aged 15.15 +/- 5.58 years, on chronic haemodialysis from 2 to 156 (mean 45.3) months, 4 of whom were hypertensive and 9 normotensive; group B-19 children with chronic hypertension (essential or renal hypertension) aged 15.28 +/- 2.27 years. 84.62% of children from group A and 31.58% from group B (p = 0.0037) had blunted circadian blood pressure rhythm (a nocturnal reduction of blood pressure is less than 10% of daytime values). Pre- and postdialytic systolic, diastolic and mean arterial blood pressure did not differ significantly and were in correlation with interdialytic blood pressure (r = 0.9; p

2. Netherlands pubmed.ncbi.nlm.nih.gov

Hypertension in chronic kidney disease: role of ambulatory blood pressure monitoring. [2023] Children with chronic kidney disease have a markedly increased risk of cardiovascular morbidity and children with end stage renal disease have an estimated 30 times greater risk of cardiovascular mortality than the general pediatric population. In adults, the link between hypertension and cardiovascular disease is well-documented but that association has not been so readily apparent in children with chronic kidney disease. This may be in part because the early changes in blood pressure that occur in these patients do not necessarily manifest with changes in casual blood pressure measurements. Ambulatory blood pressure monitoring, with its ability to gather multiple readings both during the normal activities of the day and the night, is felt to be a more veritable measure of blood pressure. Its use in children has been hampered by limited data on normative values and difficulties in blood pressure classification, while its use in adults is ever expanding. However, with an increasing number of studies in children with chronic kidney disease, ambulatory blood pressure has revealed a greater prevalence of abnormal findings in this population and has been shown to better predict cardiovascular risk than current standards. Two large multi-center studies in Europe and North America have revealed even greater utility of ambulatory blood pressure measures in this population. It is hoped that continued use of ambulatory monitoring in children will help overcome some of its perceived limitations while also validating its use in those at high risk of cardiovascular morbidity.

3. United States pubmed.ncbi.nlm.nih.gov

Is Blood Pressure Improving in Children With Chronic Kidney Disease? A Period Analysis. [2019] Uncontrolled hypertension in children with chronic kidney disease (CKD) has been identified as one of the main factors contributing to progression of CKD and increased risk for cardiovascular disease. Recent efforts to achieve better blood pressure (BP) control have been recommended. The primary objective of this analysis was to compare BP control over 2 time periods among participants enrolled in the CKiD study (Chronic Kidney Disease in Children). Casual BP and 24-hour ambulatory BP monitor data were compared among 851 participants during 2 time periods: January 1, 2005, through July 1, 2008 (period 1, n=345), and July 1, 2010, through December 31, 2013 (period 2, n=506). Multivariable logistic regression to model the propensity of a visit record being in period 2 as a function of specific predictors was performed. After controlling for confounding variables (age, sex, race, socioeconomics, CKD duration, glomerular filtration rate, proteinuria, body mass index, growth failure, and antihypertensives), no significant differences were detected between time periods with respect to casual BP status (prehypertension: 15% versus 15%; uncontrolled hypertension: 18% versus 17%; P=0.87). Analysis of ambulatory BP monitor data demonstrated higher ambulatory BP indices, most notably masked hypertension in period 2 (36% versus 49%; P&lt;0.001). Average sleep BP index (P&lt;0.05) and sleep BP loads (P&lt;0.05) were higher in period 2. Despite publication of hypertension recommendations and guidelines for BP control in patients with CKD, this study suggests that hypertension remains undertreated and under-recognized in children with CKD. This analysis also underscores the importance of routine ambulatory BP monitor assessment in children with CKD.

4. United States pubmed.ncbi.nlm.nih.gov

Measurement and treatment of elevated blood pressure in the pediatric patient with chronic kidney disease. [2019] Hypertension, as in adults, is a frequent complication found in children with chronic kidney disease (CKD). Indeed, hypertension has now become one of the most prevalent chronic diseases of childhood. The most recent data available (2003) indicate that at least 38% of children with CKD in the United States are receiving antihypertensive therapy. Only recently has it been shown in children that hypertension, traditionally considered a marker for disease severity in children, is additionally a significant and independent risk factor for accelerated deterioration of kidney function and progression of CKD and a significant risk factor for cardiovascular disease. The following review outlines the differences and similarities of childhood versus adult hypertension with respect to measurement, diagnosis, treatment, and consequence in CKD. The definition of hypertension changes continually as a child grows with or without CKD. Despite numerous guidelines, the diagnosis of childhood hypertension continues to be based on epidemiologic data rather than evidence. For children, the current definition includes 2 categories: high normal, which is blood pressure (BP) between the 90th and 95th percentile, and hypertensive, which is BP above the 95th percentile. The evaluation of all hypertensive children should include a complete assessment of end-organ damage, including eyes, cardiovascular system (including blood vessels), kidneys, and nervous system. For children with CKD and end-stage renal disease (ESRD), a high percentage have left ventricular hypertrophy (LVH). The finding of end-organ damage or comorbidity (CKD, diabetes) in any child is an absolute indication for immediate pharmacologic therapy, whereas the presence of hypertension above the 95th percentile in children without CKD warrants initial intervention such as life style modification. The guidelines for measurement of BP in children with CKD are similar to those in children without CKD and include casual BP measurement, self-measured BP, and ambulatory BP monitoring. The recommendation for BP measurement in children is, when permitted, by auscultative method with a well-calibrated mercury manometer. Most casual BP measurements are performed with an automated oscillometric device whose validation has not been confirmed in children with CKD. The ambulatory BP monitor (ABPM) has 2 advantages: it significantly correlates with the presence of end-organ damage, and it identifies abnormal BP patterns that are frequently present in CKD patients, such as hypertension during the sleep period. An abnormal ABPM pattern can also be predictive of the development of end-organ damage. Treatment of hypertension in children, with and without CKD, is based on 3 factors: degree of BP elevation, the presence of cardiovascular risk factors, and the presence of end-organ damage. Additionally, the initial antihypertensive agent may be selected on available and age-appropriate formulations (eg, suspension and dosage selection). A physician treating a hypertensive child with CKD faces multiple challenges. They include selecting the convenience of available automated devices and the ABPM versus traditional auscultatory techniques upon which all normative standards have been based. Current research initiatives propose to develop pharmacokinetic and pharmacodynamics properties of antihypertensive medications and to study the effect of early intervention on end-organ damage.

5. Poland pubmed.ncbi.nlm.nih.gov

Antihypertensive treatment prescription in pediatric dialysis patients in Poland: A comparison between two nationwide studies 2003/2004-2013. [2018] Blood pressure in pediatric dialyzed patients is under poor control.

6. United States pubmed.ncbi.nlm.nih.gov

The growing epidemic of hypertension among children and adolescents: a challenging road ahead. [2022] Currently, it is clear that primary hypertension begins in childhood and that it contributes to the early development of chronic kidney disease (CKD). Hypertension also increases the risk of cardiovascular morbidity and mortality, and that risk rises as blood pressure levels escalate. As among adult patients, overweight and obesity rates are on the rise among children and adolescents with primary hypertension and can develop target organ damage including left ventricular hypertrophy. An elevated level of C-reactive protein (CRP) and microalbuminuria are early manifestations of cardiovascular disease and CKD in hypertensive patients. Lifestyle interventions are recommended for all children with hypertension. Pharmacologic therapy should be added for symptomatic children, those with stage 2 hypertension, and children with prehypertension and stage 1 hypertension who exhibit an insufficient response to lifestyle modifications. Although the recommendations for choice of drugs generally are similar for children and adults, dosages for children should be lower, based on weight, and adjusted very carefully. Medications that are effective and safe for children and adolescents include thiazide diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel-blockers. Hypertension is not being detected early enough for initiation of a treatment regimen to reduce death and disability. Initiatives should be undertaken to make health care providers and the general population more aware of the seriousness of hypertension in children and adolescents. This review focuses on the principles underlying the importance of a team approach for hypertension control, especially one that incorporates increased data sharing using enhanced health information technology for early detection and intervention.

7. England pubmed.ncbi.nlm.nih.gov

Application since 1980 of antihypertensive agents to treat pediatric disease. [2005] Strategies for using antihypertensive agents have changed significantly since 1980. This paper reviews clinical studies devoted to the use of antihypertensive agents in children beyond the newborn period. The availability of converting enzyme inhibitors and calcium channel blockers has significantly improved BP control in children with secondary forms of hypertension. The role of antihypertensive agents to chronically treat primary hypertension in children remains unclear. Additionally, some treatment protocols used in adults that apply to the treatment of hypertensive children and that have been used in the treatment of nonhypertensive disease are discussed. Preliminary studies suggest that the rate of decline of renal function in some forms of progressive renal disease may be retarded by the use of converting enzyme inhibitors.