Chronotherapy for Pediatric Chronic Kidney Disease

Overseen By Christine Bakhoum, MD, MAS

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Yale University

Must be taking: Antihypertensives

Must not be taking: Diuretics

Disqualifiers: Organ transplant, Oncological disease, Dialysis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 1 month

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether taking blood pressure medication at night, rather than in the morning, can better manage blood pressure in children and teens with chronic kidney disease. It targets those on a stable dose of blood pressure medication for at least three months and diagnosed with high blood pressure that does not decrease at night as expected. Participants will initially maintain their usual routine, then switch to taking their medication at night to assess any differences. As an unphased trial, this study provides participants the chance to contribute to valuable research that could enhance treatment strategies for young patients 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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that taking at least one blood pressure medication at bedtime, rather than in the morning, can safely help control blood pressure. Studies suggest that this timing can also reduce the risk of heart problems, such as heart attacks, in people with chronic kidney disease (CKD) and high blood pressure.

In some cases, taking medication at night helped most patients return to normal blood pressure patterns. One small study found that taking these medications in the evening significantly lowered heart-related issues for people with CKD.

These findings suggest that changing the timing of medication, without altering the medication itself, is generally safe for patients. This approach builds on treatments already used in various ways. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores a novel approach to managing pediatric chronic kidney disease through chronotherapy, which involves retiming the administration of anti-hypertensive drugs. Unlike traditional treatments that focus on the type or dosage of medication, this approach investigates the timing of drug delivery, specifically nighttime dosing. This could potentially improve blood pressure control by aligning medication administration with the body's natural rhythms, leading to more effective management of the condition with possibly fewer side effects. By comparing the current regimen to nighttime dosing, researchers hope to discover whether timing plays a crucial role in enhancing treatment outcomes for young patients.

What evidence suggests that re-timing of anti-hypertensive medication might be an effective treatment for pediatric chronic kidney disease?

Research has shown that taking blood pressure medication at night can be more effective than taking it in the morning. In this trial, one group of participants will continue with their current regimen, while another group will switch to nighttime dosing of one anti-hypertensive medication. Studies have found that evening dosing significantly lowers blood pressure during the night, which is especially beneficial for people with chronic kidney disease. For instance, one study found that taking medication at night reduced the systolic blood pressure by an average of 7 mm Hg at night, without affecting daytime blood pressure. Another study demonstrated that this approach helps maintain normal blood pressure patterns over 24 hours. These findings suggest that evening dosing could lead to better blood pressure control. ^{6 7 8 9 10}

Who Is on the Research Team?

Christine Bakhoum

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Current regimen
• Re-timing of anti-hypertensive drug

Trial Overview

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.

How Is the Trial Designed?

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

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

American Heart Association

Collaborator

Trials

352

Recruited

6,196,000+

Published Research Related to This Trial

In a study of 32 children with end-stage renal failure and chronic hypertension, 84.62% of those on chronic hemodialysis exhibited a blunted circadian blood pressure rhythm, indicating potential risks for end-organ damage.

Blood pressure measurements taken before and after dialysis were found to be reliable indicators of average blood pressure between dialysis sessions, correlating strongly with left ventricular mass index, which is important for assessing heart health in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Continuous blood pressure monitoring over a 24-hour period in children with terminal renal failure treated with hemodialysis]. Pejcić, I., Peco-Antić, A., Parezanović, V., et al.[2009]

A study of 851 children with chronic kidney disease (CKD) showed no significant improvement in casual blood pressure control between two time periods (2005-2008 and 2010-2013), indicating ongoing challenges in managing hypertension in this population.

However, the analysis revealed a concerning increase in masked hypertension and higher average sleep blood pressure indices in the later period, highlighting the need for better recognition and treatment of hypertension in children with CKD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is Blood Pressure Improving in Children With Chronic Kidney Disease? A Period Analysis. Barletta, GM., Pierce, C., Mitsnefes, M., et al.[2019]

In a study of 59 pediatric dialysis patients, antihypertensive treatment showed little change over the past decade, with 50% of patients using ACE inhibitors and 67.5% using amlodipine, but only 45% achieved satisfactory blood pressure control.

Despite the availability of various antihypertensive medications, the overall effectiveness of treatment in managing hypertension in pediatric dialyzed patients remains unsatisfactory, indicating a need for improved strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antihypertensive treatment prescription in pediatric dialysis patients in Poland: A comparison between two nationwide studies 2003/2004-2013. Wróblewski, K., Hincz, K., Miklaszewska, M., et al.[2018]

Antihypertensive agents, particularly converting enzyme inhibitors and calcium channel blockers, have significantly improved blood pressure control in children with secondary hypertension, as highlighted by clinical studies.

The effectiveness of antihypertensive agents for treating primary hypertension in children is still uncertain, but preliminary studies indicate that converting enzyme inhibitors may help slow the decline of renal function in certain progressive renal diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application since 1980 of antihypertensive agents to treat pediatric disease. Gruskin, AB., Dabbagh, S., Fleishmann, LE., et al.[2005]

Children with chronic kidney disease are at a significantly higher risk for cardiovascular issues, with those in end-stage renal disease facing a 30 times greater risk of cardiovascular mortality compared to healthy children.

Ambulatory blood pressure monitoring has shown a higher prevalence of abnormal blood pressure readings in children with chronic kidney disease and is better at predicting cardiovascular risk than traditional blood pressure measurements, as supported by large multi-center studies in Europe and North America.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypertension in chronic kidney disease: role of ambulatory blood pressure monitoring. VanDeVoorde, RG., Mitsnefes, MM.[2023]

Hypertension is a common complication in children with chronic kidney disease (CKD), affecting at least 38% of these children in the U.S., and is a significant risk factor for worsening kidney function and cardiovascular disease.

The diagnosis and treatment of hypertension in children differ from adults, with specific guidelines for blood pressure measurement and the need for immediate pharmacologic therapy in cases of end-organ damage, highlighting the importance of tailored approaches in managing pediatric hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Measurement and treatment of elevated blood pressure in the pediatric patient with chronic kidney disease. Swinford, RD., Portman, RJ.[2019]

Primary hypertension in children can lead to chronic kidney disease and increased cardiovascular risks, highlighting the need for early detection and intervention.

Lifestyle changes are essential for managing hypertension in children, and medication may be necessary for those with more severe cases, with careful dosage adjustments based on weight.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The growing epidemic of hypertension among children and adolescents: a challenging road ahead. Assadi, F.[2022]

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