Effect of Chronotherapy on Blood Pressure - Time of Intake of Blood Pressure Lowering Drugs
Primary Purpose
Hypertension, Drug Therapy, Primary Health Care
Status
Recruiting
Phase
Not Applicable
Locations
Sweden
Study Type
Interventional
Intervention
Time of ordinary antihypertensive medication intake
Sponsored by
About this trial
This is an interventional treatment trial for Hypertension focused on measuring Cross-over study
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of hypertension
- Stable antihypertensive treatment at least 8 weeks prior to inclusion
- One to four antihypertensive drugs
Exclusion Criteria:
- Atrial fibrillation/flutter
- Diabetes
- Previous stroke or TIA
- Heart failure
- Ischemic heart disease
- Peripheral artery disease
- Malignant disease with less than one year expected survival
- Inability to follow study protocol (for instance shift work)
Sites / Locations
- Sahlgrenska University Hospital, MölndalRecruiting
- Närhälsan Billingen Primary Health Care CentreRecruiting
- Närhälsan Norrmalm Primary Health Care Centre
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
Morning intake
Bedtime intake
Arm Description
Intake of antihypertensive medication in the morning
Intake of antihypertensive medication at bedtime
Outcomes
Primary Outcome Measures
24 hours blood pressure changes between 8 and 16 weeks.
Ambulatory blood pressure changes between 8 and 16 weeks. Systolic and diastolic mean blood pressure level.
Change of dipping of blood pressure between 8 and 16 weeks.
Ratio between daytime and nighttime blood pressure registered after 8 and 16 weeks. Systolic and diastolic mean blood pressure level.
Secondary Outcome Measures
Daytime blood pressure changes between 8 and 16 weeks.
Ambulatory daytime blood pressure registered after 8 and 16 weeks. Systolic and diastolic mean blood pressure level.
Nighttime blood pressure changes between 8 and 16 weeks.
Ambulatory nighttime blood pressure registered after 8 and 16 weeks. Systolic and diastolic mean blood pressure level.
Office blood pressure changes between 8 and 16 weeks.
Office blood pressure registered after 8 and 16 weeks. Systolic and diastolic mean blood pressure level.
Difference in morning surge of blood pressure between 8 and 16 weeks.
Occurrence of morning (yes/no)
Difference in LDL cholesterol levels between 8 and 16 weeks.
LDL cholesterol changes according to time of intake of antihypertensive drugs
Difference in HDL cholesterol levels between 8 and 16 weeks.
HDL cholesterol changes according to time of intake of antihypertensive drugs
Difference in total cholesterol levels between 8 and 16 weeks.
Total cholesterol changes according to time of intake of antihypertensive drugs
Difference in p-creatinine levels between 8 and 16 weeks.
P-creatinine changes according to time of intake of antihypertensive drugs
Full Information
NCT ID
NCT05322967
First Posted
April 4, 2022
Last Updated
April 27, 2023
Sponsor
Vastra Gotaland Region
Collaborators
Swedish Heart Lung Foundation
1. Study Identification
Unique Protocol Identification Number
NCT05322967
Brief Title
Effect of Chronotherapy on Blood Pressure - Time of Intake of Blood Pressure Lowering Drugs
Official Title
Chronotherapy in Hypertension - a Study of Blood Pressure Levels Following Intake of Antihypertensive Medication in the Morning or at Bedtime
Study Type
Interventional
2. Study Status
Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 25, 2022 (Actual)
Primary Completion Date
December 1, 2023 (Anticipated)
Study Completion Date
December 1, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Vastra Gotaland Region
Collaborators
Swedish Heart Lung Foundation
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
A randomized clinical trials with cross-over design to evaluate changes in blood pressure, renal function (creatinine, estimated glomerular filtration), LDL and HDL-cholesterol after taking antihypertensive drugs in the morning or at bedtime. Blood pressure will be estimated by ambulatory blood pressure measurements. There will be a shift in time of drug intake after 8 weeks for each participant. Approximately 100 individuals aged 40-75 years and on stable anti-hypertensive treatment and blood pressure <150/95 mm Hg will be recruited. No new drugs will be introduced during the study.
Detailed Description
High blood pressure (hypertension, HT) is very common and can lead to serious cardiovascular complications and premature death. Despite effective drug treatment many patients do not reach the blood pressure goal. No new antihypertensive drugs have been developed lately, so there is a need for other strategies to increase attainment of goals and diminish the rate of complications. The circadian rhythm can affect sleep, body temperature, hormone levels, metabolism and the effect of drugs. The impact of antihypertensive treatment in the short and long run was described in a large randomized study in primary health care where individuals with hypertension were randomly assigned to take the drugs in the morning or at bedtime. Intake at bedtime resulted in lower blood pressure, better kidney function and lower LDL-cholesterol. Further, after a mean time follow-up of 6 years a 50% reduction of cardiovascular death was seen. There was by time running a difference in antihypertensive drugs and also co-morbidity between the groups. Despite this, there is a need to investigate if chronotherapy might play a role in antihypertensive care.
The aim of the study is to investigate the effect of intake of drugs in the morning compared to at bed-time.
Methods: Patients 40-75 years, will be recruited from two primary health care centers and one clinic of internal medicine. Medical history, current medication will be recorded. Office blood pressure, body height and weight, ECG and ambulatory blood pressure measurement (ABPM) will be performed. Blood will be analyzed for fasting blood glucose, LDL and HDL-cholesterol and creatinine.
After inclusion in the study the patients are randomly, by clinic, allocated to take their antihypertensive drugs in the morning or at bed-time during 8 week. The ordinary medication is used during the study period. The patients are instructed to keep a diary on wake-up and bed-times, side effects, sleep quality and other experiences during therapy. After 8 weeks the investigations at base-line are repeated and a visual analogue scale on sleep, daytime tiredness and urine voiding is recorded. The patients shift to intake of medication on the opposite time of day for 8 weeks. The study is completed with a repeated investigation as above. The analyses of data is performed by researchers of the team that are not aware of the patients' allocation. The diaries will be a base for later in-depth-interviews with a part of the patients. The analyses will be intention-to-treat using appropriate methods for the data. Office blood pressure, blood lipids and kidney function at baseline, 8 and 16 weeks, as well as sleep duration, urine voiding at night will be analyzed. ABPM will be analyzed using mean blood pressure around-the-clock, daytime and nighttime blood pressure, dipping and morning surge.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension, Drug Therapy, Primary Health Care
Keywords
Cross-over study
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Model Description
Participants are randomized in the initial phase to take their ordinary anti-hypertensive medication in the morning or at bedtime for 8 weeks. Then the participants are switching to the alternative intervention during 8 weeks in the second phase of the study.
Masking
Outcomes Assessor
Masking Description
It is not possible to mask patients, care provider or investigators but the outcome assessors are masked for allocation of patients
Allocation
Randomized
Enrollment
120 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Morning intake
Arm Type
Active Comparator
Arm Description
Intake of antihypertensive medication in the morning
Arm Title
Bedtime intake
Arm Type
Active Comparator
Arm Description
Intake of antihypertensive medication at bedtime
Intervention Type
Other
Intervention Name(s)
Time of ordinary antihypertensive medication intake
Intervention Description
Time of ordinary antihypertensive medication intake
Primary Outcome Measure Information:
Title
24 hours blood pressure changes between 8 and 16 weeks.
Description
Ambulatory blood pressure changes between 8 and 16 weeks. Systolic and diastolic mean blood pressure level.
Time Frame
8 and 16 weeks
Title
Change of dipping of blood pressure between 8 and 16 weeks.
Description
Ratio between daytime and nighttime blood pressure registered after 8 and 16 weeks. Systolic and diastolic mean blood pressure level.
Time Frame
8 and 16 weeks
Secondary Outcome Measure Information:
Title
Daytime blood pressure changes between 8 and 16 weeks.
Description
Ambulatory daytime blood pressure registered after 8 and 16 weeks. Systolic and diastolic mean blood pressure level.
Time Frame
8 and 16 weeks
Title
Nighttime blood pressure changes between 8 and 16 weeks.
Description
Ambulatory nighttime blood pressure registered after 8 and 16 weeks. Systolic and diastolic mean blood pressure level.
Time Frame
8 and 16 weeks
Title
Office blood pressure changes between 8 and 16 weeks.
Description
Office blood pressure registered after 8 and 16 weeks. Systolic and diastolic mean blood pressure level.
Time Frame
8 and 16 weeks
Title
Difference in morning surge of blood pressure between 8 and 16 weeks.
Description
Occurrence of morning (yes/no)
Time Frame
8 and 16 weeks
Title
Difference in LDL cholesterol levels between 8 and 16 weeks.
Description
LDL cholesterol changes according to time of intake of antihypertensive drugs
Time Frame
8 and 16 weeks
Title
Difference in HDL cholesterol levels between 8 and 16 weeks.
Description
HDL cholesterol changes according to time of intake of antihypertensive drugs
Time Frame
8 and 16 weeks
Title
Difference in total cholesterol levels between 8 and 16 weeks.
Description
Total cholesterol changes according to time of intake of antihypertensive drugs
Time Frame
8 and 16 weeks
Title
Difference in p-creatinine levels between 8 and 16 weeks.
Description
P-creatinine changes according to time of intake of antihypertensive drugs
Time Frame
8 and 16 weeks
Other Pre-specified Outcome Measures:
Title
Difference in score of Epworth sleepiness scale between 8 and 16 weeks
Description
Epworth sleepiness scale score registered by the patients according to time of antihypertensive drug intake
Time Frame
8 and 16 weeks
Title
Perceived side effects 8 weeks
Description
Perceived side effects registered by the patients (VAS) according to time of antihypertensive drug intake
Time Frame
8 weeks
Title
Perceived side effects 16 weeks
Description
Perceived side effects registered by the patients (VAS) according to time of antihypertensive drug intake
Time Frame
16 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosis of hypertension
Stable antihypertensive treatment at least 8 weeks prior to inclusion
One to four antihypertensive drugs
Exclusion Criteria:
Atrial fibrillation/flutter
Diabetes
Previous stroke or TIA
Heart failure
Ischemic heart disease
Peripheral artery disease
Malignant disease with less than one year expected survival
Inability to follow study protocol (for instance shift work)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kristina B Boström, Prof, MD
Phone
0702409091
Email
kristina.a.bengtsson@vgregion.se
First Name & Middle Initial & Last Name or Official Title & Degree
Georgios Mourtzinis, PhD, MD
Phone
0735522153
Email
georgios.mourtzinis@vgregion.se
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Karin Manhem, Prof, MD
Organizational Affiliation
Sahlgrenska University Hospital, Sweden
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sahlgrenska University Hospital, Mölndal
City
Gothenburg
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Johan-Emil Bager, PhD, MD
Phone
+46739728299
Email
johan-emil.bager@vgregion.se
Facility Name
Närhälsan Billingen Primary Health Care Centre
City
Skövde
ZIP/Postal Code
541 41
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kristina Bengtsson Boström
Phone
+46702409091
Email
kristina.a.bengtsson@vgregion.se
Facility Name
Närhälsan Norrmalm Primary Health Care Centre
City
Skövde
ZIP/Postal Code
541 41
Country
Sweden
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tobias Andersson
Phone
+46707 143437
Email
tobias.e.andersson@vgregion.se
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
31641769
Citation
Hermida RC, Crespo JJ, Dominguez-Sardina M, Otero A, Moya A, Rios MT, Sineiro E, Castineira MC, Callejas PA, Pousa L, Salgado JL, Duran C, Sanchez JJ, Fernandez JR, Mojon A, Ayala DE; Hygia Project Investigators. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J. 2020 Dec 21;41(48):4565-4576. doi: 10.1093/eurheartj/ehz754.
Results Reference
background
PubMed Identifier
27221952
Citation
Hermida RC. Sleep-time ambulatory blood pressure as a prognostic marker of vascular and other risks and therapeutic target for prevention by hypertension chronotherapy: Rationale and design of the Hygia Project. Chronobiol Int. 2016;33(7):906-36. doi: 10.1080/07420528.2016.1181078. Epub 2016 May 24.
Results Reference
background
PubMed Identifier
29106031
Citation
Fujiwara T, Hoshide S, Yano Y, Kanegae H, Kario K. Comparison of morning vs bedtime administration of the combination of valsartan/amlodipine on nocturnal brachial and central blood pressure in patients with hypertension. J Clin Hypertens (Greenwich). 2017 Dec;19(12):1319-1326. doi: 10.1111/jch.13128. Epub 2017 Nov 5.
Results Reference
background
PubMed Identifier
1798888
Citation
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991 Dec;14(6):540-5. doi: 10.1093/sleep/14.6.540.
Results Reference
background
PubMed Identifier
29872338
Citation
Bilo G, Grillo A, Guida V, Parati G. Morning blood pressure surge: pathophysiology, clinical relevance and therapeutic aspects. Integr Blood Press Control. 2018 May 24;11:47-56. doi: 10.2147/IBPC.S130277. eCollection 2018.
Results Reference
background
PubMed Identifier
30267334
Citation
Bowles NP, Thosar SS, Herzig MX, Shea SA. Chronotherapy for Hypertension. Curr Hypertens Rep. 2018 Sep 28;20(11):97. doi: 10.1007/s11906-018-0897-4. Erratum In: Curr Hypertens Rep. 2018 Dec 4;21(1):1.
Results Reference
background
PubMed Identifier
28980662
Citation
Callaway E, Ledford H. Medicine Nobel awarded for work on circadian clocks. Nature. 2017 Oct 2;550(7674):18. doi: 10.1038/nature.2017.22736. No abstract available.
Results Reference
background
PubMed Identifier
30640882
Citation
2018 Practice Guidelines for the management of arterial hypertension of the European Society of Hypertension and the European Society of Cardiology: ESH/ESC Task Force for the Management of Arterial Hypertension: Erratum. J Hypertens. 2019 Feb;37(2):456. doi: 10.1097/HJH.0000000000002026. No abstract available.
Results Reference
background
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Effect of Chronotherapy on Blood Pressure - Time of Intake of Blood Pressure Lowering Drugs
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