PREVENTKD (Prevent Risks by Early interVEntion at Nighttime in Type 1 Diabetes for Kidney Disease)

• Sponsor: Northwestern University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00729365
• Collaborator: Juvenile Diabetes Research Foundation (Other), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 65
• Locations: 6
• Arms: 3
• Duration (Months): 23
• Patients Per Site: 10.8
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if the early treatment with a blood pressure medication (an ACE Inhibitor) can prevent or delay the development of kidney disease (microalbuminuria) in patients with Type 1 diabetes who have normal blood pressure and urine albumin levels.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes	Drug: Ramipril; Drug: Placebo; Drug: Placebo	Phase 3

Detailed Description

Only a fraction of persons with Type 1 diabetes (less than 40%) develop diabetic kidney disease (nephropathy). When the urinary albumin (a protein normally excreted in small amounts) is within the normal range, the prevalence of high blood pressure (hypertension) based on office blood pressure readings is very low. Many of these persons, however, develop nocturnal hypertension (high nighttime blood pressure) before the development of abnormally high urinary albumin excretion (a condition referred to as microalbuminuria). Currently, early treatment with medications called ACE inhibitors is only recommended after there is an indication of kidney damage, as reflected by the presence of microalbuminuria. Beginning ACE inhibitor therapy is currently not recommended prior to the development of microalbuminuria, unless patients have high blood pressure, because it would result in over-treatment of many people. By the time that microalbuminuria develops, however, kidney damage may be present and many patients will develop kidney disease. It would therefore be beneficial to identify those subjects who will develop microalbuminuria, so that treatment could be started early for those individuals. Persons who may go on to develop protein in their urine and eventual kidney disease perhaps could be identified on the basis of an abnormal fall (too little) in blood pressure at night. This pattern should not be confused with high blood pressure, but instead seen as an early indication present before the development of high blood pressure and microalbuminuria.

The purpose of the current study is therefore aimed at demonstrating that it is possible to prevent kidney disease in patients with type 1 diabetes and normal office blood pressure and urine protein excretion by selecting them on the basis of an abnormal fall in blood pressure at night. Moreover, this clinical trial will reveal the impact of long-term administration of an ACE inhibitor on nighttime blood pressure and also assess changes in the relative stiffness of blood vessels(endothelial dysfunction) in persons with type 1 diabetes over time.

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Nocturnal Hypertension and Prevention of Microalbuminuria in Type 1 Diabetes
• Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Dippers - Placebo Treated Subjects with normal nighttime blood pressure profile that decreases at night (Dippers). This group are all given placebo.	Drug: Placebo; Dippers (category of subjects with a nighttime dip in blood pressure) will all be given Placebo. Control group.
Placebo Comparator: NonDippers - Placebo Treated Subjects with nighttime blood pressure that does not drop during the night (non-dippers). This group will be given placebo.	Drug: Placebo; Subjects with nighttime blood pressure that does not drop during the night ("non-dippers") maybe randomized into the control group and given Placebo.
Active Comparator: NonDippers - Ramipril Treated Subjects with nighttime blood pressure that does not drop during the night (non-dippers). This group will be given ACE inhibitor (study medication).	Drug: Ramipril; ACE inhibitor known as Ramipril Subjects with nighttime blood pressure that does not drop during the night ("non-dippers") maybe randomized into this group and given an ACE inhibitor (study medication). Therefore, the "Non-Dippers" groups II and III will be randomized to receive either drug or placebo.; Other Names: ACE Inhibitor

Outcome Measures

Primary Outcome Measures

1. Development of Microalbuminuria (High Urine Albumin). Hypertension, Urine and Blood Markers Will Also be Evaluated for Assessment of Kidney Disease State. [at 3months and then every 6months during the 5years of the study]

Secondary Outcome Measures

1. We Will Assess Changes in the Relative Stiffness of Your Arteries (Endothelial Dysfunction) in Persons With Type 1 Diabetes Over the 5year Study. [year 1, 3, 5 and after the washout phase (5years and 1month)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects with type 1 diabetes confirmed by C peptide measurements.

• Male and Female subjects of all races will be included in this study.

• Subjects age must be between 13 to 50 years

• Duration of the disease (from time of diagnosis of diabetes) must be between 5 to 28 years.

• Subjects must be normotensive defined as a systolic blood pressure of ≤ 130 mmHg and diastolic of ≤ 85 mmHg in subjects 18 and older and for children (ages 13-17) blood pressure will be in the normal range based on standard tables which takes in to account gender, height and age.

• The mean 24 blood pressure must meet the same criteria as the office blood pressures outlined above.

• Subject must have normoalbuminuria (UAE < 30 mg/24 hrs)

• If subject is a female she must not be breast-feeding, and not of child-bearing potential, defined as post-menopausal for at least 1 year or surgically sterile; if she is of child bearing potential, then she must be practicing one of the following methods of birth control: 1) condoms, sponge, foams, jellies, diaphragm or intrauterine device (IUD), 2) contraceptives (oral or parenteral) initiated three months prior to study drug administration, 3) maintain a monogamous relationship with a vasectomized partner, or 4) total abstinence from sexual intercourse.

Exclusion Criteria:

• Type 2 diabetics and other types of diabetics such as those with maturity onset diabetes or the young (MODY) will be excluded on the basis of established clinical criteria.

• Subjects who have a history of hypertension or is taking any hypertensive medications.

• Females who are pregnant or express a desire to become pregnant during the study. Females who are breast-feeding. Refer to details in inclusion criteria above regarding females.

• Subjects who have a history of taking ACE inhibitors within the last six months or have a current indication for ACE inhibitor therapy.

• Subjects (18 years of age and over) with a current blood pressure above 130mmHg/85mmHg. Subjects (13-17 years of age) who do not meet the normal range based on the standard tables

• Subjects who are currently microalbuminuric i.e. 24hr albumin > 30mg

• Subjects who have participated in an interventional clinical trial involving ABPM 6 months prior to this study.

• Subjects that have a diagnosis of chronic atrial fibrillation.

• Subjects with a lifestyle that would disrupt normal circadian rhythm (i.e. night-shift workers).

• Subjects with a current serious co-morbid condition for which life expectancy is <2 years.

• Subjects with a history of non-compliance, or psychiatric disturbance that would preclude successful completion of the study.

• Inability to give informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Gainesville	Florida	United States	32611
2	Northwestern University Feinberg School of Medicine	Chicago	Illinois	United States	60611
3	Rush University Medical Center, Endocrinology Section	Chicago	Illinois	United States	60612
4	University of Illinois at Chicago	Chicago	Illinois	United States	60612
5	University of Chicago	Chicago	Illinois	United States	60637
6	Loyola University Chicago	Maywood	Illinois	United States	60153

Sponsors and Collaborators

• Northwestern University
• Juvenile Diabetes Research Foundation
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Mark E Molitch, MD, Professor of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

• Dolan E, Stanton A, Thijs L, Hinedi K, Atkins N, McClory S, Den Hond E, McCormack P, Staessen JA, O'Brien E. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension. 2005 Jul;46(1):156-61. Epub 2005 Jun 6.
• Haller MJ, Stein J, Shuster J, Theriaque D, Silverstein J, Schatz DA, Earing MG, Lerman A, Mahmud FH. Peripheral artery tonometry demonstrates altered endothelial function in children with type 1 diabetes. Pediatr Diabetes. 2007 Aug;8(4):193-8.
• Lurbe A, Redón J, Pascual JM, Tacons J, Alvarez V, Batlle DC. Altered blood pressure during sleep in normotensive subjects with type I diabetes. Hypertension. 1993 Feb;21(2):227-35.
• Lurbe E, Redon J, Kesani A, Pascual JM, Tacons J, Alvarez V, Batlle D. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med. 2002 Sep 12;347(11):797-805.

• Responsible Party: Mark Molitch, Professor of Medicine, Northwestern University
• ClinicalTrials.gov Identifier: NCT00729365
• Other Study ID Numbers: 1U01DK071733-01A1; 1U01DK071733-01A1
• First Posted: Aug 7, 2008
• Last Update Posted: Mar 17, 2015
• Last Verified: Feb 1, 2015

• Keywords provided by Mark Molitch, Professor of Medicine, Northwestern University: Urine albumin excretion rates; Nighttime and daytime blood pressure; Endothelial Dysfunction
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Ramipril; Angiotensin-Converting Enzyme Inhibitors

Study Results

Participant Flow

Arm/Group Title	Dippers - Placebo Group	Non-dippers - Placebo	Non-Dippers - Ramipril
Arm/Group Description	Subjects with normal nighttime blood pressure profile that decreases at night (Dippers). This group are all given placebo. Placebo: Dippers (category of subjects with a nighttime dip in blood pressure) will all be given Placebo. Control group.	Subjects with nighttime blood pressure that does not drop during the night (non-dippers). This group will be given placebo. Placebo: Subjects with nighttime blood pressure that does not drop during the night ("non-dippers") maybe randomized into the control group and given Placebo.	Subjects with nighttime blood pressure that does not drop during the night (non-dippers). This group will be given ACE inhibitor (study medication). Ramipril: ACE inhibitor known as Ramipril Subjects with nighttime blood pressure that does not drop during the night ("non-dippers") maybe randomized into this group and given an ACE inhibitor (study medication). Therefore, the "Non-Dippers" groups II and III will be randomized to receive either drug or placebo.
Period Title: Overall Study
STARTED	33	6	7
COMPLETED	0	0	0
NOT COMPLETED	33	6	7

Baseline Characteristics

Arm/Group Title	Dippers - Placebo	Non-Dippers - Placebo	Non-Dippers - Ramipril	Total
Arm/Group Description	Subjects with normal nighttime blood pressure profile that decreases at night (Dippers). This group are all given placebo. Placebo: Dippers (category of subjects with a nighttime dip in blood pressure) will all be given Placebo. Control group.	Subjects with nighttime blood pressure that does not drop during the night (non-dippers). This group will be given placebo. Placebo: Subjects with nighttime blood pressure that does not drop during the night ("non-dippers") maybe randomized into the control group and given Placebo.	Subjects with nighttime blood pressure that does not drop during the night (non-dippers). This group will be given ACE inhibitor (study medication). Ramipril: ACE inhibitor known as Ramipril Subjects with nighttime blood pressure that does not drop during the night ("non-dippers") maybe randomized into this group and given an ACE inhibitor (study medication). Therefore, the "Non-Dippers" groups II and III will be randomized to receive either drug or placebo.	Total of all reporting groups
Overall Participants	33	6	7	46
Age (Count of Participants)
<=18 years	1 3%	1 16.7%	0 0%	2 4.3%
Between 18 and 65 years	32 97%	5 83.3%	7 100%	44 95.7%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	30.0	27.5	30.0	29.5
Sex: Female, Male (Count of Participants)
Female	22 66.7%	6 100%	4 57.1%	32 69.6%
Male	11 33.3%	0 0%	3 42.9%	14 30.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	33 100%	6 100%	7 100%	46 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	3 9.1%	1 16.7%	0 0%	4 8.7%
White	28 84.8%	5 83.3%	7 100%	40 87%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	2 6.1%	0 0%	0 0%	2 4.3%
Region of Enrollment (participants) [Number]
United States	33 100%	6 100%	7 100%	46 100%

Outcome Measures

1. Primary Outcome

Title	Development of Microalbuminuria (High Urine Albumin). Hypertension, Urine and Blood Markers Will Also be Evaluated for Assessment of Kidney Disease State.
Time Frame	at 3months and then every 6months during the 5years of the study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dippers - Placebo Group	Non-dippers - Placebo	Non-Dippers - Ramipril
Arm/Group Description	Subjects with normal nighttime blood pressure profile that decreases at night (Dippers). This group are all given placebo. Placebo: Dippers (category of subjects with a nighttime dip in blood pressure) will all be given Placebo. Control group.	Subjects with nighttime blood pressure that does not drop during the night (non-dippers). This group will be given placebo. Placebo: Subjects with nighttime blood pressure that does not drop during the night ("non-dippers") maybe randomized into the control group and given Placebo.	Subjects with nighttime blood pressure that does not drop during the night (non-dippers). This group will be given ACE inhibitor (study medication). Ramipril: ACE inhibitor known as Ramipril Subjects with nighttime blood pressure that does not drop during the night ("non-dippers") maybe randomized into this group and given an ACE inhibitor (study medication). Therefore, the "Non-Dippers" groups II and III will be randomized to receive either drug or placebo.
Measure Participants	0	0	0

2. Secondary Outcome

Title	We Will Assess Changes in the Relative Stiffness of Your Arteries (Endothelial Dysfunction) in Persons With Type 1 Diabetes Over the 5year Study.
Time Frame	year 1, 3, 5 and after the washout phase (5years and 1month)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dippers - Placebo	Non-Dippers - Placebo	Non-Dippers - Ramipril
Arm/Group Description	Subjects with normal nighttime blood pressure profile that decreases at night (Dippers). This group are all given placebo. Placebo: Dippers (category of subjects with a nighttime dip in blood pressure) will all be given Placebo. Control group.	Subjects with nighttime blood pressure that does not drop during the night (non-dippers). This group will be given placebo. Placebo: Subjects with nighttime blood pressure that does not drop during the night ("non-dippers") maybe randomized into the control group and given Placebo.	Subjects with nighttime blood pressure that does not drop during the night (non-dippers). This group will be given ACE inhibitor (study medication). Ramipril: ACE inhibitor known as Ramipril Subjects with nighttime blood pressure that does not drop during the night ("non-dippers") maybe randomized into this group and given an ACE inhibitor (study medication). Therefore, the "Non-Dippers" groups II and III will be randomized to receive either drug or placebo.
Measure Participants	0	0	0

Adverse Events

Time Frame	1 year
Arm/Group Title	Dippers - Placebo		Non-Dippers - Placebo		Non-Dippers - Ramipril
Arm/Group Description	Subjects with normal nighttime blood pressure profile that decreases at night (Dippers). This group are all given placebo. Placebo: Dippers (category of subjects with a nighttime dip in blood pressure) will all be given Placebo. Control group.		Subjects with nighttime blood pressure that does not drop during the night (non-dippers). This group will be given placebo. Placebo: Subjects with nighttime blood pressure that does not drop during the night ("non-dippers") maybe randomized into the control group and given Placebo.		Subjects with nighttime blood pressure that does not drop during the night (non-dippers). This group will be given ACE inhibitor (study medication). Ramipril: ACE inhibitor known as Ramipril Subjects with nighttime blood pressure that does not drop during the night ("non-dippers") maybe randomized into this group and given an ACE inhibitor (study medication). Therefore, the "Non-Dippers" groups II and III will be randomized to receive either drug or placebo.
All Cause Mortality
	Dippers - Placebo		Non-Dippers - Placebo		Non-Dippers - Ramipril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dippers - Placebo		Non-Dippers - Placebo		Non-Dippers - Ramipril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Dippers - Placebo		Non-Dippers - Placebo		Non-Dippers - Ramipril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

The study was terminated prematurely because of new information from the literature from other studies showing that this study could not be successful. Only 59 patients were screened and consented and 46 were found acceptable who were randomized.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.