End Stage Renal Disease
Conditions
Brief summary
This project will examine if enhancing Nitric Oxide (NO) bioavailability increases the rates of arteriovenous fistula (AVF) maturation in end stage renal disease patients requiring vascular access for hemodialysis. To enhance NO bioavailability the study team will utilize a program of forearm exercise training, application of nitroglycerin ointment or both. Goals of this study are (A) to measure if recruited subjects can tolerate the intervention protocols, and determine if dependent variable measures, including surgery outcome, and measurement of physiologic and biologic markers, can be obtained; (B) To measure subject compliance and adherence rates for each of the intervention arms and testing visits; (C) To examine which intervention or combination of interventions demonstrates the strongest preliminary effects in order to estimate power for a pivotal intent to treat trial; and (D) explore group differences in clinical vascular markers and biologic markers in vein tissue.
Detailed description
This project will examine if enhancing Nitric Oxide (NO) bioavailability increases the rates of arteriovenous fistula (AVF) maturation in end stage renal disease patients requiring vascular access for hemodialysis. To enhance NO bioavailability the study team will utilize a program of forearm exercise training, application of nitroglycerin ointment or both. Following entry into the study, approximately 4 weeks prior to surgery subjects will undergo a series of non-invasive tests of vascular function in the arm of fistula creation. Following this vascular function testing, subjects will follow the intervention treatment for 4 weeks. After 4 weeks of intervention treatment and prior to surgery, the vascular function analysis will be repeated to determine if the interventions had an effect on arm vascular function. Surgery to create the AVF will follow the second vascular function analysis. A discard sample of the vein used to create the AVF and a blood sample will be collected during surgery to assess potential biologic differences between intervention groups. The interventions will be continued until 4 weeks following surgery. Subjects will be followed to determine if the AVF matured and was successfully used for dialysis.
Interventions
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Life expectancy of at least 6 months 2. Chronic kidney disease with anticipated start of hemodialysis within six months or current hemodialysis dependence. 3. Ability to understand and comply with the requirements of the entire study and communicate with the study team. 4. Written informed consent using a document that has been approved by the Duke Human Institutional Review Board. 5. If female and of childbearing potential (premenopausal and not surgically sterile) must have a negative pregnancy test and be willing to use contraception until completion of 8 weeks of intervention. This will include abstinence, barrier methods, hormones, or intra-uterine device.
Exclusion criteria
1. Patients currently on medication that is contraindicated with nitropaste, including isosorbide nitrate therapy, nitroglycerin, minoxidil, or PDE inhibitors (i.e. Sildenafil). 2. Patients with a diastolic blood pressure below 65 or a systolic blood pressure below 90. 3. Patients with a history of illicit drug use in the previous 5 years. 4. Patients who would require AVF placement before completion of the initial 4 weeks of intervention therapy 5. Patients who are otherwise are not suitable for 8 weeks of handgrip training or nitropaste therapy. 6. Patients under the 18 of age are not eligible for nitropaste interventions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Count of Participants With Mature Arteriovenous Fistula (AVF) | 3 month post surgery to create AVF | Use of AVF for dialysis for dialysis dependent participants, or fistula deemed mature based on physical exam in predialysis participants (diameter \>6 mm, blood flow \>600 ml by ultrasound or estimated by physical exam). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Count of Participants With a Patent Fistula | 3 months post surgery | Determination that AVF is patent (has blood flow, no occlusion). |
| Count of Participants Using Their AVF for Dialysis | 12 months post surgery | Successful use of AVF at 12 months in dialysis dependent patients. Not relevant in participants that are predialysis or that discontinue dialysis prior to AVF use. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Control Group Standard of care | 4 |
| Handgrip Training Group Perform isometric handgrip exercises for 15 minutes twice per day for a total of 30 minutes
Handgrip training | 3 |
| Nitroglycerin Ointment Group Apply 15mg of nitroglycerin ointment to the back of the hand of the surgical arm nightly
Nitroglycerin ointment | 1 |
| Combined Handgrip Training /Nitroglycerin Ointment Group Perform isometric handgrip exercises for 15 minutes twice each day for a total of 30 minutes and apply 15mg of nitroglycerin ointment to the back of the hand of the surgical arm nightly
Handgrip training
Nitroglycerin ointment | 3 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Control Group | Handgrip Training Group | Nitroglycerin Ointment Group | Combined Handgrip Training /Nitroglycerin Ointment Group | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 8 Participants |
| Age, Continuous | 61.8 years STANDARD_DEVIATION 13.9 | 51.0 years STANDARD_DEVIATION 28 | 41 years STANDARD_DEVIATION 0 | 53.7 years STANDARD_DEVIATION 10.1 | 54.7 years STANDARD_DEVIATION 16.7 |
| Body Mass Index | 33.1 kg/m^2 STANDARD_DEVIATION 14.7 | 27.6 kg/m^2 STANDARD_DEVIATION 5.8 | 33.1 kg/m^2 STANDARD_DEVIATION 0 | 27.2 kg/m^2 STANDARD_DEVIATION 8 | 30.0 kg/m^2 STANDARD_DEVIATION 9.7 |
| Coronary Artery Disease (CAD) Status CAD: No | 4 Participants | 2 Participants | 1 Participants | 2 Participants | 9 Participants |
| Coronary Artery Disease (CAD) Status CAD: Yes | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Diabetes Mellitus (DM) Status DM: No | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 6 Participants |
| Diabetes Mellitus (DM) Status DM: Yes | 2 Participants | 2 Participants | 0 Participants | 1 Participants | 5 Participants |
| Dialysis Status | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| History of thrombotic disorder (TD) TD: No | 4 Participants | 2 Participants | 1 Participants | 1 Participants | 8 Participants |
| History of thrombotic disorder (TD) TD: Yes | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Hyperlipidemia Status Hyperlipidemia: No | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 5 Participants |
| Hyperlipidemia Status Hyperlipidemia: Yes | 2 Participants | 2 Participants | 0 Participants | 2 Participants | 6 Participants |
| Hypertension Status Hypertension: No | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Hypertension Status Hypertension: Yes | 4 Participants | 3 Participants | 1 Participants | 3 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 3 Participants | 1 Participants | 2 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 4 participants | 3 participants | 1 participants | 3 participants | 11 participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 1 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 2 / 3 | 1 / 1 | 2 / 3 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 | 0 / 1 | 2 / 3 |
Outcome results
Primary
Count of Participants With Mature Arteriovenous Fistula (AVF)
Use of AVF for dialysis for dialysis dependent participants, or fistula deemed mature based on physical exam in predialysis participants (diameter \>6 mm, blood flow \>600 ml by ultrasound or estimated by physical exam).
Time frame: 3 month post surgery to create AVF
Population: Two subjects withdrew from this study prior to their AVF surgery, therefore they were not included in the analysis population.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Control Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Mature AVF: Predialysis | 2 Participants |
| Control Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Mature AVF: dialysis dependent | 0 Participants |
| Control Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Not Mature AVF: predialysis | 0 Participants |
| Control Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Not Mature AVF: dialysis dependent | 2 Participants |
| Handgrip Training Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Mature AVF: dialysis dependent | 0 Participants |
| Handgrip Training Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Not Mature AVF: predialysis | 1 Participants |
| Handgrip Training Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Not Mature AVF: dialysis dependent | 1 Participants |
| Handgrip Training Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Mature AVF: Predialysis | 0 Participants |
| Nitroglycerin Ointment Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Not Mature AVF: predialysis | 0 Participants |
| Nitroglycerin Ointment Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Mature AVF: dialysis dependent | 0 Participants |
| Nitroglycerin Ointment Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Not Mature AVF: dialysis dependent | 0 Participants |
| Nitroglycerin Ointment Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Mature AVF: Predialysis | 1 Participants |
| Combined Handgrip Training /Nitroglycerin Ointment Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Not Mature AVF: dialysis dependent | 0 Participants |
| Combined Handgrip Training /Nitroglycerin Ointment Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Mature AVF: dialysis dependent | 1 Participants |
| Combined Handgrip Training /Nitroglycerin Ointment Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Mature AVF: Predialysis | 0 Participants |
| Combined Handgrip Training /Nitroglycerin Ointment Group | Count of Participants With Mature Arteriovenous Fistula (AVF) | Not Mature AVF: predialysis | 1 Participants |
Secondary
Count of Participants Using Their AVF for Dialysis
Successful use of AVF at 12 months in dialysis dependent patients. Not relevant in participants that are predialysis or that discontinue dialysis prior to AVF use.
Time frame: 12 months post surgery
Population: Only subjects who were on dialysis at 12 months are included in the analysis. Only 5 participants were on dialysis at this time.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Control Group | Count of Participants Using Their AVF for Dialysis | AVF used for dialysis: Yes | 2 Participants |
| Control Group | Count of Participants Using Their AVF for Dialysis | AVF used for dialysis: No | 0 Participants |
| Handgrip Training Group | Count of Participants Using Their AVF for Dialysis | AVF used for dialysis: No | 0 Participants |
| Handgrip Training Group | Count of Participants Using Their AVF for Dialysis | AVF used for dialysis: Yes | 2 Participants |
| Nitroglycerin Ointment Group | Count of Participants Using Their AVF for Dialysis | AVF used for dialysis: Yes | 0 Participants |
| Nitroglycerin Ointment Group | Count of Participants Using Their AVF for Dialysis | AVF used for dialysis: No | 0 Participants |
| Combined Handgrip Training /Nitroglycerin Ointment Group | Count of Participants Using Their AVF for Dialysis | AVF used for dialysis: Yes | 1 Participants |
| Combined Handgrip Training /Nitroglycerin Ointment Group | Count of Participants Using Their AVF for Dialysis | AVF used for dialysis: No | 0 Participants |
Secondary
Count of Participants With a Patent Fistula
Determination that AVF is patent (has blood flow, no occlusion).
Time frame: 3 months post surgery
Population: Two subjects withdrew from this study prior to their AVF surgery, therefore they were not included in the analysis population.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Control Group | Count of Participants With a Patent Fistula | AVF Patent: No | 0 Participants |
| Control Group | Count of Participants With a Patent Fistula | AVF Patent: Yes | 4 Participants |
| Handgrip Training Group | Count of Participants With a Patent Fistula | AVF Patent: No | 0 Participants |
| Handgrip Training Group | Count of Participants With a Patent Fistula | AVF Patent: Yes | 2 Participants |
| Nitroglycerin Ointment Group | Count of Participants With a Patent Fistula | AVF Patent: Yes | 1 Participants |
| Nitroglycerin Ointment Group | Count of Participants With a Patent Fistula | AVF Patent: No | 0 Participants |
| Combined Handgrip Training /Nitroglycerin Ointment Group | Count of Participants With a Patent Fistula | AVF Patent: No | 0 Participants |
| Combined Handgrip Training /Nitroglycerin Ointment Group | Count of Participants With a Patent Fistula | AVF Patent: Yes | 2 Participants |