Arteriovenous Fistula
Conditions
Keywords
Arteriovenous Fistula Surgery, Vascular Injury, Hemodialysis Access
Brief summary
A study to evaluate the efficacy of SRM003 treatment versus participating sites' standard practice treatment in improving the rate of AVF maturation and use in subjects with end-stage renal disease undergoing surgery for creation of an AVF to facilitate hemodialysis access. It is hypothesized that when placed outside the blood vessel, the seeded SRM003 gelatin matrix containing endothelial cells can provide a continuous supply of multiple growth regulatory compounds to the underlying cells within the blood vessel, while being protected from the effects of blood flow in the vessel(s) or complications resulting from being in direct contact with the point of injury.
Interventions
BIOLOGICALSRM003
One time implant (2 SRM003 pieces) on surgery day.
Subjects will receive sites' standard practice treatment during the surgical procedure.
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subject must be 18 years of age or older at the time of signing and dating informed consent (no upper age limit), can be male or female. 2. Subject who is of child bearing potential must agree to use adequate contraception for 6 months after randomization. 3. Subject must be currently undergoing hemodialysis or anticipating the start of hemodialysis and must require a new permanent, suitable access for the AVF creation in the upper extremity. 4. Subject must have a life expectancy of at least 26 weeks after randomization. 5. Subject must be able to understand and be willing to complete all study requirements.
Exclusion criteria
1. Subject is currently on an active organ transplant list from a deceased donor or is undergoing assessment and expects to be placed on the active organ or bone marrow transplant list within the next 26 weeks from surgery, or expects to receive a living donor organ or bone marrow within the next 26 weeks and is unwilling to change transplant list status to hold for 3 months after randomization. 2. Subject has had more than 1 access placement surgery (defined as a new access, not a revision) in the target limb. 3. Subject has medical conditions and diseases that may cause non-compliance with the protocol 4. Subject has a known allergy to bovine/porcine products or collagen/gelatin products. 5. Subject has a history of intravenous drug use within 6 months prior to screening 6. Subject is morbidly obese, defined as having a body mass index \>40. 7. Pregnant or nursing woman, or plans to become pregnant during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Arteriovenous Fistula (AVF) Maturation by Week 12 Visit Based on Hemodialysis or Color-flow Doppler Ultrasound (CDUS) And Vascular Access Examination | 12 weeks after surgery | Maturation based on CDUS was assessed in a continuous fashion and was defined by the following criteria: presence of bruit throughout systole and diastole at least 8 centimeters (cm) proximal to the venous anastomosis, blood flow through the outflow vein of at least 500 milliliters (ml) per minute, and a lumen diameter of the outflow vein at least 4 mm. Maturation was determined by CDUS and vascular access examination or by first use of the AVF for hemodialysis based on investigator-reported use. Participants who discontinued prior to the Week 12 visit without assessment of maturity were considered treatment failures. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to AVF Maturation Based on Hemodialysis or CDUS and Vascular Access Examination | Up to 26 weeks after surgery | Time to AVF maturation was defined as the duration of time (in days) from the date of randomization (AVF creation) to the date of maturation, where the date of maturation corresponds to the earlier of either the date of the first use of the study AVF for hemodialysis as determined by the investigator following discussion with the participant, or the date the AVF meets all of the following 3 criteria as determined through CDUS and vascular access examination: presence of bruit throughout systole and diastole at least 8 centimeters proximal to the venous anastomosis, blood flow through the outflow vein of at least 500 milliliters (ml) per minute, and a lumen diameter of the outflow vein at least 4 mm. Participants who died, underwent a kidney transplant, or were either lost to follow-up or did not mature during the study follow-up were censored at the time of death, time of transplant, or time of last visit, respectively. |
| Percentage of Participants With Loss of Unassisted Primary Patency | Up to 26 weeks after surgery | The time to loss of unassisted primary patency (intervention--free access survival) was defined as the duration of time in days from the date of randomization (AVF creation) until the first date of (a) any intervention designed to establish, maintain, or restore patency; (b) occlusion (commonly due to thrombosis); or (c) access abandonment. |
| Percentage of Participants With Loss of Assisted Primary Patency | Up to 26 weeks after surgery | The time to loss of assisted primary patency (thrombosis--free access survival) was defined as the duration of time in days from the date of randomization (AVF creation) until the first date of (a) occlusion (commonly due to thrombosis) or (b) access abandonment. |
| Percentage of Participants With AVF Maturation by Week 26 Visit Based on Hemodialysis or CDUS And Vascular Access Examination | 26 weeks after surgery | Maturation based on CDUS was assessed in a continuous fashion and was defined by the following criteria: presence of bruit throughout systole and diastole at least 8 centimeters (cm) proximal to the venous anastomosis, blood flow through the outflow vein of at least 500 milliliters (ml) per minute, and a lumen diameter of the outflow vein at least 4 mm. Maturation was determined by CDUS and vascular access examination or by first use of the AVF for hemodialysis based on investigator-reported use. Participants who discontinued prior to the Week 26 visit without assessment of maturity were considered treatment failures. |
| Change From Week 1 in Average Vascular Access Lumen Diameter Using CDUS | 1, 12, and 26 weeks after surgery | B-mode lumen diameter measurements were obtained in the outflow vein as 3 separate images for each location: at 1, 3, and 5 centimeter into the vein and from the toe of the venous anastomosis. The average of lumen diameter measurements obtained at 1, 3, and 5 cm from the anastomosis was used for this endpoint. |
| Percentage of Participants With Clinical Success Based on First Use of The Study AVF For Hemodialysis | 12 and 26 weeks after surgery | Clinical success was defined as the ability to undergo hemodialysis using the AVF. The date of clinical success corresponded to the date of the first use of the study AVF for hemodialysis as determined by the investigator, following discussion with the subject. Clinical success was assessed in a continuous fashion and, once achieved, the AVF was considered a clinical success at that and all subsequent time points. The date of clinical success based on the first use of the AVF for hemodialysis was compared with the dates of each study visit (Week 12 and Week 26); for study visits occurring prior to the date of clinical success based on the first use of the AVF for hemodialysis, the subject was counted as a nonsuccess and for study visits occurring on or after the date of maturation based on the first use of the AVF for hemodialysis, the subject was counted as a success. |
| Number of Interventions to Establish, Maintain, or Restore Patency | 12 and 26 weeks after surgery | The total number of interventions to establish, maintain, or restore patency was recorded for each participant. |
| Percentage of Participants With Loss of Secondary Patency | Up to 26 weeks after surgery | The time to loss of secondary patency (access survival until abandonment) was defined as the duration of time in days from the date of randomization (AVF creation) until the date of access abandonment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Participating Site's Standard Practice Participants received the site's standard practice treatment during the surgical procedure. Post-surgery, each participant was to undergo 26 weeks of follow-up for assessment of efficacy and safety. | 29 |
| SRM003 Participants received a one-time implant of 2 SRM003 pieces on surgery day after the completion of the arteriovenous fistula (AVF) creation. One sponge was wrapped around the venous anastomosis site and the other was placed longitudinally on the vein segment, immediately distal to the venous anastomosis. Subjects were not permitted to undergo additional applications with SRM003 sponges after the initial application. Post-surgery, each participant was to undergo 26 weeks of follow-up for assessment of efficacy and safety. | 35 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Participating Site's Standard Practice | SRM003 | Total |
|---|---|---|---|
| Age, Continuous | 65.2 years STANDARD_DEVIATION 13.5 | 61.1 years STANDARD_DEVIATION 10.8 | 63.0 years STANDARD_DEVIATION 12.2 |
| Age, Customized <65 years | 12 Participants | 23 Participants | 35 Participants |
| Age, Customized ≥65 years | 17 Participants | 12 Participants | 29 Participants |
| Sex: Female, Male Female | 11 Participants | 13 Participants | 24 Participants |
| Sex: Female, Male Male | 18 Participants | 22 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 29 | 25 / 35 |
| serious Total, serious adverse events | 16 / 29 | 13 / 35 |
Outcome results
Primary
Percentage of Participants With Arteriovenous Fistula (AVF) Maturation by Week 12 Visit Based on Hemodialysis or Color-flow Doppler Ultrasound (CDUS) And Vascular Access Examination
Maturation based on CDUS was assessed in a continuous fashion and was defined by the following criteria: presence of bruit throughout systole and diastole at least 8 centimeters (cm) proximal to the venous anastomosis, blood flow through the outflow vein of at least 500 milliliters (ml) per minute, and a lumen diameter of the outflow vein at least 4 mm. Maturation was determined by CDUS and vascular access examination or by first use of the AVF for hemodialysis based on investigator-reported use. Participants who discontinued prior to the Week 12 visit without assessment of maturity were considered treatment failures.
Time frame: 12 weeks after surgery
Population: The Intent- to-Treat (ITT) population, defined as all randomly assigned participants regardless of receiving treatments or having post-baseline outcome data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participating Site's Standard Practice | Percentage of Participants With Arteriovenous Fistula (AVF) Maturation by Week 12 Visit Based on Hemodialysis or Color-flow Doppler Ultrasound (CDUS) And Vascular Access Examination | 96.6 percentage of participants |
| SRM003 | Percentage of Participants With Arteriovenous Fistula (AVF) Maturation by Week 12 Visit Based on Hemodialysis or Color-flow Doppler Ultrasound (CDUS) And Vascular Access Examination | 85.7 percentage of participants |
p-value: 0.119795% CI: [-0.242, 0.025]Cochran-Mantel-Haenszel
Secondary
Change From Week 1 in Average Vascular Access Lumen Diameter Using CDUS
B-mode lumen diameter measurements were obtained in the outflow vein as 3 separate images for each location: at 1, 3, and 5 centimeter into the vein and from the toe of the venous anastomosis. The average of lumen diameter measurements obtained at 1, 3, and 5 cm from the anastomosis was used for this endpoint.
Time frame: 1, 12, and 26 weeks after surgery
Population: The ITT population, defined as all randomly assigned participants regardless of receiving treatments or having post-baseline outcome data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participating Site's Standard Practice | Change From Week 1 in Average Vascular Access Lumen Diameter Using CDUS | Week 12, n=21, 28 | 1.897 millimeters | Standard Deviation 1.2587 |
| Participating Site's Standard Practice | Change From Week 1 in Average Vascular Access Lumen Diameter Using CDUS | Week 26, n=20, 25 | 2.489 millimeters | Standard Deviation 1.4525 |
| SRM003 | Change From Week 1 in Average Vascular Access Lumen Diameter Using CDUS | Week 12, n=21, 28 | 1.253 millimeters | Standard Deviation 1.9908 |
| SRM003 | Change From Week 1 in Average Vascular Access Lumen Diameter Using CDUS | Week 26, n=20, 25 | 2.416 millimeters | Standard Deviation 2.3941 |
Comparison: Treatment difference at week 1295% CI: [-2.213, 0.423]
Comparison: Treatment difference at week 2695% CI: [-1.791, 1.327]
Secondary
Number of Interventions to Establish, Maintain, or Restore Patency
The total number of interventions to establish, maintain, or restore patency was recorded for each participant.
Time frame: 12 and 26 weeks after surgery
Population: The ITT population, defined as all randomly assigned participants regardless of receiving treatments or having post-baseline outcome data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participating Site's Standard Practice | Number of Interventions to Establish, Maintain, or Restore Patency | Week 26 | 0.2 interventions | Standard Deviation 0.49 |
| Participating Site's Standard Practice | Number of Interventions to Establish, Maintain, or Restore Patency | Week 12 | 0.1 interventions | Standard Deviation 0.31 |
| SRM003 | Number of Interventions to Establish, Maintain, or Restore Patency | Week 26 | 0.8 interventions | Standard Deviation 1.52 |
| SRM003 | Number of Interventions to Establish, Maintain, or Restore Patency | Week 12 | 0.3 interventions | Standard Deviation 0.61 |
Comparison: Analysis of week 1295% CI: [-0.096, 0.404]
Comparison: Analysis of week 2695% CI: [-0.023, 1.152]
Secondary
Percentage of Participants With AVF Maturation by Week 26 Visit Based on Hemodialysis or CDUS And Vascular Access Examination
Maturation based on CDUS was assessed in a continuous fashion and was defined by the following criteria: presence of bruit throughout systole and diastole at least 8 centimeters (cm) proximal to the venous anastomosis, blood flow through the outflow vein of at least 500 milliliters (ml) per minute, and a lumen diameter of the outflow vein at least 4 mm. Maturation was determined by CDUS and vascular access examination or by first use of the AVF for hemodialysis based on investigator-reported use. Participants who discontinued prior to the Week 26 visit without assessment of maturity were considered treatment failures.
Time frame: 26 weeks after surgery
Population: The ITT population, defined as all randomly assigned participants regardless of receiving treatments or having post-baseline outcome data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participating Site's Standard Practice | Percentage of Participants With AVF Maturation by Week 26 Visit Based on Hemodialysis or CDUS And Vascular Access Examination | 96.6 percentage of participants |
| SRM003 | Percentage of Participants With AVF Maturation by Week 26 Visit Based on Hemodialysis or CDUS And Vascular Access Examination | 88.6 percentage of participants |
p-value: 0.196295% CI: [-0.204, 0.045]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Clinical Success Based on First Use of The Study AVF For Hemodialysis
Clinical success was defined as the ability to undergo hemodialysis using the AVF. The date of clinical success corresponded to the date of the first use of the study AVF for hemodialysis as determined by the investigator, following discussion with the subject. Clinical success was assessed in a continuous fashion and, once achieved, the AVF was considered a clinical success at that and all subsequent time points. The date of clinical success based on the first use of the AVF for hemodialysis was compared with the dates of each study visit (Week 12 and Week 26); for study visits occurring prior to the date of clinical success based on the first use of the AVF for hemodialysis, the subject was counted as a nonsuccess and for study visits occurring on or after the date of maturation based on the first use of the AVF for hemodialysis, the subject was counted as a success.
Time frame: 12 and 26 weeks after surgery
Population: The ITT population, defined as all randomly assigned participants regardless of receiving treatments or having post-baseline outcome data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Participating Site's Standard Practice | Percentage of Participants With Clinical Success Based on First Use of The Study AVF For Hemodialysis | Week 12 | 37.9 percentage of participants |
| Participating Site's Standard Practice | Percentage of Participants With Clinical Success Based on First Use of The Study AVF For Hemodialysis | Week 26 | 55.2 percentage of participants |
| SRM003 | Percentage of Participants With Clinical Success Based on First Use of The Study AVF For Hemodialysis | Week 12 | 34.3 percentage of participants |
| SRM003 | Percentage of Participants With Clinical Success Based on First Use of The Study AVF For Hemodialysis | Week 26 | 62.9 percentage of participants |
Comparison: Analysis of week 1295% CI: [-0.273, 0.2]
Comparison: Analysis of week 2695% CI: [-0.165, 0.318]
Secondary
Percentage of Participants With Loss of Assisted Primary Patency
The time to loss of assisted primary patency (thrombosis--free access survival) was defined as the duration of time in days from the date of randomization (AVF creation) until the first date of (a) occlusion (commonly due to thrombosis) or (b) access abandonment.
Time frame: Up to 26 weeks after surgery
Population: The ITT population, defined as all randomly assigned participants regardless of receiving treatments or having post-baseline outcome data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participating Site's Standard Practice | Percentage of Participants With Loss of Assisted Primary Patency | 6.9 percentage of participants |
| SRM003 | Percentage of Participants With Loss of Assisted Primary Patency | 17.1 percentage of participants |
Comparison: Analysis of time to loss of patencyp-value: 0.231Log Rank
Secondary
Percentage of Participants With Loss of Secondary Patency
The time to loss of secondary patency (access survival until abandonment) was defined as the duration of time in days from the date of randomization (AVF creation) until the date of access abandonment.
Time frame: Up to 26 weeks after surgery
Population: The ITT population, defined as all randomly assigned participants regardless of receiving treatments or having post-baseline outcome data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participating Site's Standard Practice | Percentage of Participants With Loss of Secondary Patency | 3.4 percentage of participants |
| SRM003 | Percentage of Participants With Loss of Secondary Patency | 14.3 percentage of participants |
Comparison: Analysis of time to loss of patencyp-value: 0.158Log Rank
Secondary
Percentage of Participants With Loss of Unassisted Primary Patency
The time to loss of unassisted primary patency (intervention--free access survival) was defined as the duration of time in days from the date of randomization (AVF creation) until the first date of (a) any intervention designed to establish, maintain, or restore patency; (b) occlusion (commonly due to thrombosis); or (c) access abandonment.
Time frame: Up to 26 weeks after surgery
Population: The ITT population, defined as all randomly assigned participants regardless of receiving treatments or having post-baseline outcome data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participating Site's Standard Practice | Percentage of Participants With Loss of Unassisted Primary Patency | 20.7 percentage of participants |
| SRM003 | Percentage of Participants With Loss of Unassisted Primary Patency | 37.1 percentage of participants |
Comparison: Analysis of time to loss of patencyp-value: 0.193Log Rank
Secondary
Time to AVF Maturation Based on Hemodialysis or CDUS and Vascular Access Examination
Time to AVF maturation was defined as the duration of time (in days) from the date of randomization (AVF creation) to the date of maturation, where the date of maturation corresponds to the earlier of either the date of the first use of the study AVF for hemodialysis as determined by the investigator following discussion with the participant, or the date the AVF meets all of the following 3 criteria as determined through CDUS and vascular access examination: presence of bruit throughout systole and diastole at least 8 centimeters proximal to the venous anastomosis, blood flow through the outflow vein of at least 500 milliliters (ml) per minute, and a lumen diameter of the outflow vein at least 4 mm. Participants who died, underwent a kidney transplant, or were either lost to follow-up or did not mature during the study follow-up were censored at the time of death, time of transplant, or time of last visit, respectively.
Time frame: Up to 26 weeks after surgery
Population: The ITT population, defined as all randomly assigned participants regardless of receiving treatments or having post-baseline outcome data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Participating Site's Standard Practice | Time to AVF Maturation Based on Hemodialysis or CDUS and Vascular Access Examination | 9 days |
| SRM003 | Time to AVF Maturation Based on Hemodialysis or CDUS and Vascular Access Examination | 10 days |
p-value: 0.09Log Rank