Efficacy and Local Tolerability of Topically Applied Heparin on the Suitability of Newly Constructed Primary Arteriovenous Fistulas in Patients Planned for Haemodialysis

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the effect of topically applied heparin in comparison to placebo on suitability of newly constructed primary arteriovenous fistulas in patients planned for haemodialysis at 7th week (± 1 week) after first study drug administration.

Detailed Description
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The clinical dilemma surrounding the maturation and suitability of the AVF in patients undergoing hemodialysis suggests the requirement for a medication that can be added to the standard therapy with in order to help maturation and suitability of newly created AVF. Numerous research papers published over the past 25 years indicate that heparin might have a positive impact on main factors involved in the early failure of native AVF to mature. In total 56 eligible patients will be enrolled after giving informed consent. Screening will take place in the preceding 6 weeks before scheduled AVF creation. Only patients receiving a Brescia - Cimino (radio - cephalic) fistula or a distal ulnar artery to basilica vein, proximal radial artery to transposed basilica vein, brachial artery to transposed basilica vein and brachial artery to cephalic vein will later be randomized. Patients will be randomly assigned in equal proportions (each group 28 patients) to receive either topically applied heparin (Heparin 2,400 IU /ml Cutaneous Spray) or placebo using a computer-generated randomization. Participants and members of the study team will be blinded to treatment assignment. Patients will be instructed how to use and administer study medication for the consecutive 24 weeks following randomization. Assessment of the primary endpoint (suitability of newly constructed primary arteriovenous fistulas) is done at 7th week (± 1 week) after first study drug administration. The suitability and unassisted patency and local safety and tolerability by physician and patient of the AVF will also be determined at 12 weeks (± 1 week) and 24 weeks (± 1 week) after first study drug administration. Administration of study medication will be stopped at week 24 after randomization.

Official Title
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Efficacy and Local Tolerability of Topically Applied Heparin (Heparin 2,400 IU /ml Cutaneous Spray) on the Suitability of Newly Constructed Primary Arteriovenous Fistulas in Patients Planned for Haemodialysis. A Multicentre, Randomized, Double-blind and Placebo-controlled Pilot Study

Conditions
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Haemodialysis

Intervention / Treatment
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* Drug: Heparin 2,400 IU /ml Cutaneous Spray
* Drug: Placebo Cutaneous Spray


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and/or female outpatients Aged over 18 years Stage 4 or 5 Chronic kidney Disease according to KDOQI classification Surgery to create an arteriovenous fistula in the lower arm is planned If female of childbearing potential: agree to maintain reliable birth control throughout the study and negative (urine) pregnancy test Exclusion Criteria: Known hypersensitivity to any component of the study medication History of previous arm (side of planned AVF), neck, or chest surgery/trauma Anticipated kidney transplant from living donor within the next 3 months Presence of any comorbidity that limits patient's life expectancy to less than 6 months. Pregnancy / lactation or intention to fall pregnant during the time course of the study and women of childbearing potential who are not using adequate contraception Known bleeding disorder or established diagnosis of active or suspected bleeding Platelet count less than 80 x 10^9/L Uncontrolled hypertension: Diastolic blood pressure > 115 mm Hg or Systolic blood pressure > 200 mm Hg

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Heparin 2,400 IU /ml Cutaneous Spray<br>Patients are randomized to receive the active comparator heparin 2,400 IU/ml cutaneous spray for 24 weeks | Drug: Heparin 2,400 IU /ml Cutaneous Spray<br>* Randomization will be performed 2 - 14 days post fistula creation surgery following confirmation that the fistula is patent by physical examination. Patients that are randomized to this study arm, will be asked to administer the study medication twice daily. Patients will get adequate training before first administration.<br>|
| Placebo Comparator: Placebo Cutaneous Spray<br>Patients are randomized to receive placebo cutaneous spray for 24 weeks | Drug: Placebo Cutaneous Spray<br>* Randomization will be performed 2 - 14 days post fistula creation surgery following confirmation that the fistula is patent by physical examination. Patients that are randomized to this study arm, will be asked to administer the study medication (placebo) twice daily. Patients will get adequate training before first administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dialysis with a blood flow rate ≥ 300 ml/min OR, if the patient is not in need of dialysis, by combining the venous diameter > 0.4 cm and flow volume > 500ml/min assessed by duplex ultrasound, as well as via clinical impression | Primary outcome measure is the suitability of the AVF (dialysis with a blood flow rate ≥ 300 ml/min ) at 7th week (± 1 week) after first study drug administration. Suitability of the AVF will be assessed by using the AVF for dialysis. If a flow rate of at least 300 ml/min can be reached for at least 3 minutes suitability is fulfilled.If the patient is not in need of dialysis, suitability will be assessed by combining the venous diameter > 0.4 cm and flow volume > 500ml/min assessed by duplex ultrasound, as well as via clinical impression | 7 ± 1 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dialysis with a blood flow rate ≥ 300mL/min. If the patient is not in need of dialysis, by combining the venous diameter > 0.4 cm and flow volume > 500ml/min assessed by duplex ultrasound, as well as via clinical impression. | The suitability of the AVF (dialysis with a blood flow rate ≥ 300mL/min) at 12th and 24th week after first study drug administration. If a flow rate of at least 300 ml/min can be reached for at least 3 minutes suitability is fulfilled. If the patient is not in need of dialysis, the suitability will be assessed by combining the venous diameter > 0.4 cm and flow volume > 500ml/min assessed by duplex ultrasound, as well as via clinical impression. | at 12th and 24th week after first study drug administration | 
| The functional (unassisted) patency of AVF | Unassisted patency of the AVF will be assessed by palpation and auscultation for at least 30 seconds. | at 7th, 12th and 24th weeks after first study drug administration | 
| Local safety and tolerability profile of IMP by patients and investigator (Global assessment of tolerability) | A scale will be used to assess local tolerability. In addition the investigator will screen for known heparin specific reactions, i.e. skin rash and skin swelling. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Haemodialysis, Arteriovenous fistula, Severe chronic kidney disease, Newly constructed primary arteriovenous fistulas in patients planned for haemodialysis