Clinical trial NCT03784131: Tissue Engineered Veins in Patients With Chronic Venous Insufficiency
Official title: Phase I Open-label, First-in-human Study to Evaluate Feasibility and Safety of Tissue Engineered Veins in Patients With Chronic Venous Insufficiency
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Chronic Venous Insufficiency
Keywords: CVI
Leg Ulcer
Tissue Engineering
Personalized Vascular Graft
Chronic Venous Insufficiency
ATMP
Lead sponsor: Verigraft AB
Sponsor class: INDUSTRY
First posted: 2018-12-21
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study aims to evaluate the safety (incidence of adverse events including serious adverse events and clinical significant laboratory abnormalities) of personalized tissue engineered veins (P-TEV) with valves implanted in patients with severe chronic venous insufficiency (CVI). For each patient a segment of the femoral vein containing the non-functioning valve will be surgically replaced with a single P-TEV containing a functioning valve.

Detailed description: The advanced therapy medicinal product (ATMP) described herein is a personalized tissue- engineered vein (P-TEV) graft for use in surgical implantation to replace a defective or missing part of a patient's vein.

In this specific application a P-TEV graft with a functioning venous bicuspid valve is implanted to replace a nonfunctioning venous valve in the femoral vein of a patient suffering from severe CVI. The P-TEV graft for surgical implantation is 4-6 cm in length.

The P-TEV drug substance consists of an extracellular matrix (ECM) scaffold in the form of a decellularized (DC) allogeneic vein scaffold which is populated with autologous components from the patient's own peripheral whole blood (PWB) in an ATMP manufacturing process performed under GMP. As the allogeneic immunogenic material has been removed from the donated vein segment by DC and as the perfusion uses autologous PWB, no immunosuppression is required.

Successful implantation and treatment should prevent the reverse blood flow, decrease blood pooling in the lower leg, and thereby alleviate symptoms such as swelling, pain, and ulcers.

Eligibility criteria: Inclusion Criteria:

* Patients aged between 18 and 75 years (inclusive)
* CVI patients with painful swelling and/or skin changes and/or recurrent leg ulcer despite optimal conservative treatment for a period of time according to the investigator's judgement
* Patients with deep venous reflux (grade 3 and above)
* Meeting ASA (American Society of Anesthesiologists Classification) class 1 or 2 according to the PIs criteria
* Laboratory values

  * INR \<1.7 (in case the patient uses Warfarin, the test might be repeated after the anticoagulant change)
  * Platelets ≥ 100 x 10 9 /L
  * Hemoglobin ≥ 100 g/L
  * Total bilirubin ≤ 1.5 × upper limit of normal (ULN)
  * ASAT ≤ 2.5 × ULN
  * ALAT ≤ 2.5 × ULN
* Ability to understand the requirements of the study, give direct or representative written informed consent, and comply with the study procedures

Exclusion Criteria:

* Patients incapable to give direct or representative written informed consent
* Patients unlikely to cooperate fully in the study and/or with an anticipated poor compliance
* Non-walking patients or patients with lost ankle joint function
* Patients previously organ-transplanted
* Patients with cancer except in-situ stage cancer (basal-cell carcinomas and/or cervix cancer) and five year recurrence free period after treatment
* Patients with autoimmune diseases including rheumatoid arthritis, SLE and MS
* Pregnant or breast feeding women
* Patients with ongoing estrogen treatment for example for contraception. Alternative contraceptive methods (e.g. intrauterine device, bilateral tubal occlusion, vasectomized partner, sexual abstinence) should be used by women of reproductive age (defined as pre-menopausal female capable of becoming pregnant).
* BMI ≥ 35
* Patients who have participated in other clinical trials during the last 12 months
* Patients with artery pathology (ankle-brachial pressure index \< 0,9 or \> 1,3)
* Patients with thrombophilia according to the laboratory results at inclusion visit. One of the following criteria is needed for thrombophilia: Protein C \< 40% or Protein S \< 40 % or Leiden factor mutation or Antithrombin III \< 40 % or present Lupus anticoagulant or Homocysteine \> 1.5 ULN
* Patients with an active infection requiring systemic antibiotic treatment
* Patients with clinically significant cardiac disease (New York Heart Association, Class III or IV) or measured LVEF 40%
* Patients with uncontrolled hypertension
* Patients with renal dysfunction eGFR \< 45 ml/min (according to the MDRD calculation)
* Patients with moderate or severe hepatic impairment (Child Pugh ≥ 7 points, i.e. class B or C)
* Patients with ongoing immunosuppression, systemic Cortisol treatment etc.
* Less than 3 months since previous ipsilateral venous intervention (e.g. Iliac recanalization)
* Clinically significant iliocaval stenosis or occlusion
* Current smoker of more than 20 cigarettes per day
* Other uncontrolled intercurrent illness that would jeopardize the patient's safety, interfere with the objectives of the protocol, or limit the patient's compliance with study requirements, as determined by the Investigator in consultation with the Sponsor
* Patients with severe SARSCoV-2 virus infection requiring hospitalization in the past 6 months

Primary outcomes:
measure: Thrombosis leading to occlusion of the graft measured by Color Duplex Ultrasound
timeFrame: 12 months
measure: Infection leading to surgical excision of the graft measured by blood samples
timeFrame: 12 months
measure: Infection leading to surgical excision of the graft measured by Color Duplex Ultrasound
timeFrame: 12 months
measure: Infection leading to surgical excision of the graft measured by Computer Tomography
timeFrame: 12 months
measure: Reporting of surgical complications
timeFrame: 12 months
Secondary outcomes:
measure: Change in symptoms assessed according to VCSS (Venous Clinical Severity Score)
timeFrame: 12 months
measure: Change in symptoms assessed according to CEAP classification (clinical, etiologic, anatomic, pathophysiologic)
timeFrame: 12 months
measure: Health Related Quality of Life assessed by VEINES questionnaire
timeFrame: 12 months
measure: Health Related Quality of Life assessed by EQ-5D-5L questionnaire
timeFrame: 12 months
measure: Durability of the P-TEV assessed by Color Duplex Ultrasound
timeFrame: 12 months
measure: Vessel dilatation in the implant assessed by Duplex Color Ultrasound
timeFrame: 12 months
measure: Flow abnormalities in the implant assessed by Duplex Color Ultrasound
timeFrame: 12 months
measure: Wall degeneration in the implant assessed by Duplex Color Ultrasound
timeFrame: 12 months
Other outcomes:
Locations:
city: Sevilla
country: Spain
facility: Junta de Andalusia
Study officials:
affiliation: Verigraft AB
name: Björquist
role: STUDY_DIRECTOR
References: