Clinical trial NCT02756884: Safety and Preliminary Efficacy of Adipose Derived Stem Cells and Low Frequency Ultrasound in PAD
Official title: Phase I/Phase II Safety and Preliminary Efficacy Study Using Low Frequency Ultrasound in Addition to Adipose Derived Stem Cells (ADSCs) in Patients With Moderate to Severe Lower Extremity Peripheral Arterial Disease (PAD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Peripheral Arterial Disease
Lead sponsor: Arkansas Heart Hospital
Sponsor class: OTHER
Collaborators: name: SonaCare Medical
First posted: 2016-04-29
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a single center, open label, prospective, randomized, controlled study in patients with non- revascularizable moderate or severe lower extremity Peripheral Arterial Disease (PAD) receiving autologous stem cells therapy (minimally manipulated). This study will enroll a maximum of 10 subjects in this study. The patients will be divided into two groups. One group will receive Adipose Derived Stem Cells (ADSCs) alone and the other group will receive low frequency ultrasound before the addition of ADSCs. The randomization will be 1:1. If the results of this pilot study are not clearly different, there will be a need for a phase II study to support the results.

Baseline, 6 week, 3 month and 6 month assessments of 6 min walking distance (6MWT), Ankle Brachial Indexes (ABIs)/Toe Brachial Indexes (TBIs), Transcutaneous Partial Oxygenation (TcPO2) and Rutherford assessments will be performed for the study group. Prior to the stem cell treatment, the ultrasound group patient will receive noninvasive transcutaneous pulsed focused ultrasound around the involved vessel(s) in the affected extremity. All patients will then receive 200 million autologous stromal vascular fraction cells containing adipose derived stem cell therapy: 1/3 of the cells will be delivered intra-venous proximal to the lesion (not retrograde), 1/3 of the cells will be delivered intra- adventitia proximal to the lesion and 1/3 of the cells will be delivered by intra- muscular injection along the vessel path (20-30 injections each separated by1.5 inch). Standard therapy for PAD patients will not be interrupted for the duration of the study. Standard therapy for PAD is defined as cardiovascular general measures like lifestyle changes, smoke cessation, exercise, cardiovascular rehabilitation, etc. All participants have already received maximal non-surgical therapy. Safety will be monitored on an ongoing basis.

Detailed description: This is a single center, open label, prospective, randomized, controlled study in patients with non- revascularizable moderate or severe lower extremity PAD receiving autologous stem cells therapy. We will enroll a maximum of 10 subjects in this study. The patients will be divided into two groups. One group will receive ADSCs alone and the other group will receive low frequency ultrasound before the addition of ADSCs. The randomization will be 1:1. If the results of this pilot study are not clearly different, there will be a need for a phase II study to support the results.

Baseline, 6 week, 3 month and 6 month assessments of 6 min walking distance, ABIs/TBIs, TcPO2, Rutherford assessments will be performed for the study group. Prior to the stem cell treatment, the ultrasound group patient will receive noninvasive transcutaneous pulsed focused ultrasound around the involved vessel(s) in the affected extremity. All patients will then receive 100 to 200 million autologous adipose derived stem cell therapy: 1/3 of the cells will be delivered intra-venous proximal to the lesion (not retrograde), 1/3 of the cells will be delivered intra- adventitia proximal to the lesion and 1/3 of the cells will be delivered by intra- muscular injection along the vessel path (20-30 injections each separated by 1.5 inch). Standard therapy for PAD patients will not be interrupted for the duration of the study. Standard therapy for PAD is defined as cardiovascular general measures like lifestyle changes, smoke cessation, exercise, cardiovascular rehabilitation, etc. All participants have already received maximal non-surgical therapy. Safety will be monitored on an ongoing basis.

SUBJECT PARTICIPATION A screening evaluation to determine if a potential subject is suitable for participation in this trial will be conducted prior to enrollment and treatment by the Investigator. This includes obtaining written informed consent, collection of a complete medical history, including current and past medications, physical examination and clinical laboratory tests, PAD related testing (ABI/TBI, 6MWT, TcPO2, QoL questionnaires, etc.).

Eligible subjects will be randomized and treated at the Sponsor hospital as approved by the sponsor. Study medical staff will evaluate the patients upon admission according to the scheduled medical assessments to ensure eligibility of the subjects. Ultrasound group will receive LFUS over the affected limb (see page XIV). Intra-venous, intra-adventitia and intramuscular dosing of the autologous ADSC will occur on the morning of Day 0. Conscious sedation (I.V.) may be used during the tissue harvesting and intra-adventitia administration of the cells.. Subjects must remain in the clinic/hospital until they are clinically stable for discharge; subjects that are clinically stable will be discharged into the care of a responsible individual. Follow-up visits will occur at 6 weeks and 3 and 6 months post-treatment, and may occur with the patient's personal physician who will be provided the follow-up assessment forms. If this occurs, the Investigator and/or Sponsor or sponsor's designee may also contact the patient by telephone to collect follow-up safety information. Adverse events, concomitant medications, vital signs, clinical laboratory test results and physical examinations will be collected or conducted at follow-up visits according to the schedule of assessments (Appendix B). All previous medical care, including medications and rehabilitation, for the patient's current medical conditions will be continued as prescribed by the patient's personal physician(s). Use of other investigational agents or treatments is not allowed during this study.

Eligibility criteria: Inclusion Criteria:

1. Males and Females ≥18 years
2. Patients with a Rutherford classification of 3 or 4.
3. Non revascularizable lesions by balloon or stent angioplasty of the lower extremity SFA (Superficial femoral artery), Popliteal, AT (anterior tibial), PT (posterior tibial) or peroneal arteries. Non-revascularizable lesions will be determined based on a CT angiogram and/ or angiography.
4. Life expectancy greater than 6 months.
5. Ability to understand and provide signed informed consent.
6. Reasonable expectation that patient will receive standard post-treatment care and attend all scheduled safety follow-up visits
7. Written informed consent

Exclusion Criteria:

1. Immunosuppressive agents, including but not limited to, corticosteroids and steroidal anti- inflammatory agents (SAIDS)
2. Non-steroidal anti- inflammatory agents (NSAIDS)
3. Patients taking currently P2Y12 inhibitors or calcium channel blockers.
4. Uncontrolled seizure disorder
5. Dementia
6. Evidence or presence of immune deficiency.
7. Presence of any other clinically-significant medical condition, psychiatric condition, or laboratory abnormality that in the judgment of the Investigator or Sponsor would pose a safety risk to the subject
8. Participation in another study with an investigational drug or device within one month prior to treatment
9. Females known to be pregnant, lactating or having a positive pregnancy test (will be tested during screening) or planning to become pregnant during the study
10. Inability to comply with the conditions of the protocol.
11. Allergy to sodium citrate or any "caine" type of local anesthetic

Primary outcomes:
measure: Safety measured by incidence of adverse events
timeFrame: 6 months
Secondary outcomes:
measure: Efficacy of stem cells in improving ABI
timeFrame: 6 months
measure: Efficacy of stem cells in improving 6MWT
timeFrame: 6 months
measure: Efficacy of stem cells in improving the TcPO2
timeFrame: 6 months
measure: Efficacy of stem cells in improving Quality of Life using EQ-5D 5L questionnaire
timeFrame: 6 months
measure: Efficacy of stem cells in improving Quality of Life using the VascuQol questionnaire
timeFrame: 6 months
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Heart Hospital
state: Arkansas
city: Little Rock
country: United States
facility: Arkansas Site Management Services LLC
state: Arkansas
Study officials:
affiliation: Arkansas Heart Hospital
name: Wilson Wong, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tebebi PA, Burks SR, Kim SJ, Williams RA, Nguyen BA, Venkatesh P, Frenkel V, Frank JA. Cyclooxygenase-2 or tumor necrosis factor-alpha inhibitors attenuate the mechanotransductive effects of pulsed focused ultrasound to suppress mesenchymal stromal cell homing to healthy and dystrophic muscle. Stem Cells. 2015 Apr;33(4):1173-86. doi: 10.1002/stem.1927.