Clinical trial NCT02144610: Efficacy and Safety of AMG0001 in Subjects With Critical Limb Ischemia
Official title: A Phase 3 Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Safety and Efficacy of AMG0001 in Subjects With Critical Limb Ischemia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Critical Limb Ischemia
Keywords: CLI
Lead sponsor: AnGes USA, Inc.
Sponsor class: INDUSTRY
First posted: 2014-05-22
Enrollment: 46
Sex: ALL
Minimum age (years): 40
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Study to Evaluate the Efficacy and Safety of AMG0001 in Subjects with Critical Limb Ischemia.

Detailed description: This is a double-blind, randomized, placebo-controlled, phase 3, multinational, multicenter study of AMG0001 (HGF plasmid) in subjects with Critical Limb Ischemia (CLI).

Eligibility criteria: Inclusion Criteria:

1. Subjects with CLI (Severe Rutherford 4 and Rutherford 5) who have:

   * No option for revascularization by endovascular intervention or surgical bypass

   or
   * Poor option (high risk) for revascularization by surgery and no option for an endovascular intervention (see Section 3.1 Study Population for full definition for appropriate inclusions).
2. Subjects 40-90 years of either gender who have signed an informed consent form either directly or through a legally authorized representative.
3. Subjects currently are taking a statin and an anti-platelet agent (e.g., clopidogrel, ticlopidine, aspirin, etc.) for 2 weeks or more prior to Day 0 as part of their standard of care, unless contraindicated. Subjects for whom these agents are contraindicated will have the reason for contraindication recorded in their case report form (CRF).
4. If female, the subjects must not be of child bearing potential, e.g., post-menopausal or surgically sterile.
5. If a male subject is of reproductive potential, he must agree to use an accepted and effective (barrier) form of birth control starting with the first dose of study product and continue for 12 weeks from the last dose of study product. This applies to both courses of treatment.
6. Subjects with a previous medical history of myocardial infarction and/or stroke should have adequate management of risk factors to prevent secondary occurrence. (See Section 4.2 Medical History for guidelines on appropriate secondary prevention.)
7. Subjects should have the ability to understand the requirements of the protocol and agree to return for the required study visits, assessments and follow up.

   * The index leg will be the leg with the greater severity of CLI disease. Entry requirements apply to the index leg. The index leg may also be referred to as the treated leg or affected leg in the text of this protocol or other study documents. If the subject has two legs that have the same Rutherford classification (severe Rutherford 4 or Rutherford 5) and are both eligible for treatment, the leg with greater disease severity (based on more extensive necrosis or more extensive/deeper ulceration(s), difference in ABI (ankle brachial index) or TBI (toe brachial index) ≥ 0.1, and/or more extensive vascular disease based on the angiogram) will be chosen as the index leg. If there is no clinical, hemodynamic or angiographic or other evidence to determine which leg has greater disease severity, the subject will be excluded from the study.
   * These entry criteria will be enforced (prior to randomization) by the Sponsor, as well as an Entry Committee who will review all relevant clinical data including but not limited to medical illness, CLI status, the findings of an angiogram, ulcer photographs and measurements and hemodynamic data.

Exclusion Criteria:

1. Subjects whose CLI status is unstable (spontaneous marked improvement or marked worsening during the screening period) or who have excessive tissue necrosis that is unlikely to benefit from medication, or those poor option subjects requiring immediate revascularization by surgery. Stability of the CLI status will be confirmed by the Principal Investigator prior to randomization and retrospectively reviewed by the Adjudication Committee.
2. Subjects who may require a major amputation (amputation at or above the ankle) within 4 weeks of Day 0 (± 4 weeks of Day 0).
3. Subjects with ulcers with exposure of tendons, osteomyelitis or uncontrolled infection or with the largest ulcer that is greater than 20 cm2 in area (\>10 cm2 area if on the heel).
4. Subjects with purely neuropathic, or with venous ulcers.
5. Subjects in Rutherford 6 class.
6. Subjects who have had revascularization by surgery or angioplasty within 3 months, unless the procedure has failed based on the anatomy or the hemodynamic measurements.
7. Subjects with a diagnosis of Buerger's disease (Thrombo-angiitis Obliterans).
8. Subjects currently receiving immunosuppressive, chemo or radiation therapy.
9. Evidence or history of malignant neoplasm (clinical, laboratory or imaging) except for successfully excised basal cell or squamous cell carcinoma, or successfully excised early melanoma of the skin. Subjects, who had successful tumor resection or radio-chemotherapy of breast cancer more than 10 years prior to inclusion in the study, and with no recurrence, may be enrolled in the study. Subjects, who had successful tumor resection or radio-chemotherapy of all other tumor types and have been in remission for more than 5 years prior to inclusion in the study, and with no recurrence, may be enrolled in the study. A dermatological exam will have ruled out any skin cancer.
10. Subjects who have proliferative retinopathy, or moderate or severe non-proliferative retinopathy, from any cause (ETDRS Score \> 35), clinically significant macular oedema or previous panretinal photocoagulation therapy (Results from the Early Treatment Diabetic Retinopathy Study. Ophthalmology May 1991 Supplement 98: 823-833).
11. Females of child-bearing potential defined as subjects that are not surgically sterile or post-menopausal.
12. Subjects with severe renal disease defined as significant renal dysfunction evidenced by an estimated creatinine clearance of \<30 mL/minute (calculated using the Cockcroft Gault formula), or receiving chronic hemodialysis therapy.
13. Any co-morbid condition likely to interfere with assessment of safety or efficacy endpoints, acute cardiovascular events (i.e., CVA (cardiovascular accident), MI (myocardial infarction), etc.) within 3 months of treatment, or any disease that in the opinion of the Investigator may result in subject mortality in less than 3 months.
14. Subjects with known liver disease (e.g., hepatitis B or C or cirrhosis of the liver).
15. A subject with HIV, AIDS, severe uncontrolled inflammatory disease or severe uncontrolled autoimmune disease (e.g., ulcerative colitis, Crohn's disease, etc).
16. Subjects who have a significant psychiatric disorder or mental disability that could interfere with the subject's ability to provide informed consent or comply with study procedures.
17. Subjects with a current, uncorrected history of alcohol or substance abuse.
18. Diabetic subjects with an uncorrected HbA1c \> 9.0% during the screening period.
19. Subjects that have been administered rhPDGF (e.g, becaplermin) or other growth factors locally within one month of randomization.
20. Subjects who have received another investigational drug within 30 days of randomization or have previously received any gene transfer therapy within 3 years of entering the study.

Primary outcomes:
measure: Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI)
timeFrame: 18 months
measure: Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale
timeFrame: 18 months
measure: Ulcer Improvement
timeFrame: 18 months
measure: VAS Improvement
timeFrame: 18 months
measure: Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure
timeFrame: 18 months
measure: Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure
timeFrame: 18 months
measure: Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure
timeFrame: 18 months
measure: Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg
timeFrame: 18 months
measure: Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg
timeFrame: 18 months
measure: Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months
timeFrame: 18 months
measure: Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months
timeFrame: 18 months
Secondary outcomes:
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Carondelet Heart and Vascular Institute
state: Arizona
city: Little Rock
country: United States
facility: Central Arkansas Veteran's Healthcare System
state: Arkansas
city: La Jolla
country: United States
facility: University of California, San Diego (UCSD)
state: California
city: Laguna Hills
country: United States
facility: Alliance Research Centers
state: California
city: San Francisco
country: United States
facility: San Francisco Veterans Affairs Medical Center
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Sarasota
country: United States
facility: Sarasota Memorial Hospital Clinical Research Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Rome
country: United States
facility: Harbin Clinic, LLC
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Winfield
country: United States
facility: Northwestern Medicine Central DuPage Hospital
state: Illinois
city: Salisbury
country: United States
facility: Peninsula Region Medical Center
state: Maryland
city: Boston
country: United States
facility: Boston University School of Medicine
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Kansas City
country: United States
facility: Saint Luke's Hospital
state: Missouri
city: Kansas City
country: United States
facility: Kansas City Vascular P.C.
state: Missouri
city: Saint Louis
country: United States
facility: Mercy Hospital St. Louis
state: Missouri
city: Springfield
country: United States
facility: Mercy Medical Research Institute
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Teaneck
country: United States
facility: Holy Name Medical Center
state: New Jersey
city: New York
country: United States
facility: New York Presbyterian Hospital - Columbia University Medical Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Tulsa
country: United States
facility: University of Oklahoma - Physicians Surgical Specialists
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Pittsburgh
country: United States
facility: Veterans Affairs Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Sioux Falls
country: United States
facility: Sanford Health
state: South Dakota
city: Houston
country: United States
facility: The Methodist Hospital Research Institute
state: Texas
city: Edegem
country: Belgium
facility: Antwerpen University Hospital
city: Genk
country: Belgium
facility: Ziekenhuis Oost Limburg
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Viborg
country: Denmark
facility: Regionshospitalet Viborg
city: Helsinki
country: Finland
facility: Helsinki University Hospital
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Lille Cedex
country: France
facility: Hopital Cardiologique - CHU Lille
state: Nord
city: Amiens
country: France
facility: CHU Amiens - Groupe Hospitalier Hopital Sud
city: Bordeaux
country: France
facility: Hôpital Saint André
city: Grenoble
country: France
facility: CHU de Grenoble - Hôpital Albert Michallon
city: Budapest
country: Hungary
facility: Magyar Honvedseg Egeszsegugyi Kozpont
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont, Belgyogyaszati Klinika
city: Gyula
country: Hungary
facility: Bekes Megyei Pandy Kalman Korhaz Ersebeszet
city: Gyula
country: Hungary
facility: Bekes Megyei Pandy Kalman Korhaz
city: Györ
country: Hungary
facility: Petz Aladar Megyei Oktato Korhaz
city: Kaposvar
country: Hungary
facility: Somogy Megyei Kaposi Mor Oktato Korhaz Altalanos- Mellkas es Ersebeszeti Osztaly
city: Miskolc
country: Hungary
facility: Borsod-Abauj-Zemplen Megyei Korhaz es Egyetemi Oktato Korhaz
city: Nyiregyhaza
country: Hungary
facility: SzSzB Megyei Korhazak es Egyetemi Oktatokorhaz
city: Pecs
country: Hungary
facility: Pecsi Tudomanyegyetem AOK
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinika Központ
city: Szekesfehervar
country: Hungary
facility: Fejer Megyei Szent Gyorgy Egyetemi Oktato Korhaz
city: Roma
country: Italy
facility: Universita Cattolica Policlinico Gemelli
city: Leiden
country: Netherlands
facility: Leiden Universitair Medisch Centrum
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki nr 1 im. Dr A. Jurasza w Bydgoszczy
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Poznan
country: Poland
facility: Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego
city: Stockholm
country: Sweden
facility: Karlkirurgiska Kliniken, Karolinska Universitetssjukhuset
Study officials:
affiliation: Dartmouth-Hitchcock Medical Center
name: Richard J. Powell, MD
role: PRINCIPAL_INVESTIGATOR
References: