Efficacy and Safety of AMG0001 in Subjects With Critical Limb Ischemia

NCT02144610 | Terminated Phase 3 Results DMC FDA Drug

• 2 other identifiers: AG-CLI-02062014-001129-34
• Study Type: interventional
• Target: 46
• Locations: 11 countries
• Sites: 60

Brief Summary

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

Conditions

Critical Limb Ischemia

Keywords

CLI

Outcome Measures

Primary Outcomes (11)

• Major Amputation or Revascularization (of the Index Leg), All-cause Death, and Incidence of Stroke and Myocardial Infarction (MI)

  A frequency table for Day 0 to 6 months, Day 0 to 12 months and Day 0 to 18 months intervals by treatment group; the Fisher's Exact test was used for treatment comparison.

  18 months

• Change in Ischemic Rest Pain (in the Index Leg) From Baseline Using a 10 cm Visual Analog Scale (VAS) Scale

  The severity of rest pain (based on the average over previous 7 days) recorded using the 10 cm visual analog scale (VAS). VAS is a 10-cm line (with score ranges 0 to 10), oriented horizontally; the left end of the line (0 mark) indicates "no pain"; the right end indicates "pain as bad as it can be." 1. The subject is asked to mark a place on the line corresponding to the average pain intensity experienced in the last 7 days. 2. The distance along the scale is converted into a numeric reading by measuring the distance of the subjects mark in cm from the beginning of the scale (the 0 mark).

  18 months

• Ulcer Improvement

  A table showing the number of subjects with complete healing of the target ulcer by treatment. Ulcer healing of the largest ulcer on the index limb was assessed clinically by the Principal Investigator by direct visual inspection at each study visit. If the largest ulcer on the index leg was considered completely healed, photographs of the healed ulcer area was captured. If an ulcer healed completely during the study period, the ulcer was re-evaluated 2 weeks later to confirm it has remained healed. Confirmation of complete ulcer healing was made by an outside physician unconnected with the study and nominated for this purpose.

  18 months

• VAS Improvement

  A table showing the number of subjects with improvement in VAS (≥ 20 mm) by treatment.

  18 months

• Hemodynamic Measurements - Mean Change From Baseline in Brachial (Right/Left) Systolic Pressure

  Summary statistics were provided for baseline and change from baseline for right/left brachial systolic pressure by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.

  18 months

• Hemodynamic Measurements - Mean Change From Baseline in Ankle (Dorsalis Pedis/Posterior Tibial) Systolic Pressure

  Summary statistics were provided for baseline and change from baseline for ankle systolic pressure measured at dorsalis pedis and posterior tibial by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.

  18 months

• Hemodynamic Measurements - Mean Change From Baseline in Toe Systolic Pressure

  Summary statistics were provided for baseline and change from baseline for toe systolic pressure by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.

  18 months

• Hemodynamic Measurements - Mean Change From Baseline in ABI of Index Leg

  Summary statistics were provided for baseline and change from baseline for calculated ABI by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.

  18 months

• Hemodynamic Measurements - Mean Change From Baseline in TBI of Index Leg

  Summary statistics were provided for baseline and change from baseline for calculated TBI by visit and treatment (only subjects with non-missing baseline and visit values). A two-way analysis of covariance (ANCOVA) with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.

  18 months

• Changes in the Quality of Life Using the Vascular Quality of Life Questionnaire (VascuQol) Over 18 Months

  The VascuQol contains 5 domains (pain, symptom, activities, social, and emotional functioning); responses were scored from 0 (lowest QOL, death) to 7 (best QOL, maximum health). Responses were averaged for composite overall and domain-specific scores, giving equal weight to each question and domain. The composite overall is the average of domain-specific scores. Responses after revascularization or major amputation were included in the analysis. In the event of death, subjects were scored as 0. For the effect of treatment on individual domains, pain, symptoms, and activities were considered the most important of the 5 domains. Summary statistics were provided for baseline and change from baseline by visit and treatment for VascuQol, including subscore, for subjects who had a non-missing value at both baseline and the specific visit. A two-way ANCOVA with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.

  18 months

• Changes in the Quality of Life From Baseline Using the EQ-5D-5L Over 18 Months

  The EQ-5D-5L descriptive system covers 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 5 levels: no problems (1), slight problems (2), moderate problems (3), severe problems (4), and extreme problems (5); death was coded as a worst case. The EQ-5D-5L health state for each subject, referred to as a 5 digit code that combines 1 level from each of the 5 dimensions, was converted into a single index value using a published weighing system. The index value ranges from -0.109 to 1, where 1 indicates no problems in all 5 dimensions, and is reduced when a patient reports increasing problems. Summary statistics were provided for baseline and change from baseline by visit and treatment for EQ-5D-5L, including subscore, for subjects who had a non-missing value at both baseline and the specific visit. A two-way ANCOVA with treatment and region as fixed factors and baseline as a covariate were performed for each visit and LOCF.

  18 months

Study Arms (2)

Gene Therapy HGF Plasmid (AMG0001)

EXPERIMENTAL

Randomized subjects will receive 4 sets of intramuscular (IM) injections of HGF plasmid two weeks apart starting at Day 0 and again at Month 3 (first cycle) and at Month 9 and again at Month 12 (second cycle) in muscles of the affected lower limb.

Biological: HGF Plasmid (AMG0001)

Placebo

PLACEBO COMPARATOR

Randomized subjects will receive 4 sets of intramuscular (IM) injections of matching placebo two weeks apart starting at Day 0 and again at Month 3 (first cycle) and at Month 9 and again at Month 12 (second cycle) in muscles of the affected lower limb.

Biological: Matching Placebo

Interventions

HGF Plasmid (AMG0001) BIOLOGICAL

IM

Also known as: Beperminogene perplasmid (INN)

Gene Therapy HGF Plasmid (AMG0001)

Matching Placebo BIOLOGICAL

IM

Placebo

Eligibility Criteria

• Age: 40 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects with CLI (Severe Rutherford 4 and Rutherford 5) who have:
• No option for revascularization by endovascular intervention or surgical bypass
• Subjects 40-90 years of either gender who have signed an informed consent form either directly or through a legally authorized representative.
• 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).
• If female, the subjects must not be of child bearing potential, e.g., post-menopausal or surgically sterile.
• 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.
• 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.)
• 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.

You may not qualify if:

• 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.
• Subjects who may require a major amputation (amputation at or above the ankle) within 4 weeks of Day 0 (± 4 weeks of Day 0).
• 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).
• Subjects with purely neuropathic, or with venous ulcers.
• Subjects in Rutherford 6 class.
• 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.
• Subjects with a diagnosis of Buerger's disease (Thrombo-angiitis Obliterans).
• Subjects currently receiving immunosuppressive, chemo or radiation therapy.
• 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).
• Females of child-bearing potential defined as subjects that are not surgically sterile or post-menopausal.
• 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.
• 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.
• Subjects with known liver disease (e.g., hepatitis B or C or cirrhosis of the liver).
• A subject with HIV, AIDS, severe uncontrolled inflammatory disease or severe uncontrolled autoimmune disease (e.g., ulcerative colitis, Crohn's disease, etc).
• 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.

Sponsors & Collaborators

• AnGes USA, Inc.: lead

Study Sites (60)

Carondelet Heart and Vascular Institute

Tucson, Arizona, 85745, United States

Location

Central Arkansas Veteran's Healthcare System

Little Rock, Arkansas, 72205, United States

Location

University of California, San Diego (UCSD)

La Jolla, California, 92037-1300, United States

Location

Alliance Research Centers

Laguna Hills, California, 92653, United States

Location

San Francisco Veterans Affairs Medical Center

San Francisco, California, 94121, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

Sarasota Memorial Hospital Clinical Research Center

Sarasota, Florida, 34239, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Harbin Clinic, LLC

Rome, Georgia, 30165, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Northwestern Medicine Central DuPage Hospital

Winfield, Illinois, 60190, United States

Location

Peninsula Region Medical Center

Salisbury, Maryland, 21801, United States

Location

Boston University School of Medicine

Boston, Massachusetts, 02118, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Saint Luke's Hospital

Kansas City, Missouri, 64111, United States

Location

Kansas City Vascular P.C.

Kansas City, Missouri, 64116, United States

Location

Mercy Medical Research Institute

Springfield, Missouri, 65806, United States

Location

Mercy Hospital St. Louis

St Louis, Missouri, 63141, United States

Location

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

Holy Name Medical Center

Teaneck, New Jersey, 07666, United States

Location

New York Presbyterian Hospital - Columbia University Medical Center

New York, New York, 10032, United States

Location

Wake Forest Baptist Health

Winston-Salem, North Carolina, 27157, United States

Location

University of Oklahoma - Physicians Surgical Specialists

Tulsa, Oklahoma, 74104, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Veterans Affairs Medical Center

Pittsburgh, Pennsylvania, 15240, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Sanford Health

Sioux Falls, South Dakota, 57104, United States

Location

The Methodist Hospital Research Institute

Houston, Texas, 77030, United States

Location

Antwerpen University Hospital

Edegem, 2650, Belgium

Location

Ziekenhuis Oost Limburg

Genk, 3600, Belgium

Location

Universitair Ziekenhuis Gent

Ghent, 9000, Belgium

Location

Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

Regionshospitalet Viborg

Viborg, 8800, Denmark

Location

Helsinki University Hospital

Helsinki, 00290, Finland

Location

Kuopio University Hospital

Kuopio, 70029, Finland

Location

Kuopio University Hospital

Kuopio, 70210, Finland

Location

Tampere University Hospital

Tampere, 33520, Finland

Location

Hopital Cardiologique - CHU Lille

Lille, Nord, 59037, France

Location

CHU Amiens - Groupe Hospitalier Hopital Sud

Amiens, 80054, France

Location

Hôpital Saint André

Bordeaux, 33075, France

Location

CHU de Grenoble - Hôpital Albert Michallon

Grenoble, 38043, France

Location

Magyar Honvedseg Egeszsegugyi Kozpont

Budapest, 1134, Hungary

Location

Debreceni Egyetem Klinikai Kozpont, Belgyogyaszati Klinika

Debrecen, 4032, Hungary

Location

Petz Aladar Megyei Oktato Korhaz

Győr, 9024, Hungary

Location

Bekes Megyei Pandy Kalman Korhaz Ersebeszet

Gyula, 5700, Hungary

Location

Bekes Megyei Pandy Kalman Korhaz

Gyula, Hungary

Location

Somogy Megyei Kaposi Mor Oktato Korhaz Altalanos- Mellkas es Ersebeszeti Osztaly

Kaposvár, 7400, Hungary

Location

Borsod-Abauj-Zemplen Megyei Korhaz es Egyetemi Oktato Korhaz

Miskolc, 3526, Hungary

Location

SzSzB Megyei Korhazak es Egyetemi Oktatokorhaz

Nyíregyháza, 4400, Hungary

Location

Pecsi Tudomanyegyetem AOK

Pécs, 7623, Hungary

Location

Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinika Központ

Szeged, 6720, Hungary

Location

Fejer Megyei Szent Gyorgy Egyetemi Oktato Korhaz

Székesfehérvár, 8000, Hungary

Location

Universita Cattolica Policlinico Gemelli

Roma, 00168, Italy

Location

Leiden Universitair Medisch Centrum

Leiden, 2333 ZA, Netherlands

Location

Maastricht University Medical Center

Maastricht, 6229 HX, Netherlands

Location

Universitair Medisch Centrum Utrecht

Utrecht, 3584 CX, Netherlands

Location

Szpital Uniwersytecki nr 1 im. Dr A. Jurasza w Bydgoszczy

Bydgoszcz, 85-094, Poland

Location

Uniwersyteckie Centrum Kliniczne

Gdansk, 80-952, Poland

Location

Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego

Poznan, 61-848, Poland

Location

Karlkirurgiska Kliniken, Karolinska Universitetssjukhuset

Stockholm, 171 76, Sweden

Location

MeSH Terms

Conditions

Chronic Limb-Threatening Ischemia

Condition Hierarchy (Ancestors)

Peripheral Arterial Disease; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Peripheral Vascular Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Ischemia

Limitations and Caveats

Because of early termination of study due to low subject enrollment, subject exposure to study treatment and the duration were highly variable.

Results Point of Contact

• Title: Dr. Susan Pitman Lowenthal
• Organization: AnGes USA, Inc.

spitmanlowenthal@anges-usa.com

240-780-9025

Study Officials

• Richard J. Powell, MD

  Dartmouth-Hitchcock Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 20, 2014
• First Posted: May 22, 2014
• Study Start: November 12, 2014
• Primary Completion: November 28, 2016
• Study Completion: November 28, 2016
• Last Updated: August 13, 2019
• Results First Posted: August 13, 2019

Record last verified: 2019-07

Locations

IT (1); NL (3); US (28); FI (4); PL (3); SE (1); BE (3); CA (1); DK (1); FR (4); HU (11)