Efficacy and Safety of AMG0001 in Subjects With Critical Limb Ischemia

Critical Limb Ischemia Clinical Trial

— AGILITY  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02144610
• Other study ID #: AG-CLI-0206
• Secondary ID: 2014-001129-34
• Status: Terminated
• Phase: Phase 3
• Start date: November 12, 2014
• Est. completion date: November 28, 2016

Study information

• Verified date: July 2019
• Source: AnGes USA, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 46
• Est. completion date: November 28, 2016
• Est. primary completion date: November 28, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 90 Years

Eligibility

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.

Related Conditions & MeSH terms

• Critical Limb Ischemia
• Ischemia

Intervention

Biological:
• HGF Plasmid (AMG0001)
IM
• Matching Placebo
IM

Locations

Country	Name	City	State
Belgium	Antwerpen University Hospital	Edegem
Belgium	Ziekenhuis Oost Limburg	Genk
Belgium	Universitair Ziekenhuis Gent	Gent
Canada	Jewish General Hospital	Montreal	Quebec
Denmark	Regionshospitalet Viborg	Viborg
Finland	Helsinki University Hospital	Helsinki
Finland	Kuopio University Hospital	Kuopio
Finland	Kuopio University Hospital	Kuopio
Finland	Tampere University Hospital	Tampere
France	CHU Amiens - Groupe Hospitalier Hopital Sud	Amiens
France	Hôpital Saint André	Bordeaux
France	CHU de Grenoble - Hôpital Albert Michallon	Grenoble
France	Hopital Cardiologique - CHU Lille	Lille Cedex	Nord
Hungary	Magyar Honvedseg Egeszsegugyi Kozpont	Budapest
Hungary	Debreceni Egyetem Klinikai Kozpont, Belgyogyaszati Klinika	Debrecen
Hungary	Petz Aladar Megyei Oktato Korhaz	Györ
Hungary	Bekes Megyei Pandy Kalman Korhaz	Gyula
Hungary	Bekes Megyei Pandy Kalman Korhaz Ersebeszet	Gyula
Hungary	Somogy Megyei Kaposi Mor Oktato Korhaz Altalanos- Mellkas es Ersebeszeti Osztaly	Kaposvar
Hungary	Borsod-Abauj-Zemplen Megyei Korhaz es Egyetemi Oktato Korhaz	Miskolc
Hungary	SzSzB Megyei Korhazak es Egyetemi Oktatokorhaz	Nyiregyhaza
Hungary	Pecsi Tudomanyegyetem AOK	Pecs
Hungary	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinika Központ	Szeged
Hungary	Fejer Megyei Szent Gyorgy Egyetemi Oktato Korhaz	Szekesfehervar
Italy	Universita Cattolica Policlinico Gemelli	Roma
Netherlands	Leiden Universitair Medisch Centrum	Leiden
Netherlands	Maastricht University Medical Center	Maastricht
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Poland	Szpital Uniwersytecki nr 1 im. Dr A. Jurasza w Bydgoszczy	Bydgoszcz
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego	Poznan
Sweden	Karlkirurgiska Kliniken, Karolinska Universitetssjukhuset	Stockholm
United States	Emory University	Atlanta	Georgia
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Boston University School of Medicine	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University	Chicago	Illinois
United States	University of Florida	Gainesville	Florida
United States	The Methodist Hospital Research Institute	Houston	Texas
United States	Kansas City Vascular P.C.	Kansas City	Missouri
United States	Saint Luke's Hospital	Kansas City	Missouri
United States	University of California, San Diego (UCSD)	La Jolla	California
United States	Alliance Research Centers	Laguna Hills	California
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Central Arkansas Veteran's Healthcare System	Little Rock	Arkansas
United States	New York Presbyterian Hospital - Columbia University Medical Center	New York	New York
United States	Veterans Affairs Medical Center	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Harbin Clinic, LLC	Rome	Georgia
United States	Mercy Hospital St. Louis	Saint Louis	Missouri
United States	Peninsula Region Medical Center	Salisbury	Maryland
United States	San Francisco Veterans Affairs Medical Center	San Francisco	California
United States	Sarasota Memorial Hospital Clinical Research Center	Sarasota	Florida
United States	Sanford Health	Sioux Falls	South Dakota
United States	Mercy Medical Research Institute	Springfield	Missouri
United States	Holy Name Medical Center	Teaneck	New Jersey
United States	Carondelet Heart and Vascular Institute	Tucson	Arizona
United States	University of Oklahoma - Physicians Surgical Specialists	Tulsa	Oklahoma
United States	Northwestern Medicine Central DuPage Hospital	Winfield	Illinois
United States	Wake Forest Baptist Health	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
AnGes USA, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Denmark,  Finland,  France,  Hungary,  Italy,  Netherlands,  Poland,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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."; The subject is asked to mark a place on the line corresponding to the average pain intensity experienced in the last 7 days.; 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
Primary	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
Primary	VAS Improvement	A table showing the number of subjects with improvement in VAS (= 20 mm) by treatment.	18 months
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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