Clinical Trials Register

Summary
EudraCT Number:	2014-001129-34
Sponsor's Protocol Code Number:	AG-CLI-0206
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-09-05
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Finland - Fimea

A.2

EudraCT number

2014-001129-34

A.3

Full title of the trial

A PHASE 3 DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND EFFICACY OF AMG0001 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A PHASE 3 DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND EFFICACY OF AMG0001 IN SUBJECTS WITH CRITICAL LIMB ISCHEMIA

A.4.1

Sponsor's protocol code number

AG-CLI-0206

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02144610

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AnGes Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AnGes MG.
B.4.2	Country	Japan
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Quintiles Contact Center
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	The Alba Campus
B.5.3.2	Town/ city	Rosebank, Livingston
B.5.3.3	Post code	EH54 7EG
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44862 261 3634
B.5.6	E-mail	QEudraCThelpdesk@quintilescontact.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Hepatocyte Growth Factor (HGF) cDNA Plasmid
D.3.2	Product code	AMG0001 (plasmid pVAX1HGF/MGBI)
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	beperminogene perplasmid
D.3.9.2	Current sponsor code	pVAX1HGF/MGBI plasmid
D.3.9.3	Other descriptive name	Collategene
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	2.25 to 2.75
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate and solvent for solution for injection
D.8.4	Route of administration of the placebo	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Critical limb ischemia

E.1.1.1

Medical condition in easily understood language

Critical limb ischemia

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10058069
E.1.2	Term	Critical limb ischemia
E.1.2	System Organ Class	100000004866

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. To estimate the treatment benefit (AMG0001 compared to placebo), in terms of a combined endpoint (major amputations or all-cause death)
2. To evaluate the overall safety and efficacy of AMG0001.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subjects with CLI (Severe Rutherford 4 and Rutherford5) 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. 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.

E.4

Principal 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 Cockroft 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, MI, 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.

E.5 End points

E.5.1

Primary end point(s)

Time to major amputation of the index leg (at or above the ankle) or all-cause death

E.5.1.1

Timepoint(s) of evaluation of this end point

Number of subjects followed up to 3 months: subjects with a follow-up visit at day 90 ±10 (days 80 to 100) will be counted
Months 6, 9, 12, 15 and 18 evaluation: subjects with follow-up visits at day 182 ± 15 (days 167 to 197), day 273 ± 15 (days 258 to 288), day 365 ± 30 (days 335 to 395), day 455 ±35 (days 420 to 490), and day 548 ± 45 (days 503 to 593) will be counted.
Months 24, 30, 36, and 42 evaluation: subjects with follow-up visits at month 24 ± 2 (months 22 to 26), month 30 ± 2 (months 28 to 32), month 36 ± 2 (months 34 to 38) , and month 42 ± 3 (months 39 to 45) will be counted.

E.5.2

Secondary end point(s)

- Percentage of subject who have undergone major amputation or revascularization of the index leg
- Time to complete ulcer healing of the largest baseline ulcer on the index leg up to 18 months (ulcer should remain healed for at least 2 weeks)
- Ischemic rest pain reduction of the index leg using a 10 cm VAS scale in Rutherford 4 and 5 subjects over 18 months
- Changes in the quality of life (using EuroQol (EQ-5D-5L) and VascuQol) over 18 months
- Time to major amputation (of the index leg) or CLI-related deaths up to 18 months
CLI- related deaths include but are not limited to: deaths due to complications of CLI (e.g., septicemia), peri-operative deaths occurring within one month of bypass surgery or major amputation. Deaths will be adjudicated by at Adjudication Committee in a blinded manner.
- Incidence of Stroke and Myocardial Infarction up to 18 months
- Primary bypass graft patency for those subjects that receive open surgical bypass at 18 months

E.5.2.1

Timepoint(s) of evaluation of this end point

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Belgium

Canada

Denmark

Finland

France

Germany

Hungary

Italy

Netherlands

Norway

Poland

Sweden

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

250

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

250

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception