Gene Expression and Tolerability Study of NV1FGF in Patients With Peripheral Artery Occlusive Disease Planned to Undergo Major Amputation

Study Overview
=================
Brief Summary
-----------------
The primary objective is to evaluate the transgene expression (synthesis of FGF-1 mRNA) in injected tissue, at injection site, after Intra Muscular (IM) administration of increasing single doses of NV1FGF. Secondary objectives : To evaluate the safety and tolerability of IM administration of increasing single doses of NV1FGF To evaluate the transgene expression (FGF-1 protein) in injected tissues (injection site and remote site) To evaluate the presence of FGF-1 receptors in injected tissues (injection site and remote site) To evaluate the NV1FGF biodistribution in injected tissues (injection site and remote site), in multiple organs/tissues when appropriate, and plasma To evaluate the transgene expression (synthesis of FGF-1 mRNA) in injected tissue at remote site To collect data from plasma NV1FGF pharmacokinetics To evaluate healing of the amputation site

Detailed Description
-----------------
Screening of 1 to 4 weeks before study drug administration; Single study drug administration 3 to 8 days before planned amputation; 6 months of follow up

Official Title
-----------------
Phase I, Double Blind, Parallel-Group, Multi-center, Gene Expression (Synthesis of FGF-1 mRNA) and Tolerability Study of Increasing Single Dose of NV1FGF Administered by Intra-Muscular Injection in Subjects With Severe Peripheral Artery Occlusive Disease (PAOD) Planned to Undergo Amputation Above the Ankle

Conditions
-----------------
Peripheral Arterial Occlusive Disease

Intervention / Treatment
-----------------
* Drug: XRP0038 (NV1FGF)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with prior decision for amputation above the ankle because of severe PAOD Males or females above 18 years Females must be either: Non pregnant, non lactating , having practicing a medically accepted method of birth control for more than 2 months prior screening visit; or surgically sterilized (tubal ligation or hysterectomy) or post menopausal for at least one year Exclusion Criteria: Subjects with urgent need for amputation that cannot await until completion of the screening period (up to 4 weeks), added to the minimum required 48 hours between study test medication administration and tissue sample collection Previous or current history of malignant disease (subjects with successful tumor resection more than 5 years -without any recurrence- prior to study start could be enrolled) Abnormal Chest X-ray or mammography with suspicion of malignant disease Positive stool hemoccult (except in case of hemorrhoids or any other identified cause with no malignancy origin) Men with positive Prostate Specific Antigen (PSA) (above 2.5 ng/ml in subjects < 50 years and above 5 ng/ml in subjects above 50 years) Females with Papanicolaou smear of Class IV or Class V characterization Serious concomitant medical conditions not adequately controlled Alcohol or drug abuse Active proliferate retinopathy defined by the presence of new vessel formation and scarring Participation in clinical trials of non-approved experimental agents within four weeks before study entry; Positive serology for HIV1 or 2 Creatinine above 2.0 mg/dl (176 µmol/l), unless the subject is on hemodialysis / peritoneal dialysis and diagnosed with complete and irreversible renal failure or end-stage renal disease (ESRD) Subjects who had a stroke or a neurological deficit presumably due to a stroke, within 3 months prior to study treatment (Amendment #1) Alpha-fetoprotein (AFP) in serum > 15 µg/l, unless liver ultrasound ruled out any malignant disease Positive serology for hepatitis B or C, unless liver ultrasound ruled out any malignant disease. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NV1FGF 500 μg<br>8 intramuscular injections for a total of 500 μg administered in one single administration 3 to 8 days before major amputation | Drug: XRP0038 (NV1FGF)<br>* Pharmaceutical form : solution Route of administration : intramuscular<br>|
| Experimental: NV1FGF 2000 μg<br>8 intramuscular injections for a total of 2000 μg administered in one single administration 3 to 8 days before major amputation | Drug: XRP0038 (NV1FGF)<br>* Pharmaceutical form : solution Route of administration : intramuscular<br>|
| Experimental: NV1FGF 4000 μg<br>8 intramuscular injections for a total of 4000 μg administered in one single administration 3 to 8 days before major amputation | Drug: XRP0038 (NV1FGF)<br>* Pharmaceutical form : solution Route of administration : intramuscular<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Detection of FGF-1 mRNA (by real-time RT-PCR) in injected tissues at injection site |  | 3 to 8 days after amputation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Detection of FGF-1 protein (by immunohistochemistry) in injected tissues (injection and remote site) |  | 3 to 8 days after amputation | 
| Detection of FGF-1 mRNA (by real-time RT-PCR) in injected tissues at remote site |  | 3 to 8 days after amputation | 
| Detection of FGF-1 receptor (by immunohistochemistry) in injected tissues (injection and remote site) |  | 3 to 8 days after amputation | 
| Detection of NV1FGF (by real-time PCR) in injected tissues (injection and remote site), in multiple organs/tissues when appropriate, and in plasma |  | 2 months | 
| Evaluation of healing of the amputation site |  | 6 months |