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

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

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

Study Overview

• Status: Completed
• Conditions: Peripheral Arterial Occlusive Disease
• Intervention / Treatment: Drug: XRP0038 (NV1FGF)

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

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Bern, Switzerland
• United States
  • Minnesota
    • Minneapolis, Minnesota, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Study Director: International Clinical Development Clinical Study Director, Sanofi

Publications and helpful links

General Publications

• Niebuhr A, Henry T, Goldman J, Baumgartner I, van Belle E, Gerss J, Hirsch AT, Nikol S. Long-term safety of intramuscular gene transfer of non-viral FGF1 for peripheral artery disease. Gene Ther. 2012 Mar;19(3):264-70. doi: 10.1038/gt.2011.85. Epub 2011 Jun 30.

Study record dates

Study Major Dates

• Study Start: January 1, 2002
• Primary Completion (Actual): October 1, 2003
• Study Completion (Actual): October 1, 2003

Study Registration Dates

• First Submitted: July 2, 2010
• First Submitted That Met QC Criteria: July 2, 2010
• First Posted (Estimate): July 5, 2010

Study Record Updates

• Last Update Posted (Estimate): July 5, 2010
• Last Update Submitted That Met QC Criteria: July 2, 2010
• Last Verified: July 1, 2010

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arterial Occlusive Diseases
• Other Study ID Numbers: TED10105; PM105 (Gencell)