Efficacy Study of Oral L-Citrulline in Patients Taking Simvastatin With Peripheral Arterial Disease

Peripheral Arterial Disease Clinical Trial

Official title:

Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Oral L-Citrulline Compared to Placebo in Patients Taking Background Simvastatin 40 mg qD and With Peripheral Arterial Disease Including Intermittent Claudication

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00351286
• Other study ID #: ANGX-1039-02
• Status: Active, not recruiting
• Phase: Phase 2
• First received: July 10, 2006
• Last updated: October 17, 2006
• Start date: March 2006

Study information

• Verified date: July 2006
• Source: Angiogenix
• Contact: n/a
• Is FDA regulated: No
• Health authority: Russia: Ministry of Health of the Russian Federation
• Study type: Interventional

Clinical Trial Summary

To prove the combination of L-citrulline with simvastatin leads to greater improvement in the symptoms of peripheral arterial disease (PAD) than simvastatin alone by evaluating oral L- citrulline or placebo against simvastatin for improvement in treadmill walking distance in patients, 40–75 years of age, who have PAD with intermittent claudication.

Description:

The primary objective of this study is to prove the combination of L-citrulline with simvastatin leads to greater improvement in the symptoms of PAD than simvastatin alone. This will be accomplished by evaluating efficacy of orally administered L-citrulline or placebo against background therapy with simvastatin for improvement in treadmill absolute claudication walking distance (ACWD) in patients, 40–75 years of age, who have PAD with intermittent claudication in Fontaine stage II and symptom-limited treadmill walking distance.

Secondary objectives include comparing the combination therapy to simvastatin alone for improvement in treadmill pain-free walking distance (PFWD) and ischemic window.

Other secondary objectives include evaluating the safety and tolerability of L-citrulline alone or combined with simvastatin in this patient population and assessing the effects of treatment on quality of life (QOL) as measured by two QOL instruments.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 160
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Male or female, 40–75 years of age

2. If female, post-menopausal for the past year, surgically sterile (i.e., tubal ligation, hysterectomy), or using an adequate method of birth control (i.e., oral contraceptives, double barrier method, IUD cover, sterilized partner, or other method deemed appropriate by Investigator)

3. If male capable of fathering children, using an adequate method of birth control (i.e., condom or partner using adequate method of birth control)

4. Peripheral arterial disease with stable, reproducible, intermittent claudication and symptom-limited treadmill walking distance of at least 6 months duration

5. Rest ankle-brachial index (ABI) =0.90 and 10 mm Hg decrease in ankle pressure 1 minute after completing the ETT

6. ACWD on a standardized (Skinner-Gardner protocol) ETT =50 m (164 feet) but =300 m (984 feet) determined by the average result on two consecutive ETTs performed at least 7 days apart during the screening phase (Fontaine stage II)

7. ACWD variability <25% between two consecutive ETTs performed at least 7 days apart during the screening phase. The percent variability is calculated by the difference of the two walking distances divided by the greater of the two walking distances multiplied by 100%. If the variability exceeds 25% a third ETT may be performed and the variability between the second and third test used to determine baseline and inclusion criteria

8. Willingness to receive dietary counseling and follow a low-cholesterol diet during the study

9. Ability to give written informed consent and has signed a written informed consent form approved by the Investigator’s Independent Ethics Committee (IEC)

Exclusion Criteria:

1. Critical limb ischemia (defined as presence of rest pain requiring analgesics for more than 2 weeks or the presence of lower limb ulcers or gangrene)

2. Coronary artery or peripheral artery angioplasty or surgical limb arterial bypass within the last 3 months

3. Any previous amputation on the lower limbs

4. Anticipated requirement of surgical or percutaneous revascularization within 3 months of randomization

5. Currently participating in a supervised exercise regimen

6. Stroke, myocardial infarction, or deep-vein thrombosis within the last 3 months

7. Non-atherosclerotic PAD (e.g., thromboangiitis obliterans)

8. Known abdominal aortic aneurysm =4.5 cm

9. Unstable angina pectoris within the last 3 months

10. Congestive heart failure (New York Heart Association Class III or IV) despite treatment

11. Severe, uncontrolled hypertension (sitting systolic blood pressure >180 mm Hg or sitting diastolic blood pressure >95 mm Hg)

12. Anemia (hemoglobin <10 g/dL in women and 11 g/dL in men) or any clinically significant bleeding episode within the last year

13. Abnormal platelet count (platelets >150,000/mm3 or <60,000/mm3)

14. Type I diabetes mellitus or Type II diabetes mellitus if it is accompanied by diabetic peripheral neuropathy

15. Morbid obesity (body mass index >40 kg/m2)

16. Severe renal insufficiency (creatinine >221 µmol/L (2.5 mg/dL))

17. Severe hepatic insufficiency (ALT [SGPT] and AST [SGOT] = 3x upper limit of normal on two separate tests

18. Any disorder that would affect the interpretation of ETT results

19. Use of medications that are not allowed and which cannot be discontinued during the study

20. Participation in an investigational drug or device study within previous 30 days

21. Underlying disease other than PAD resulting in a life expectancy of less than 1 year

22. If female, breast feeding, pregnancy confirmed by a positive serum pregnancy test, or using inadequate birth control

23. Other conditions that could impair informed consent or compliance

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Intermittent Claudication
• Peripheral Arterial Disease
• Peripheral Vascular Diseases

Intervention

Drug:
• L-citrulline tablets, 1000 mg

• Placebo tablets matching L-citrulline tablets

• Background simvastatin at a stable dose of 40 mg qHS

Locations

Country	Name	City	State
Russian Federation	Municipal Healthcare Institution, Gatchina Central District Hospital	Gatchina	Russia
Russian Federation	Russian State Medical University at Filatov City Hospital #15	Moscow	Russia
Russian Federation	Vishnevsky Institute of Surgery, Russian Medical Academy of Science	Moscow	Russia
Russian Federation	Municipal Prophylaxis and Treatment Institution, City Hospital #13	N. Novgorod	Russia
Russian Federation	Municipal Medical Institution City Hospital #1 of Saratov	Saratov	Russia
Russian Federation	St. Petersburg State Healthcare Institution, Hospital #2	St. Petersburg	Russia
Russian Federation	St. Petersburg State Healthcare Institution, Hospital #26	St. Petersburg	Russia
Russian Federation	St. Petersburg State Healthcare Institution, Pokrovskaya Hospital	St. Petersburg	Russia
Russian Federation	St. Petersburg State Healthcare Institution, Research for Emergency Medical Care	St. Petersburg	Russia
Russian Federation	State Educational Institution of Higher Professional Education	St. Petersburg	Russia

Sponsors (1)

Lead Sponsor	Collaborator
Angiogenix

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in absolute claudication walking distance from baseline to end of 12-week double-blind treatment period.
Secondary	Change in pain-free walking distance
Secondary	Changes in QOL scores from baseline to 12 and 36 weeks
Secondary	Change in absolute claudication walking distance from baseline to 36 weeks