Efficacy and Safety of Bevacizumab for the Treatment Hemorrhagic Hereditary Telangiectasia (HHT) Associated With Severe Hepatic Vascular Malformations. Phase II Study (METAFORE)

• ClinicalTrials.gov Identifier: NCT00843440
• Recruitment Status: Completed
• First Posted: February 13, 2009
• Last Update Posted: May 30, 2013
• Sponsor: Hospices Civils de Lyon
• Information provided by (Responsible Party): Hospices Civils de Lyon

Tracking Information

• First Submitted Date: February 12, 2009
• First Posted Date: February 13, 2009
• Last Update Posted Date: May 30, 2013
• Study Start Date: March 2009
• Actual Primary Completion Date: March 2009 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 12, 2009): cardiac output measured at 3 months [ Time Frame: 3 months ]
• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures (submitted: February 12, 2009): Evaluation at 6 and 12 months [ Time Frame: 12 months ]
• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of Bevacizumab for the Treatment Hemorrhagic Hereditary Telangiectasia (HHT) Associated With Severe Hepatic Vascular Malformations. Phase II Study
• Official Title: Efficacy and Safety of Bevacizumab for the Treatment Hemorrhagic Hereditary Telangiectasia (HHT) Associated With Severe Hepatic Vascular Malformations. Phase II Study.

Brief Summary

The efficacy of anti-VEGF treatments such as Bevacizumab in cases of HHT can be considered because of the molecular mechanisms implied in angiogenesis and HHT, as well as the mechanisms of action of this type of treatment. Two articles that have recently reported spectacular improvement thanks to Bevacizumab in patients with HHT complicated with severe liver involvement and cardiac effects support us in this sense.

Up to now, the only treatment recommended in the severe hepatic forms of HHT is a liver transplant, the disadvantages of which are both multiple and well known: long waiting lists, surgical morbidity and mortality, immunosuppressive treatment for life. Furthermore, treatment with Bevacizumab is not a contraindication, should the drug be ineffective, for a subsequent liver transplant if necessary.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hemorrhagic Hereditary Telangiectasia

Intervention

Drug: Bevacizumab

5 mg / kg every 14 days with a total of 6 injections.A two-phase Gehan method will be used with a first phase designed to eliminate a non effective treatment quickly and a second phase allowing assessment of efficacy.

Other Name: AVASTIN

Study Arms

Experimental: Bevacizumab

Study using a Gehan design, 7 patients will be included in the first phase and 18 additional patients will enter the second phase.

Intervention: Drug: Bevacizumab

• Publications *: Dupuis-Girod S, Ginon I, Saurin JC, Marion D, Guillot E, Decullier E, Roux A, Carette MF, Gilbert-Dussardier B, Hatron PY, Lacombe P, Lorcerie B, Rivière S, Corre R, Giraud S, Bailly S, Paintaud G, Ternant D, Valette PJ, Plauchu H, Faure F. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA. 2012 Mar 7;307(9):948-55. doi: 10.1001/jama.2012.250.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 12, 2009): 25
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: March 2012
• Actual Primary Completion Date: March 2009 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• General criteria:

  • Age ≥ 18 years and < 70 years
  • Subjects must have given their free and enlightened consent and have signed the consent form.

• HHT related criteria

  • Patients monitored for clinically confirmed HHT disease.
  • Patients with severe liver involvement in relationship with the HHT disease
  • Patients with a high cardiac output on ultrasound.

• Associated disease related criteria

  • Blood: neutrophil ≥ 1.0x109 / L and platelets ≥ 100x109 / L.
  • INR (International Normalized Ratio) ≤ 1.5 (except for patients on anticoagulants) and TCA ≤ 1.5 x upper limit of the standard laboratory
  • Renal function: creatinine ≤ 1.25 x upper limit of the standard laboratory. Patients who proteinuria to strip ≥ 2 + will have control of the Proteinuria of 24 hours to be ≤ 1g / 24 hours

Exclusion Criteria:

• • General criteria
• Women who are pregnant or liable to become pregnant in the course of the trial.
• Patients who have reached their majority but who are protected by the terms of the law (French public health code).
• Refusal to give enlightened consent.

• Patients who are not affiliated to a health insurance regime

  • Criteria for the medical history

• Patients in whom the diagnosis of HHT disease has not been confirmed.
• The presence of atrial fibrillation on the electrocardiogram at the inclusion.
• The presence of cerebral arteriovenous malformations on the angioMRI done in the year prior to inclusion.
• Existence of diverticulitis of the colon or sigmoid
• Thrombosis within 6 months before inclusion
• Infectious disease treated by antibiotics and unresolved at inclusion.

• Patients with blood pressure that is not being controlled at the time of inclusion (systolic blood pressure> 150 mmHg and / or diastolic> 100 mmHg) with or without treatment. Patients who have high blood pressure can be included when the blood pressure numbers have been standardized by appropriate medical treatment.

  • Surgical criteria

• Major surgery (including open biopsy) or severe trauma within 28 days preceding the start of treatment.

  • Medical treatments

• Current or recent use of non steroidal anti-inflammatory drugs or antiplatelet therapy 10 days before the first administration of Bevacizumab.
• Use of oral or parenteral anticoagulants or thrombolytic agents within 28 days preceding inclusion (anticoagulants given prophylactically are permitted).
• Participation in another clinical trial within 28 days preceding inclusion.
• Vaccination with live vaccines or against yellow fever during the treatment period.

• Administration of phenytoin (Di-hydan ® DILANTIN ®) during the treatment period.

  • Allergy

• Hypersensitivity to the active substance or any of its excipients.
• Hypersensitivity to products made from Chinese hamster ovary (CHO) cells or to any other human or humanized recombinant antibodies.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT00843440
• Other Study ID Numbers: 2008.510/11
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Hospices Civils de Lyon
• Study Sponsor: Hospices Civils de Lyon
• Collaborators: Not Provided

Investigators

• Principal Investigator: Sophie DUPUIS-GIROD, MD; Hospices Civils de Lyon

• PRS Account: Hospices Civils de Lyon
• Verification Date: October 2009