Clinical trial NCT00035334: Study of the Safety and Efficacy of NC-503 in Secondary (AA) Amyloidosis
Official title: A Phase II/III Study of the Safety and Efficacy of NC-503 in Patients Suffering From Secondary (AA) Amyloidosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Secondary (AA) Amyloidosis
Rheumatoid Arthritis
Nephrotic Syndrome
Familial Mediterranean Syndrome
Kidney Diseases
Gastrointestinal Diseases
Keywords: Familial Mediterranean Fever
Amyloidosis
Secondary (AA) Amyloidosis
Nephrotic Syndrome
Lead sponsor: Bellus Health Inc. - a GSK company
Sponsor class: INDUSTRY
Collaborators: name: FDA Office of Orphan Products Development
First posted: 2002-05-03
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main objective of this study is to evaluate the safety and efficacy of NC-503 compared to placebo in patients with secondary (AA) amyloidosis using a composite assessment of clinical improvement/worsening of both renal and gastrointestinal functions.

Detailed description: AA amyloidosis is associated with chronic inflammatory conditions (rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease), chronic infection (tuberculosis, osteomyelitis), and Familial Mediterranean Fever. Rheumatoid arthritis is the major cause of AA amyloidosis in Western Europe and North America. The most common clinical feature of AA amyloidosis is renal dysfunction manifested as nephrotic-range proteinuria or renal insufficiency at the time of diagnosis. End-stage renal failure is the cause of death in 40-60% of cases. Gastrointestinal involvement is also frequent and is usually manifested as chronic diarrhea, body weight loss and malabsorption. Enlargement of the liver and spleen may also occur in some patients. The median survival time from diagnosis varies from 2 to 8 years depending on the stage of the disease at time of diagnosis. The goal of the current therapy in AA amyloidosis is the control of the associated disease. However, the current approaches for the treatment of AA amyloidosis are unspecific, toxic, invasive, and not sufficiently effective in many cases. NC-503 was specifically designed to compete with the naturally occurring sulfated GAGs for the binding to amyloidogenic precursor proteins, and to inhibit amyloid deposition into tissues. The proposed therapy with NC-503 is based on the prevention of the amyloid fibril formation. The objective of this clinical phase II/III study is to determine the efficacy and safety of NC-503 compared to a placebo in patients suffering from secondary (AA) amyloidosis by the assessment of clinical improvement/ worsening of both renal and gastrointestinal functions.

Eligibility criteria: PROTOCOL INCLUSION CRITERIA

* Patients must be 18 years of age or older.
* Males and females. If women of childbearing potential (i.e., not surgically sterilized or post-menopausal greater than one year) the patient must be using effective birth control.
* Diagnosis of AA amyloidosis demonstrated by positive biopsy (Congo red staining) and immunohistochemistry or immunoelectron microscopy at screening visit. Tissue from previous biopsy can be used for confirmation of diagnosis, if available.
* Persistent proteinuria defined as urinary protein excretion ? 1g/24h in two distinct 24-h urine collections at least 1 week apart within 3 months prior to study entry (baseline, Month 0 visit) without evidence of urinary tract infection or overt heart failure (NYHA class III or more); OR creatinine clearance ? 60 mL/min in two distinct measures at least 1 week apart within 3 months prior to study entry (baseline, Month 0 visit).
* Creatinine clearance ? 20 mL/min AND serum creatinine ? 3 mg/dl within 3 months prior to study entry (baseline, Month 0 visit).
* Written informed consent.

PROTOCOL EXCLUSION CRITERIA

* Evidence or suspicion of renal or renovascular diseases other than renal AA amyloidosis.
* Presence of diabetes mellitus (Type I and II).
* Evidence of a cause of potentially reversible reduced renal function, such as accelerated hypertension or drug nephrotoxicity.
* AST, ALT, or ALP \> 5 times the upper limit of normal, or total bilirubin 50% above upper limits of normal.
* Presence of any other clinically significant diseases that could interfere with the interpretation of study results or compromise patient safety or any conditions that could reduce life expectancy to less than two years.
* Use of an investigational drug within thirty days prior to the screening visit.
* Active alcohol and/or drug abuse.
* Initiation of or any changes in ACE inhibitor therapy within 3 months prior to the screening visit.
* Initiation of or any changes in cytotoxic agents/colchicine therapy within 3 months prior to the screening visit.
* Inability to provide legal consent.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Indiana University School of Medicine, Department of Pathology and Laboratory Medicine,
state: Indiana
city: Boston
country: United States
facility: Boston Medical Center, Renal Division
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Heinola
country: Finland
facility: Rheumatism Foundation Hospital
city: Le Mans
country: France
facility: Centre Hospitalier du Mans, Service de Rhumatologie
city: Lille
country: France
facility: Hôpital Claude Huriez, Service de médecine Interne, Clinique Médicale A
city: Paris
country: France
facility: Hôpital Cochin, Centre de Recherche et d'Explorations Fonctionnelles
city: Haifa
country: Israel
facility: Bnai Zion Medical Center
city: Tel Hashomer
country: Israel
facility: Heller Institute of Medical Research, Sheba Medical Center
city: Pavia
country: Italy
facility: Italian Group for Systemic Amyloidosis, Biotechnology Research Laboratories, IRCCS Policlinico San Matteo, Internal Medicine and Medical Oncology
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital
city: Groningen
country: Netherlands
facility: University Hospital Groningen, Department of Medicine, Division of Rheumatology
city: Warszawa
country: Poland
facility: Instytut Reumatologiczny
city: Wroclaw
country: Poland
facility: Okregowy Szpital Kolejowy, Zaklad Reumatologii
city: Moscow
country: Russian Federation
facility: Institute of Rheumatology RAMS
city: Yekaterinburg
country: Russian Federation
facility: Regional Hospital No. 1
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias I Pujol, Servicio de Reumatologia
city: Barcelona
country: Spain
facility: Hospital Clinic I Provincial de Barcelona, Jefe del Departamento de Reumatologia
city: Llobregat
country: Spain
facility: Ciutad Sanitària y Universitària de Bellvitge, Servicio de Reumatologia, Hospitalet de Llobregat
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos de Madrid, Servicio de Reumatologia
city: Askaray, Istanbul, Turkey
country: Turkey
facility: Cerrehpasa Tip Fakultesi
city: Istanbul
country: Turkey
facility: Istanbul Faculty of Medicine, Department of Internal Medicine, Division of Rheumatology
city: Uskudar, Altunizade, Istanbul
country: Turkey
facility: Marmara University Medical School Hospital, Department of Rheumatology
city: London
country: United Kingdom
facility: Royal Free and University College Medical School, Department of Medicine, National Amyloidosis Centre
city: Scotland
country: United Kingdom
facility: Gartnavel General Hospital
Study officials:
References:
citation: Safety, Tolerability and Pharmacokinetic Profile of FibrillexTM (Anti-AA Amyloid Agent) in Healthy and Renal Impaired Subjects. Garceau D., Gurbindo C., Laurin J. Neurochem Inc. Reference: Proceedings from the IXth International Symposium on Amyloidosis , 2001 (Budapest, Hungary)
citation: Dember LM, Hawkins PN, Hazenberg BP, Gorevic PD, Merlini G, Butrimiene I, Livneh A, Lesnyak O, Puechal X, Lachmann HJ, Obici L, Balshaw R, Garceau D, Hauck W, Skinner M; Eprodisate for AA Amyloidosis Trial Group. Eprodisate for the treatment of renal disease in AA amyloidosis. N Engl J Med. 2007 Jun 7;356(23):2349-60. doi: 10.1056/NEJMoa065644.