Dose Ranging Study of ART621 in Subjects Diagnosed With Rheumatoid Arthritis Taking Methotrexate

Rheumatoid Arthritis Clinical Trial

Official title:

Multi-Centre Randomised Double-Blind Pbo-Controlled Dose-Ranging Study to Evaluate the Safety, Tolerability, Efficacy, PK and Immunogenicity of Multiple Doses of ART621 for 3 Months in Patients With Rheumatoid Arthritis Taking Methotrexate

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00928317
• Other study ID #: ART621-221
• Status: Terminated
• Phase: Phase 2
• First received: June 24, 2009
• Last updated: January 4, 2010
• Start date: April 2009
• Est. completion date: December 2009

Study information

• Verified date: January 2010
• Source: Arana Therapeutics Ltd
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaAustralia: Department of Health and Ageing Therapeutic Goods AdministrationCzech Republic: State Institute for Drug ControlIndia: Central Drugs Standard Control OrganizationNew Zealand: MedsafeMalaysia: Ministry of HealthPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
• Study type: Interventional

Clinical Trial Summary

The purpose of this clinical trial is to assess the safety, efficacy, tolerability, immunogenicity and pharmacokinetics of 3 dose levels of ART621 in the treatment of rheumatoid arthritis.

Description:

Despite being effective in approximately 60% of subjects, there are limitations to existing anti-TNF therapies especially in relation to immunogenicity, safety and administration. In addition, due to their high molecular weight, currently marketed products are largely confined to the blood stream.

ART621 is an anti-TNF molecule that contains 2 identical domain "antibodies" that have the binding activity of a full antibody but with a substantially smaller molecular size. The molecular weight of approximately half that of full size antibodies is predicted to, a) have improved tissue penetration and, b) to be less immunogenic than full size antibodies.

This clinical trial is designed to assess the safety, efficacy, tolerability, immunogenicity and pharmacokinetics of ART621 when administered with an intravenous loading dose followed by subcutaneous administration every week.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 13
• Est. completion date: December 2009
• Est. primary completion date: November 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Provision of a valid written informed consent.

• Male or female subjects = 18 and = 80 years old.

• Women of childbearing potential, or men of fathering potential, must be using adequate (in the investigator's opinion) birth control measures (e.g. abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, or surgical sterilisation) during the study. Female subjects of childbearing potential must test negative for pregnancy prior to enrolling in the study. Post menopausal (cessation of menses for more than 2 years) women are eligible for this study.

• Diagnosis of RA according to the revised (1987) American College of Rheumatology criteria for at least 6 months and no longer than 3 years prior to screening.

• Meet ACR functional class criteria I, II or III.

• Have active RA at the time of screening and at baseline, defined as = 6 swollen joints and = 6 tender joints (from 68 joint count) together with at least 2 of the following 3 criteria:

• CRP level = 1.5 mg/dl;

• ESR by Westergren method = 28 mm in the first hour; or

• morning stiffness = 45 minutes.

• At least one of the following should be present at screening:

• documented history or current presence of positive rheumatoid factor;

• presence of serum anti-CCP antibodies; or

• screening radiographic erosion

• Have been tolerating concomitant methotrexate (oral or subcutaneous) for at least 3 months prior to screening and on a stable dose between 10-25 mg per week for at least 6 weeks prior to the first study dose. The route of administration must also be stable. Use of methotrexate dose of 25-50 mg every 2 weeks is also acceptable. (Other DMARDs taken concomitantly with methotrexate are not allowed. Those subjects concomitantly receiving additional DMARDs with methotrexate may enter the study by stopping the additional DMARD at least 4 weeks prior to first study dose).

• If using the following medication, the subject must be on a stable dose for the 4 weeks prior to the first study dose and maintain that dose throughout the study:

• oral corticosteroids, equivalent to = 10 mg of prednisone/day.

• one nonsteroidal anti-inflammatory drug (NSAID).

• 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) or fibrates (see Section 7.1 for acceptable doses).

• Does not have active or latent TB according to eligibility assessment and screening rules (see Section 8.3.1).

• Is willing and able to comply with study visits and other protocol requirements.

Exclusion Criteria:

• Pregnant, nursing, or planning a pregnancy (both men and women) within 9 months of enrolment.

• Subjects weighing > 100 kgs.

• Screening laboratory tests:

• hemoglobin = 8.0 gm/dl

• white blood cells = 3.0 x103 cells/µl

• neutrophils = 1.5 x 103 cells/µl

• platelets =100 x 103 cells/µl

• serum transaminase level (AST and ALT) = 2 times upper limit of normal (ULN)

• serum creatinine = 0.15 mmol/l

• Subjects with diagnosis of juvenile arthritis or other inflammatory or autoimmune diseases that might confound the evaluations of benefit from ART621 such as ankylosing spondylitis, systemic lupus erythematosus and Lyme disease.

• Subjects who have previously failed to respond to any oral or injectable anti-TNFa therapy or subjects who have had to stop anti-TNFa therapy for safety reasons. Subjects who have successfully responded to anti-TNFa therapy in the past (but discontinued for reasons other than safety or lack of efficacy) > 6 months prior to study day one may enrol. Patients who have participated in a previous anti-TNFa therapy study are eligible if they are confirmed to have received placebo.

• Subjects who have previously received the following anti-rheumatic drugs:

interleukin-1 receptor antagonist [anakinra], rituximab, anti-CD4 antibody, abatacept, thalidomide, p38 MAP kinase inhibitor and other agents (other than those listed in Section 7.3).

• Subjects who have undergone plasmapheresis within 6 months prior to randomisation.

• Have received intraarticular, intramuscular, or intravenous corticosteroids, including intramuscular adrenocorticotropic hormone, during the 4 weeks prior to the first study dose, or non-stable doses of oral steroids.

• Subjects with a history of any clinically significant adverse reaction to murine or chimeric proteins, including serious allergic reactions.

• Subjects with Felty's syndrome or a history of Felty's syndrome.

• Subjects who have received or are expecting to receive any live virus or bacterial vaccinations within 1 month before first study dose, during the study, or up to 3 months after the study dose.

• Subjects with a history of, presence of, or at high risk of serious infection including:

• history of active TB, or positive Mantoux test or QuantiFERON Gold test or chest x-ray suggestive of active or healed TB or positive contact history with a subject with active TB within the past 3 months. If subjects have a positive Mantoux test but a negative QuantiFERON Gold test, they may be enrolled.

• a serious infection during the 3 months prior study entry (hospitalised or received IV antibiotics for an infection).

• chronic or recurrent infectious disease.

• systemic fungal infections

• opportunistic infection within 3 months prior to screening (refer to 1993 CDC Classification System for HIV Infection).

• subjects known, or suspected, to be infected with HIV, hepatitis B, or hepatitis C.

• subjects with planned joint replacement surgery or a history of infected joint prosthesis or who have received antibiotics for a suspected infection of a joint prosthesis if that prosthesis has not been removed or replaced.

• Subjects with a known history of demyelinating diseases such as multiple sclerosis or optic neuritis.

• Subjects with evidence of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, psychiatric, or cerebral disease.

• Concurrent CHF, including medically controlled, asymptomatic CHF or ECG findings suggestive of CHF.

• Subjects receiving cytotoxic drugs including cyclophosphamide, cyclosporine, or alkylating agents within 6 months prior to first study dose.

• Known history or evidence of malignancy, lymphoproliferative or neoplastic disease with the exception of successfully treated basal or squamous cell carcinoma of the skin or cervical intraepithelial neoplasia.

• Subjects who have undergone organ transplant (with exception of a corneal transplant more than 3 months prior to screening).

• Subjects previously enrolled in this study, currently participating in another investigational study or treated with any investigational drug within the previous 3 months or within 5 half-lives, whichever is greater, prior to first study dose.

• Any other clinically significant disease or disorder or factors such as substance abuse which in the opinion of the investigator make the subject ineligible for participation in this study.

Study Design

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

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• ART621
3.0mg/kg s.c.
• ART621
1.5mg/kg s.c.
• ART621
0.75mg/kg s.c.
• Placebo
Placebo s.c.

Locations

Country	Name	City	State
Argentina	Instituto Medico Especializado IME	Buenos Aires	BUE
Argentina	IMAI Research - Instituto Medico de Asistencia y Investigaci	Calle French
Argentina	ILAIM-CEOM Inst. Latinoamericano de Inv. Medicas	Cordoba	CRD
Argentina	Instituto Medico CER	Quilmes	Bue
Argentina	CAICI	Rosario	SFE
Argentina	Sanatorio Parque S.A.	Rosario	SFE
Argentina	Ctro Polivalente de Asist e Invest Clinica CER	San Juan	SJN
Argentina	Centro Medico Privado de Reumatologia	San Miguel de Tucuman	TUC
Argentina	Centro Medico Privado de Reumatologia	San Miguel de Tucuman
Argentina	Centro de Investigaciones Reumatológicas	Tucuman	TUC
Australia	Lyell McEwin Hospital	Elizabeth Vale	New South Wales
Australia	Coast Joint Care	Maroochydore	Queensland
Australia	Georgetown Arthritis Centre	Sydney	New South Wales
Australia	The Queen Elizabeth Hospital	Woodville	South Australia
Czech Republic	Revmatologicka ambulance	Bruntal
Czech Republic	Nemocnice Jihlava	Jihlava
Czech Republic	ARTHROMED s. r. o.	Pardubice
Czech Republic	Fakultni nemocnice Plzen	Plzen - Bory
Czech Republic	Revmatologicky ustav	Praha 2
India	M.S. Ramaiah Memorial Hospital	Bangalore	Karna
India	St. John's Medical College Hospital	Bangalore	Karna
India	Apollo Hospital Educational and Research Foundation	Hyderabaad	Andh Prad
India	Nizams Institute of Medical Sciences	Hyderabaad	Andh Prad
India	Sanjay Gandhi Postgraduate Institute	Lucknow	Uttar Prad
India	Apollo Hospitals Educational and Research Foundation	Madurai	Tamilnadu
India	K. M. C. Hospital	Mangalore
India	Centre for Rheumatic Diseases	Pune	Mahara
India	Krishna Institute of Medical Sciences	Secunderabad	Andh Prad
India	King George Hospital	Vishakhapattanam	Andh Prad
Malaysia	Putra Medical Centre	Alor Setar	Kedah
Malaysia	University Malaya Medical Centre	Kuala Lumpur
Malaysia	Hospital Ipoh	Perak
Malaysia	Sarawak General Hospital	Sarawak
New Zealand	C G M Research Trust, The Princess Margaret Hospital	Christchurch
Poland	NZOZ Centrum Osteoporozy i Chorob Kostno-Stawowych	Bialystok
Poland	Samodzielny Publiczny ZOZ w Dzialdowie	Dzialdowo
Poland	Nzoz Reumed	Lublin
Poland	Medyczne Centrum Hetmanska	Poznan
Poland	SPSK nr 1 im. Tadeusza Sokolowskiego PAM	Szczecin
Poland	Centrum Medyczne OSTEOMED	Warszawa
United States	Physician Research Collaboration, LLC	Lincoln	Nebraska
United States	Westroads Medical Group	Omaha	Nebraska
United States	Arthritis Clinic	Racine	Wisconsin
United States	Arthritis Northwest, PLLC	Spokane	Washington
United States	Arthritis Center	Springfield	Illinois
United States	Tampa Medical Group P.A.	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Arana Therapeutics Ltd

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Czech Republic,  India,  Malaysia,  New Zealand,  Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy of ART621 on the signs and symptoms of moderate to severe RA in subjects concomitantly taking methotrexate as assessed by the proportion of subjects achieving an ACR20 response.		12 weeks	No
Secondary	Dose-response relationship of ART621 against the signs and symptoms of moderate to severe RA as assessed by additional efficacy, safety and QoL parameters.		12 weeks	No
Secondary	Immunogenicity profile of ART621 as assessed by development of HAHAs.		16 weeks	No
Secondary	Plasma concentration versus time profile and population PK of ART621 in subjects with RA.		16 weeks	No
Secondary	Effect of ART621 on immunological parameters and other disease biomarkers.		12 weeks	No