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

This study has been terminated.
(Corporate re-prioritization)
Sponsor:
Information provided by:
Arana Therapeutics Ltd
ClinicalTrials.gov Identifier:
NCT00928317
First received: June 24, 2009
Last updated: January 4, 2010
Last verified: January 2010
  Purpose

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.


Condition Intervention Phase
Rheumatoid Arthritis
Drug: ART621
Drug: Placebo
Phase 2

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

Resource links provided by NLM:


Further study details as provided by Arana Therapeutics Ltd:

Primary Outcome Measures:
  • 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. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Dose-response relationship of ART621 against the signs and symptoms of moderate to severe RA as assessed by additional efficacy, safety and QoL parameters. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • Immunogenicity profile of ART621 as assessed by development of HAHAs. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  • Plasma concentration versus time profile and population PK of ART621 in subjects with RA. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  • Effect of ART621 on immunological parameters and other disease biomarkers. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Enrollment: 13
Study Start Date: April 2009
Study Completion Date: December 2009
Primary Completion Date: November 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ART621 A
ART621 0.75mg/kg per week
Drug: ART621
0.75mg/kg s.c.
Experimental: ART621 B
ART621 1.5 mg/kg per week
Drug: ART621
1.5mg/kg s.c.
Experimental: ART621 C
ART621 3.0mg/kg per week
Drug: ART621
3.0mg/kg s.c.
Placebo Comparator: Placebo arm Drug: Placebo
Placebo s.c.

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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-TNFα therapy or subjects who have had to stop anti-TNFα therapy for safety reasons. Subjects who have successfully responded to anti-TNFα 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-TNFα 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00928317

  Show 46 Study Locations
Sponsors and Collaborators
Arana Therapeutics Ltd
  More Information

No publications provided

Responsible Party: David Fuller, Chief Medical Officer, Arana Therapeutics Limited
ClinicalTrials.gov Identifier: NCT00928317     History of Changes
Other Study ID Numbers: ART621-221
Study First Received: June 24, 2009
Last Updated: January 4, 2010
Health Authority: United States: Food and Drug Administration
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Australia: Department of Health and Ageing Therapeutic Goods Administration
Czech Republic: State Institute for Drug Control
India: Central Drugs Standard Control Organization
New Zealand: Medsafe
Malaysia: Ministry of Health
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Methotrexate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on July 22, 2014