Aminopterin Dose Finding Treatment for Methotrexate-Naïve Rheumatoid Arthritis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01724931
Recruitment Status : Completed
First Posted : November 12, 2012
Last Update Posted : May 20, 2015
Information provided by (Responsible Party):
Syntrix Biosystems, Inc.

Brief Summary:
The purpose of this study is to determine whether aminopterin is effective in the treatment of rheumatoid arthritis (RA).

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Drug: LD-aminopterin Drug: placebo Phase 2

Detailed Description:
This is a double-blind, randomized, placebo-controlled, dose ranging study that will evaluate the safety, efficacy, and pharmacokinetic properties (the absorption, distribution and excretion) of aminopterin following oral administration by subjects with active rheumatoid arthritis (≥ 6 tender and ≥ 6 swollen joints) who have not been treated with methotrexate (MTX). Subjects are randomized to one of three treatments: placebo, 1 mg of LD-aminopterin, or 3 mg of LD-aminopterin in a 1:1:1 ratio. The study hypothesis is that the 3 mg LD-aminopterin per week is effective at treating rheumatoid arthritis compared to placebo.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 175 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2 Double-Blind, Placebo-Controlled, Randomized Dose Finding Study For The Efficacy And Safety Of Aminopterin In Methotrexate-Naive Rheumatoid Arthritis
Study Start Date : February 2013
Primary Completion Date : September 2014
Study Completion Date : February 2015

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Placebo Comparator: Placebo
Placebo once weekly
Drug: placebo
Experimental: 3 mg LD-Aminopterin
3 mg LD-aminopterin once weekly
Drug: LD-aminopterin
Experimental: 1 mg LD-aminopterin
1 mg LD-aminopterin once weekly
Drug: LD-aminopterin

Primary Outcome Measures :
  1. ACR20 [ Time Frame: Study Day 84 ]
    The primary efficacy endpoint, determined at study day 84 or last observation carried forward (LOCF), is the percent of subjects who obtain ACR20 in the 3 mg/week LD-AMT dose compared to placebo.

Secondary Outcome Measures :
  1. ACR20 [ Time Frame: Study Day 84 ]
    A secondary efficacy endpoint, determined at study day 84 or LOCF, is the percent of subjects who obtain ACR20 in the 1 mg LD-AMT/week dose.

Other Outcome Measures:
  1. Adverse Event [ Time Frame: Study Day 126 ]
    Adverse events, including laboratory measurements of serum chemistry and hematology, and the occurrence of dose-limiting toxicity. Safety endpoints will be evaluated throughout the study and for an additional 42 days after a subject goes off study.

Information from the National Library of Medicine

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, Learn About Clinical Studies.

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. > 18 years of age.
  2. A diagnosis of RA established by the ACR/EULAR 2010 criteria applied to patients who: 1) have >1 joint with definite clinical synovitis (swelling); 2) with the synovitis not better explained by another disease.

Add scores of categories A-D; a score >6/10 is required for study entry.

A. Joint involvement:

1 large joint=0; 2-10 large joints=1; 1-3 small joints (with or without involvement of large joints=2; 4-10 small joints (with or without involvement of large joints)=3; >10 joints (at least 1 small joint)=5.

B. Serology (at least 1 test result is needed for classification):

Negative RF and negative ACPA=0; Low-positive RF or low-positive ACPA=2; High-positive RF or high-positive ACPA=3.

C. Acute-phase reactants (at least 1 test result is needed for classification):

Normal CRP and normal ESR=0; Abnormal CRP or abnormal ESR=1.

D. Duration of symptoms:

less than 6 weeks=0; 6 weeks or greater=1.

3. Class I, II or III functional according to the ACR 1992 revised criteria for the classification of global functional status in RA.

4. RA is active, defined as ≥ 6 swollen joints and ≥ 6 tender joints.

5. Ability to understand and sign written informed consent.

6. For sexually active men and for women of childbearing potential, an adequate form of contraception.

7. For pre-menopausal women, a negative pregnancy test, obtained within 1 week prior to first study drug dose.

8. Negative serology for hepatitis B and hepatitis C.

9. The following screening laboratory blood tests must have the following values, or not clinically significant as determined by the PI and Medical Monitor: WBC WNL; absolute neutrophil count > lower limit of normal; platelet count WNL; hemoglobin >10.0 g/dL; AST WNL.

10. Adequate renal function: GFR estimated by Cockcroft-Gault formula >60 ml/min

Exclusion Criteria:

  1. Known history of hepatitis, HIV infection, interstitial lung disease.
  2. Alcohol consumption on a regular basis and unwilling, or unable, to discontinue this consumption during the study period.
  3. Prior methotrexate or aminopterin therapy.
  4. Prior biologic drug therapy (e.g., etanercept, adalimumab, infliximab).
  5. Within 2 weeks prior to Study Day 0, or on Study Day 0, or at any time during the study, use of any of the following medications that may result in drug/drug interactions with AMT: trimethoprim with or without sulfamethoxazole; sulfonamides; sulfonylureas; pyrimethamine; triamethamine; dipyridamole; colchicine; probenecid; aminoglycosides; theophylline; phenytoin; and folinic acid (i.e., leucovorin).
  6. At Study Day 0 use of DMARDs and biologics (except antimalarials) including oral or injectable gold, azathioprine, penicillamine, sulfasalazine or cyclosporine. Subjects previously treated with any of these medications are eligible provided a 28 day wash-out is completed prior to Study Day 0. Antimalarial can be continued at the same dose if they have been administered at the same dose for 8 weeks before Study Day 0, and they will be administered at the same dose throughout the study. NSAIDs or corticosteroid (≤ 10 mg prednisone or equivalent/day) may be continued at the same dose if they have been used at a stable dose for two weeks prior to Study Day 0, and will be continued at the same doses throughout the study.
  7. Use of corticosteroids in excess of 10 mg prednisone or equivalent/day.
  8. Known concurrent malignancy except basal or squamous cell skin carcinoma, or cervical carcinoma in situ.
  9. Concurrent participation in another clinical trial involving experimental treatment within 30 days of Study Day 0.
  10. Current and uncontrolled infection, cardiovascular, renal, pulmonary, hepatic or GI conditions that will interfere with the conduct of the trial or pose a morbid risk.
  11. Investigator's opinion that a concurrent disease or condition impairs the subject's ability to complete the trial: includes psychological, familial, sociological, geographical or medical conditions.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01724931

Centre of Immunobiologic Therapy, State Institution "Institute of Emergency and Reconstructive Surgery
Donets'k, Ukraine, 83045
Department of Hospital Therapy #1, Regional Clinical Hospital for occupational diseases 104
Donetsk, Ukraine, 83059
Communal Establishment of Health Protection, Regional Hospital of Veterans of War, Rheumatology Department
Kharkiv, Ukraine, 61137
Department of Rheumatology, Communal Establishment of Health Protection "Kharkiv City Clinical Hospital #8"
Kharkiv, Ukraine, 61178
Kyiv, Ukraine, 03151
Department of Rheumatology and Allergology, Kyiv Regional Clinical Hospital №1
Kyiv, Ukraine, 04107
Lviv Regional Clinical Hospital, Department of Rheumatology
Lviv, Ukraine, 79010
Department of Cardio-Rheumatology, Communal Institution "Odesa Regional Clinical Hospital"
Odesa, Ukraine, 65025
Crimean State Medical University n.a. S.I. Georgievsky based on Rheumatology Department of Crimean Republic Institution "Clinical Territorial Medical Association "University Clinic"
Simferopol, Ukraine, 95017
Railway Clinical Hospital of Uzhorod Station of Lviv Railroad Administration, Therapeutic Department
Uzhorod, Ukraine, 88009
Department of Rheumatology, Vinnytsya Regional Clinical Hospital n.a. M.I
Vinnytsa, Ukraine, 21018
Zaporizhzhya City Multiple Discipline Clinical Hospital #9, Department of Therapy
Zaporizhzhya, Ukraine, 69065
Department of Rheumatology, Zaporizhzhia Regional Clinical Hospital
Zaporizhzhya, Ukraine, 69600
Department of Therapy, City Clinical Hospital № 6
Zaporizhzhya, Ukraine
Department of Therapy, City Hospital № 7
Zaporizhzhya, Ukraine
Sponsors and Collaborators
Syntrix Biosystems, Inc.
Study Director: Stuart Kahn, MD, MS Syntrix Biosystems, Inc.

Publications of Results:
Responsible Party: Syntrix Biosystems, Inc. Identifier: NCT01724931     History of Changes
Other Study ID Numbers: Syntrix-AMT-RA-202
First Posted: November 12, 2012    Key Record Dates
Last Update Posted: May 20, 2015
Last Verified: May 2015

Keywords provided by Syntrix Biosystems, Inc.:
autoimmune disease
hematological treatment
rheumatic disease
folic acid antagonist
enzyme inhibitor

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