Aminopterin Dose Finding Treatment for Methotrexate-Naïve Rheumatoid Arthritis

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by Syntrix Biosystems, Inc.
Sponsor:
Information provided by (Responsible Party):
Syntrix Biosystems, Inc.
ClinicalTrials.gov Identifier:
NCT01724931
First received: November 7, 2012
Last updated: January 17, 2014
Last verified: January 2014
  Purpose

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


Condition Intervention Phase
Rheumatoid Arthritis
Drug: LD-aminopterin
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by Syntrix Biosystems, Inc.:

Primary Outcome Measures:
  • ACR20 [ Time Frame: Study Day 84 ] [ Designated as safety issue: No ]
    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:
  • ACR20 [ Time Frame: Study Day 84 ] [ Designated as safety issue: No ]
    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:
  • Adverse Event [ Time Frame: Study Day 126 ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 192
Study Start Date: February 2013
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  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: NCT01724931

Contacts
Contact: Tetyana Byelyayeva, M.D., Ph.D. (+380 44) 499 56 00 Tetyana.Byelyayeva@kcrcro.com
Contact: Viktor Dzyuba (+380 44) 499 56 00 Viktor.Dzyuba@kcrcro.com

Locations
Ukraine
Centre of Immunobiologic Therapy, State Institution "Institute of Emergency and Reconstructive Surgery Recruiting
Donets'k, Ukraine, 83045
Principal Investigator: Andriy Gnylorybov, M.D., Ph.D.         
Sub-Investigator: Viktoria Ridzhok, M.D., Ph.D.         
Sub-Investigator: Yuliia Hushchyna, M.D.         
Department of Hospital Therapy #1, Regional Clinical Hospital for occupational diseases 104 Recruiting
Donetsk, Ukraine, 83059
Principal Investigator: Vadym Berenfus, M.D., Ph.D.         
Sub-Investigator: Kristina Tyumyenyeva, M.D.         
Sub-Investigator: Vitaliy Tolstoy, M.D.         
Sub-Investigator: Viktoriia Balatsko, M.D.         
Communal Establishment of Health Protection, Regional Hospital of Veterans of War, Rheumatology Department Recruiting
Kharkiv, Ukraine, 61137
Principal Investigator: Anatolii Oparin, M.D., Ph.D.         
Sub-Investigator: Oleksii Oparin, M.D., Ph.D.         
Sub-Investigator: Natalia Lavrova, M.D., Ph.D.         
Department of Rheumatology, Communal Establishment of Health Protection "Kharkiv City Clinical Hospital #8" Recruiting
Kharkiv, Ukraine, 61178
Principal Investigator: Vira Tseluyko, M.D.         
Sub-Investigator: Olha Radchenko, M.D.         
National Scientific Center "M.D. STRAZHESKO INSTITUTE OF CARDIOLOGY, MAS OF UKRAINE" Recruiting
Kyiv, Ukraine, 03151
Principal Investigator: Volodymyr Kovalenko, M.D.         
Sub-Investigator: Galyna Protsenko, M.D., Ph.D.         
Department of Rheumatology and Allergology, Kyiv Regional Clinical Hospital №1 Recruiting
Kyiv, Ukraine, 04107
Principal Investigator: Grygorii Lysenko, M.D.         
Sub-Investigator: Ludmila Khimion, M.D.         
Sub-Investigator: Svetlana Danyliuk, M.D.         
Lviv Regional Clinical Hospital, Department of Rheumatology Recruiting
Lviv, Ukraine, 79010
Principal Investigator: Orest Abrahamovych, M.D., Ph.D.         
Sub-Investigator: Ulyana Abrahamovych, M.D., Ph.D.         
Sub-Investigator: Iaryna Liaschuk, M.D.         
Sub-Investigator: Omelian Synenkii, M.D.         
Department of Cardio-Rheumatology, Communal Institution "Odesa Regional Clinical Hospital" Recruiting
Odesa, Ukraine, 65025
Principal Investigator: Olena Levchenko, M.D., Ph.D.         
Sub-Investigator: Andriy Yurkiv, M.D.         
Sub-Investigator: Maryna Kuznetsova, M.D.         
Sub-Investigator: Bogdana Scherbakova, M.D.         
Crimean State Medical University n.a. S.I. Georgievsky based on Rheumatology Department of Crimean Republic Institution "Clinical Territorial Medical Association "University Clinic" Recruiting
Simferopol, Ukraine, 95017
Principal Investigator: Galyna Koshukova, M.D.         
Sub-Investigator: Andriy Petrov, M.D.         
Railway Clinical Hospital of Uzhorod Station of Lviv Railroad Administration, Therapeutic Department Recruiting
Uzhorod, Ukraine, 88009
Principal Investigator: Ivan Chopey, MD, PhD, Dr Sc D         
Sub-Investigator: Yaroslav Mykhalko, M.D.         
Sub-Investigator: Samvel Turianytsia, M.D.         
Department of Rheumatology, Vinnytsya Regional Clinical Hospital n.a. M.I Recruiting
Vinnytsa, Ukraine, 21018
Principal Investigator: Mykola Stanislavchuk, M.D.         
Sub-Investigator: Galyna Movchan, M.D.         
Department of Therapy, City Hospital № 7 Recruiting
Zaporizhzhya, Ukraine
Principal Investigator: Vadym Vizir, M.D., Ph.D.         
Sub-Investigator: Oleksandr Goncharov, M.D., Ph.D.         
Sub-Investigator: Anton Sadomov, M.D., Ph.D.         
Department of Therapy, City Clinical Hospital № 6 Recruiting
Zaporizhzhya, Ukraine
Principal Investigator: Oleg Kraydashenko, M.D., Ph.D.         
Sub-Investigator: Halyna Svetlytska, M.D.         
Sub-Investigator: Diana Buidenko, M.D.         
Department of Rheumatology, Zaporizhzhia Regional Clinical Hospital Recruiting
Zaporizhzhya, Ukraine, 69600
Principal Investigator: Dmyto Rekalov, M.D., Ph.D.         
Sub-Investigator: Ganna Prytkova, M.D.         
Sub-Investigator: Viktoria Krupko, M.D.         
Zaporizhzhya City Multiple Discipline Clinical Hospital #9, Department of Therapy Recruiting
Zaporizhzhya, Ukraine, 69065
Principal Investigator: Volodymyr Koshlia, M.D., Ph.D.         
Sub-Investigator: Ivan Isaichykov, M.D., Ph.D.         
Sponsors and Collaborators
Syntrix Biosystems, Inc.
Investigators
Study Director: Stuart Kahn, MD, MS Syntrix Biosystems, Inc.
  More Information

Publications:
Responsible Party: Syntrix Biosystems, Inc.
ClinicalTrials.gov Identifier: NCT01724931     History of Changes
Other Study ID Numbers: Syntrix-AMT-RA-202
Study First Received: November 7, 2012
Last Updated: January 17, 2014
Health Authority: Ukraine: Ministry of Health

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

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

ClinicalTrials.gov processed this record on July 20, 2014