Aminopterin Dose Finding Treatment for Methotrexate-Naïve Rheumatoid Arthritis

Phase 2

Completed

• Conditions: Rheumatoid Arthritis
• Interventions: Drug: LD-aminopterin; Drug: placebo

• Registration Number: NCT01724931
• Lead Sponsor: Syntrix Biosystems, Inc.

Brief Summary

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

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 Timeline

• Study First Submitted: 2012-11-07
• Study First Submitted QC: 2012-11-09
• Study First Posted: 2012-11-12
• Study Start: 2013-02
• Primary Completion: 2014-09
• Study Completion: 2015-02
• Status Verified: 2015-05
• Last Update Submitted: 2015-05-18
• Last Update Posted: 2015-05-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 175

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
3 mg LD-Aminopterin	LD-aminopterin	3 mg LD-aminopterin once weekly
1 mg LD-aminopterin	LD-aminopterin	1 mg LD-aminopterin once weekly
Placebo	placebo	Placebo once weekly

Primary Outcome Measures

Name	Time	Method
ACR20	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

Name	Time	Method
ACR20	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.

Trial Locations

Locations (15)

Communal Establishment of Health Protection, Regional Hospital of Veterans of War, Rheumatology Department; 🇺🇦 Kharkiv, Ukraine

Department of Hospital Therapy #1, Regional Clinical Hospital for occupational diseases 104; 🇺🇦 Donetsk, Ukraine

Department of Rheumatology, Communal Establishment of Health Protection "Kharkiv City Clinical Hospital #8"; 🇺🇦 Kharkiv, Ukraine

National Scientific Center "M.D. STRAZHESKO INSTITUTE OF CARDIOLOGY, MAS OF UKRAINE"; 🇺🇦 Kyiv, Ukraine

Department of Rheumatology and Allergology, Kyiv Regional Clinical Hospital №1; 🇺🇦 Kyiv, Ukraine

Lviv Regional Clinical Hospital, Department of Rheumatology; 🇺🇦 Lviv, Ukraine

Department of Cardio-Rheumatology, Communal Institution "Odesa Regional Clinical Hospital"; 🇺🇦 Odesa, Ukraine

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

Railway Clinical Hospital of Uzhorod Station of Lviv Railroad Administration, Therapeutic Department; 🇺🇦 Uzhorod, Ukraine

Zaporizhzhya City Multiple Discipline Clinical Hospital #9, Department of Therapy; 🇺🇦 Zaporizhzhya, Ukraine

Department of Rheumatology, Zaporizhzhia Regional Clinical Hospital; 🇺🇦 Zaporizhzhya, Ukraine

Department of Therapy, City Clinical Hospital № 6; 🇺🇦 Zaporizhzhya, Ukraine

Department of Therapy, City Hospital № 7; 🇺🇦 Zaporizhzhya, Ukraine

Centre of Immunobiologic Therapy, State Institution "Institute of Emergency and Reconstructive Surgery; 🇺🇦 Donets'k, Ukraine

Department of Rheumatology, Vinnytsya Regional Clinical Hospital n.a. M.I; 🇺🇦 Vinnytsa, Ukraine