Clinical trial NCT01724931: Aminopterin Dose Finding Treatment for Methotrexate-Naïve Rheumatoid Arthritis
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Keywords: antifolate
antiinflammatory
autoimmune disease
hematological treatment
rheumatic disease
folic acid antagonist
enzyme inhibitor
Lead sponsor: Syntrix Biosystems, Inc.
Sponsor class: INDUSTRY
First posted: 2012-11-12
Enrollment: 175
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: ACR20
timeFrame: Study Day 84
Secondary outcomes:
measure: ACR20
timeFrame: Study Day 84
Other outcomes:
measure: Adverse Event
timeFrame: Study Day 126
Locations:
city: Donets'k
country: Ukraine
facility: Centre of Immunobiologic Therapy, State Institution "Institute of Emergency and Reconstructive Surgery
city: Donetsk
country: Ukraine
facility: Department of Hospital Therapy #1, Regional Clinical Hospital for occupational diseases 104
city: Kharkiv
country: Ukraine
facility: Communal Establishment of Health Protection, Regional Hospital of Veterans of War, Rheumatology Department
city: Kharkiv
country: Ukraine
facility: Department of Rheumatology, Communal Establishment of Health Protection "Kharkiv City Clinical Hospital #8"
city: Kyiv
country: Ukraine
facility: National Scientific Center "M.D. STRAZHESKO INSTITUTE OF CARDIOLOGY, MAS OF UKRAINE"
city: Kyiv
country: Ukraine
facility: Department of Rheumatology and Allergology, Kyiv Regional Clinical Hospital №1
city: Lviv
country: Ukraine
facility: Lviv Regional Clinical Hospital, Department of Rheumatology
city: Odesa
country: Ukraine
facility: Department of Cardio-Rheumatology, Communal Institution "Odesa Regional Clinical Hospital"
city: Simferopol
country: Ukraine
facility: Crimean State Medical University n.a. S.I. Georgievsky based on Rheumatology Department of Crimean Republic Institution "Clinical Territorial Medical Association "University Clinic"
city: Uzhorod
country: Ukraine
facility: Railway Clinical Hospital of Uzhorod Station of Lviv Railroad Administration, Therapeutic Department
city: Vinnytsa
country: Ukraine
facility: Department of Rheumatology, Vinnytsya Regional Clinical Hospital n.a. M.I
city: Zaporizhzhya
country: Ukraine
facility: Zaporizhzhya City Multiple Discipline Clinical Hospital #9, Department of Therapy
city: Zaporizhzhya
country: Ukraine
facility: Department of Rheumatology, Zaporizhzhia Regional Clinical Hospital
city: Zaporizhzhya
country: Ukraine
facility: Department of Therapy, City Clinical Hospital № 6
city: Zaporizhzhya
country: Ukraine
facility: Department of Therapy, City Hospital № 7
Study officials:
affiliation: Syntrix Biosystems, Inc.
name: Stuart Kahn, MD, MS
role: STUDY_DIRECTOR
References:
citation: Menter A, Thrash B, Cherian C, Matherly LH, Wang L, Gangjee A, Morgan JR, Maeda DY, Schuler AD, Kahn SJ, Zebala JA. Intestinal transport of aminopterin enantiomers in dogs and humans with psoriasis is stereoselective: evidence for a mechanism involving the proton-coupled folate transporter. J Pharmacol Exp Ther. 2012 Sep;342(3):696-708. doi: 10.1124/jpet.112.195479. Epub 2012 May 31.