Aminopterin Dose Finding Treatment for Methotrexate-Naïve Rheumatoid Arthritis

Rheumatoid Arthritis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01724931
• Other study ID #: Syntrix-AMT-RA-202
• Status: Completed
• Phase: Phase 2
• First received: November 7, 2012
• Last updated: May 18, 2015
• Start date: February 2013
• Est. completion date: February 2015

Study information

• Verified date: May 2015
• Source: Syntrix Biosystems, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Ukraine: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 175
• Est. completion date: February 2015
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• LD-aminopterin

• placebo

Locations

Country	Name	City	State
Ukraine	Centre of Immunobiologic Therapy, State Institution "Institute of Emergency and Reconstructive Surgery	Donets'k
Ukraine	Department of Hospital Therapy #1, Regional Clinical Hospital for occupational diseases 104	Donetsk
Ukraine	Communal Establishment of Health Protection, Regional Hospital of Veterans of War, Rheumatology Department	Kharkiv
Ukraine	Department of Rheumatology, Communal Establishment of Health Protection "Kharkiv City Clinical Hospital #8"	Kharkiv
Ukraine	Department of Rheumatology and Allergology, Kyiv Regional Clinical Hospital ?1	Kyiv
Ukraine	National Scientific Center "M.D. STRAZHESKO INSTITUTE OF CARDIOLOGY, MAS OF UKRAINE"	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	Department of Rheumatology, Vinnytsya Regional Clinical Hospital n.a. M.I	Vinnytsa
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	Zaporizhzhya City Multiple Discipline Clinical Hospital #9, Department of Therapy	Zaporizhzhya

Sponsors (1)

Lead Sponsor	Collaborator
Syntrix Biosystems, Inc.

Country where clinical trial is conducted

Ukraine, 

References & Publications (1)

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 th — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Adverse Event	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.	Study Day 126	Yes
Primary	ACR20	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.	Study Day 84	No
Secondary	ACR20	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.	Study Day 84	No