Low-dose Methotrexate for Change in Global Initiative for Asthma Step 5 Medications in Chronic Severe Asthma

Low-dose Methotrexate for Change in Global Initiative for Asthma Step 5 Medications in Chronic Severe Asthma: a Randomized Controlled Trial

Patients with chronic severe asthma (CSA) have a crippling disease and current available treatments are not satisfactory. Thus, management of CSA remains a major unmet need. Although the evidence from existing randomized controlled trials fails to support a definite role for immunomodulatory drugs in these patients due to major methodologic drawbacks, findings with low-dose methotrexate (MTX) are encouraging. However, larger and well designed clinical trials are required to establish the beneficial role of MTX in CSA and for the detection of the key characteristics of those who are going to respond to this drug.

This study will be the first multi-centre RCT investigating the role of an add-on immunological modifier as a clinically useful therapeutic strategy in patients with well-phenotyped chronic severe asthma. As such, this study does not overlap with any other research currently ongoing.

Study Overview

• Status: Not yet recruiting
• Conditions: Low Dose Methotrexate in Severe Chronic Asthma
• Intervention / Treatment: Drug: Placebo; Drug: Methotrexate

Detailed Description

Patients will be recruited from the accessible asthmatic patients lists of tertiary referral centers. All patients will meet the stringent diagnostic criteria for CSA, including the requirement for the regular use of Step 5 medications (i.e. oral prednisone and/or omalizumab). The experimental design of the proposed study will take the form of a double-blind parallel-randomized placebo-controlled trial consisting of a total of eight visits including run-in and run-out periods. Patients will be randomly allocated to receive either MTX or matched placebo once a week as add-on therapy to their existing medication after run-in. Physiological, laboratory and clinical assessments will be measured regularly throughout the study and compared with baseline assessments.

We expect that MTX will reduce Step 5 medications dosage in patients with CSA without compromising the overall disease control. Improvement in several indicators of asthma severity and control will be also investigated

• Study Type: Interventional
• Enrollment (Anticipated): 102
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. patients with a diagnosis of CSA taking GINA Step 5 medications (i.e. regular OCS and/or omalizumab for a minimum of 6 months);
2. failure in weaning patients completely from Step 5 medications during run-in;
3. male and female individuals age 18 - 75 years;
4. patients must be able to provide consent;

Exclusion Criteria:

1. use of immunomodulatory therapies in the preceding 3 months;
2. recent or current history of alcoholism;
3. high liver enzyme levels (greater than 2.5 times the upper limit of the normal range);
4. serum creatinine levels greater than 2.0 mg/dL
5. acute illness within 15 days of study medication administration;
6. leucopenia (below 3.0x109/L) and/or thrombocytopenia (below 100x109/L).
7. pregnancy or planning to become pregnant;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methotrexate; Starting dose of 7.5 mg/week + folic acid the day after for 3 weeks as add-on therapy to their existing medication. Study treatment dosage will be increased, the maintenance dose will be 10 mg/week + folic acid the day after for 27 weeks	Drug: Methotrexate; 7.5 mg/week + folic acid the day after; Other Names: Several brand names
Placebo Comparator: Matched placebo; Placebo pills	Drug: Placebo; matched placebo; Other Names: matched placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
At least 50% reduction in total dosage of GINA step 5 medications	80 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
clinically significant changes in clinimetric scores	80 weeks

Collaborators and Investigators

• Sponsor: Universita degli Studi di Catania
• Investigators: Principal Investigator: Riccardo Polosa, Full Professor, Università di Catania

Publications and helpful links

General Publications

• Polosa R, Bellinvia S, Caruso M, Emma R, Alamo A, Kowalski ML, Domingo C. Weekly low-dose methotrexate for reduction of Global Initiative for Asthma Step 5 treatment in severe refractory asthma: study protocol for a randomized controlled trial. Trials. 2014 Dec 18;15:492. doi: 10.1186/1745-6215-15-492.

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2021
• Primary Completion (Anticipated): April 1, 2022
• Study Completion (Anticipated): July 1, 2022

Study Registration Dates

• First Submitted: April 24, 2014
• First Submitted That Met QC Criteria: April 25, 2014
• First Posted (Estimate): April 28, 2014

Study Record Updates

• Last Update Posted (Actual): September 28, 2021
• Last Update Submitted That Met QC Criteria: September 27, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Chronic severe asthma, immunomodulation, methotrexate, steroids, omalizumab
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate
• Other Study ID Numbers: METGINA-005

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No