Self-administration of Subcutaneous Methotrexate
Eligible patients were at least 18 years of age, had been diagnosed with adult RA (controlled or uncontrolled), and had been treated with methotrexate for 3 months or longer before enrollment. Women of childbearing potential were included only if they had negative pregnancy tests at screening and day of treatment and were using effective contraception. All patients were required to be capable of administering SC self-injections and of understanding verbal or written English. All patients signed and dated an approved informed consent form before the initiation of any study procedures.
Patients were excluded from the study if they were pregnant or lactating, had a history of malignancy or neoplastic disease (except successfully treated basal or squamous cell carcinoma of the skin >1 year ago or patients who were cancer-free for >5 years), had a skin condition or disorder preventing SC administration of methotrexate, or had other clinically significant disease. Other exclusion criteria were acute illness within 7 days or major illness/hospitalization within 1 month of study drug administration, history of drug or alcohol abuse within the past year, history of human immunodeficiency virus or hepatitis B or C virus infection, or the use of any other investigational agent within 1 month before enrollment.
This was a phase 2, open-label, single-dose, single-arm, in-clinic study conducted at 8 sites in the United States. The total duration of the trial was 8 weeks, and it contained a screening period, a 1-day treatment period, and a 1-day follow-up period. During the screening period, eligible patients were enrolled and instructed to discontinue their previously prescribed methotrexate therapy. They were assigned by the investigator to 1 of 4 methotrexate dose levels (10, 15, 20, or 25 mg) according to their baseline methotrexate therapy and RA disease status (controlled or uncontrolled). At least 7 days had to have elapsed between the patient's last previously prescribed methotrexate dose and the start of study treatment. Patients were to restart their previous methotrexate therapy 1 week after the treatment visit.
The protocol was approved by the institutional review board of each study site before study initiation. The study was conducted in accordance with the Declaration of Helsinki and was in compliance with Good Clinical Practice Guidelines. This trial is registered with ClinicalTrials.gov (NCT01618955).
Patients received standardized SC self-administration training from nursing staff at the investigator sites that involved verbal instructions and a demonstration of proper use of the MTXAI through the use of a standardized script, as well as a review of written patient instructions. Self-administration was carried out independently, in the clinic, with the aid of written patient instructions. Patients used the MTXAI to administer their assigned dose of methotrexate into the anterior abdominal wall, and site personnel observed the procedure.
The primary end point for determination of safe usability was successful SC administration with the MTXAI. Successful self-administration was determined by the following: (1) SC self-administration was intentional; (2) the SC dose was administered by the patient; (3) SC self-administration was in the appropriate location on the abdomen; and (4) the device functioned appropriately as determined by inspection of used devices, including confirmation that the window was obstructed, the ram was released, and the needle guard was no longer retracted.
After self-administration on day 1, patients completed an ease-of-use questionnaire, which contained 5 statements that assessed the device and the standardized patient training for ease of use by the patient. Immediately after self-administration on day 1 and at the follow-up visit on day 2, patients rated any pain at the injection site with a visual analog scale (VAS) (0 mm = no pain, 100 mm = worst possible pain).
Secondary end points included ease-of-use questionnaire scores regarding the device, ease-of-use and training confirmation questionnaire scores regarding written patient instructions and SC self-administration training, assessment of essential tasks questionnaire scores, self-reported VAS scores for pain at the injection site, and injection-site assessment numeric grades. Injection sites were assessed predose and at 0.25, 1, 6, and 24 hours postdose. Erythema severity was graded on a scale of 0 = none, 1 = very slight/barely perceptible, 2 = obvious, but well defined, 3 = moderate to severe, and 4 = severe.
Adverse events and medical and surgical history were coded to system organ class and preferred term using the Medical Dictionary for Regulatory Activities version 14.1. An AE was considered to be a treatment-emergent AE (TEAE) if it started on or after self-administration with the MTXAI. Vital signs (including heart rate, respiratory rate, and blood pressure) were measured at screening and at 1, 6, and 24 hours postdose.
The safety population was defined as all patients who received study drug and carried out a successful or an unsuccessful self-administration. All analyses were performed on the safety population. A sample size of approximately 100 patients (approximately 25 patients per dose level with a minimum enrollment of 20 patients per group) was planned to provide a sufficient number of patients to determine the safety and tolerability of the MTXAI, based on correspondence with the US Food and Drug Administration.
Materials and Methods
Patients
Eligible patients were at least 18 years of age, had been diagnosed with adult RA (controlled or uncontrolled), and had been treated with methotrexate for 3 months or longer before enrollment. Women of childbearing potential were included only if they had negative pregnancy tests at screening and day of treatment and were using effective contraception. All patients were required to be capable of administering SC self-injections and of understanding verbal or written English. All patients signed and dated an approved informed consent form before the initiation of any study procedures.
Patients were excluded from the study if they were pregnant or lactating, had a history of malignancy or neoplastic disease (except successfully treated basal or squamous cell carcinoma of the skin >1 year ago or patients who were cancer-free for >5 years), had a skin condition or disorder preventing SC administration of methotrexate, or had other clinically significant disease. Other exclusion criteria were acute illness within 7 days or major illness/hospitalization within 1 month of study drug administration, history of drug or alcohol abuse within the past year, history of human immunodeficiency virus or hepatitis B or C virus infection, or the use of any other investigational agent within 1 month before enrollment.
Study Design
This was a phase 2, open-label, single-dose, single-arm, in-clinic study conducted at 8 sites in the United States. The total duration of the trial was 8 weeks, and it contained a screening period, a 1-day treatment period, and a 1-day follow-up period. During the screening period, eligible patients were enrolled and instructed to discontinue their previously prescribed methotrexate therapy. They were assigned by the investigator to 1 of 4 methotrexate dose levels (10, 15, 20, or 25 mg) according to their baseline methotrexate therapy and RA disease status (controlled or uncontrolled). At least 7 days had to have elapsed between the patient's last previously prescribed methotrexate dose and the start of study treatment. Patients were to restart their previous methotrexate therapy 1 week after the treatment visit.
The protocol was approved by the institutional review board of each study site before study initiation. The study was conducted in accordance with the Declaration of Helsinki and was in compliance with Good Clinical Practice Guidelines. This trial is registered with ClinicalTrials.gov (NCT01618955).
Standardized Patient Training and Assessments
Patients received standardized SC self-administration training from nursing staff at the investigator sites that involved verbal instructions and a demonstration of proper use of the MTXAI through the use of a standardized script, as well as a review of written patient instructions. Self-administration was carried out independently, in the clinic, with the aid of written patient instructions. Patients used the MTXAI to administer their assigned dose of methotrexate into the anterior abdominal wall, and site personnel observed the procedure.
The primary end point for determination of safe usability was successful SC administration with the MTXAI. Successful self-administration was determined by the following: (1) SC self-administration was intentional; (2) the SC dose was administered by the patient; (3) SC self-administration was in the appropriate location on the abdomen; and (4) the device functioned appropriately as determined by inspection of used devices, including confirmation that the window was obstructed, the ram was released, and the needle guard was no longer retracted.
After self-administration on day 1, patients completed an ease-of-use questionnaire, which contained 5 statements that assessed the device and the standardized patient training for ease of use by the patient. Immediately after self-administration on day 1 and at the follow-up visit on day 2, patients rated any pain at the injection site with a visual analog scale (VAS) (0 mm = no pain, 100 mm = worst possible pain).
Secondary end points included ease-of-use questionnaire scores regarding the device, ease-of-use and training confirmation questionnaire scores regarding written patient instructions and SC self-administration training, assessment of essential tasks questionnaire scores, self-reported VAS scores for pain at the injection site, and injection-site assessment numeric grades. Injection sites were assessed predose and at 0.25, 1, 6, and 24 hours postdose. Erythema severity was graded on a scale of 0 = none, 1 = very slight/barely perceptible, 2 = obvious, but well defined, 3 = moderate to severe, and 4 = severe.
Adverse events and medical and surgical history were coded to system organ class and preferred term using the Medical Dictionary for Regulatory Activities version 14.1. An AE was considered to be a treatment-emergent AE (TEAE) if it started on or after self-administration with the MTXAI. Vital signs (including heart rate, respiratory rate, and blood pressure) were measured at screening and at 1, 6, and 24 hours postdose.
Statistical Analysis
The safety population was defined as all patients who received study drug and carried out a successful or an unsuccessful self-administration. All analyses were performed on the safety population. A sample size of approximately 100 patients (approximately 25 patients per dose level with a minimum enrollment of 20 patients per group) was planned to provide a sufficient number of patients to determine the safety and tolerability of the MTXAI, based on correspondence with the US Food and Drug Administration.
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