This was an optional, open-label sub-study (Fig. 1) to determine whether patients/caregivers could safely and effectively administer ADL-PF using a PFP device. The study design and inclusion criteria for the main study (NCT02480153) have been described in detail elsewhere [16,17,18]; features relevant to this sub-study of ADL-PF PFP are summarized below.
Adult (age ≥ 18 years) patients with a diagnosis of active RA ≥ 4 months, based on the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria , and an inadequate response to methotrexate (MTX) participated in the main study [16, 17]. Patients must have been treated with MTX for ≥ 12 weeks and been on a stable dose of 10–25 mg/week for ≥ 4 weeks before the first dose of study drug. Lower doses of MTX (6 mg/week) were allowed if indicated in local guidance or standards of care.
The sub-study was conducted in the second year of the main study during open-label treatment with ADL-PF (TP3). Approximately 50 patients from 19 centers in four countries (Czech Republic, Lithuania, Poland, and the USA) were planned for enrollment between October 3, 2016 and May 16, 2017. Eligible patients were active participants in year 2 of the main study who completed study week 52 and moved into the open-label period (TP3), were self-injecting their study medication or had a non-healthcare professional caregiver performing their injections, and provided written informed consent.
Study Design and Treatment
At the start (TP1) of the main study, patients were randomized 1:1 (stratified by geographic region) to ADL-EU or ADL-PF, administered by PFS, in combination with MTX, for 26 weeks [16, 17]. At the start of TP2 (week 26), patients in the ADL-EU arm were blindly re-randomized (1:1) to continue ADL-EU or switch to ADL-PF. At the start of TP3 (week 52), the remaining ADL-EU patients were switched to ADL-PF (open-label).
This optional, open-label, single arm sub-study was conducted during TP3 (weeks 52–78) of the main study (Fig. 1). After receiving two doses of subcutaneous ADL-PF 40 mg by PFS during TP3 (at weeks 52 and 54), patients switched to receive subcutaneous ADL-PF 40 mg via a single-use PFP device containing an identical PFS (Fig. S1). Patients received six additional biweekly doses (weeks 56 to 66) of ADL-PF by PFP, with doses 1, 3, and 6 administered at the study site under supervision, and doses 2, 4, and 5 administered at home.
Patients and their non-healthcare professional caregivers were trained by local site personnel to administer ADL-PF using the PFP device, with their first PFP device available to them during the training. The training adhered to the PFP instructions for use provided to the patients and their caregivers. The patient or their non-healthcare professional caregiver (i.e., actual PFP user) administered the first injection in the abdomen after all procedures and assessments were completed on sub-study day 1, in the presence of the site investigator or designated observer. The site personnel who trained the patient and/or their non-healthcare professional caregiver might have been the same as or different from the site investigator/designated observer. All injections were given by patients/caregivers. Following successful completion of the sub-study, patients had the option of continuing to use the PFP for the remainder of TP3 or returning to use the PFS.
The primary endpoint for evaluating PFP device injection success was delivery system success rate (DSSR), defined as the percentage of participants achieving delivery success for an attempted injection at each of the six sub-study PFP injections. Success was based on participant (actual PFP user) and investigator/designated observer assessments of ADL-PF administration by PFP: ‘Yes’, for injection success reported on the Observer Assessment Tool (OAT; if performed at study site; Fig. S2), and lack of injection failure reported on the Participant Assessment Tool (PAT; Fig. S3).
ADL-PF PFP user (patient/caregiver) and investigator observations were collected over the 10-week sub-study duration (Fig. 1). At the three on-site administration visits, the investigator/designated observer witnessed the PFP injection and inspected the window on the PFP following administration to check if the blue bar on the pen had moved across the window. The observer then recorded the success of the drug administration using the PFP OAT (Fig. S2). The observer was not allowed to physically assist with the injection using the PFP (except if urgently required to prevent avoidable injury) but could provide verbal guidance in response to questions; any such guidance was recorded. The observer completed the OAT while blinded to the actual PFP user’s assessment of performance.
Following each injection using the PFP, the actual PFP user (patient or their non-healthcare professional caregiver, if applicable) inspected the window on the PFP to check if the blue bar on the pen had moved across the window and recorded the success of the drug administration using the PAT (Fig. S3). Secondary endpoints for PFP device injection success evaluations were: characterization of unsuccessful PFP injections and determination, by inspection, of the correct mechanical function of returned PFP devices.
All PFPs (both used and those whose container had been opened) were to be returned by the patient via an individual biohazard disposal container. Characterization of unsuccessful PFP injections was descriptive and correlated with the inspection of returned PFPs. A portion of the used PFPs were visually inspected centrally and underwent an industrial computed tomography scan to assess PFP function and correct operation.
Safety evaluations were conducted in accordance with the main study protocol, as reported in detail elsewhere [16, 17]; no additional safety assessments were conducted for the PFP sub-study. Safety endpoints included the type, incidence, severity, timing, seriousness, and relatedness of treatment-emergent adverse events (TEAEs), abnormalities, and laboratory parameters. Injection site reactions (ISRs) were among pre-specified events of special interest in the main study [16, 17] and continued to be captured as in the main study.
Safety was assessed in all patients who received at least a portion of a dose of ADL-PF using the PFP device. Any medical device complaints, including failure of the PFP to perform, regardless of whether the complaint was associated with an adverse event (AE), were recorded. PFP device injection success was evaluated in sub-study patients who attempted ≥ 1 injection using the PFP device (intent-to-treat population). If a participant engaged in multiple PFP injection attempts at a given visit, only the first attempt was to be included in the DSSR calculation.
The DSSR at each visit was accompanied by an exact, two-sided 95% CI using the Clopper–Pearson method . No formal statistical hypothesis was tested for the sub-study data; all data were summarized using descriptive statistics.
The sample size of 50 sub-study patients would have allowed for description of the success of a projected ≤ 300 PFP injections. The patient dropout rate for the sub-study was anticipated to be minimal as patients had already been maintained in the study for > 12 months before enrollment.
Compliance with Ethics Guidelines
This sub-study was conducted in compliance with the ethical principles originating in, or derived from, the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice Guidelines. The sub-study protocol and informed consent documentation were reviewed and approved by the Institutional Review Boards and/or Independent Ethics Committees at each of the investigational centers participating in the sub-study. In addition, all local regulatory requirements were followed; in particular, those affording greater protection of the safety of trial participants.
All patients provided informed consent before undergoing any screening procedures. The study was sponsored by Pfizer and registered on ClinicalTrials. Gov identifier: NCT02480153 and EudraCT number: 2014–000352-29.