The Metreleptin Effectiveness and Safety Registry (MEASuRE): concept, design and challenges

MEASuRE (ClinicalTrials.gov: NCT02325674) is a non-interventional, multicenter, prospective, observational, voluntary registry of patients treated with commercial metreleptin therapy as part of standard clinical practice in the US and EU. The registry was established as a post-authorization requirement and specific obligation following the approval of metreleptin by the FDA and EMA, respectively.

Ethics statement

MEASuRE is conducted in accordance with International Society for Pharmacoepidemiology Guidelines for Good Pharmacoepidemiology Practices [31] and with the standards of Good Clinical Practice as defined by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [32]. The registry also complies with applicable federal and local regulations, and with the ethical principles originating from the Declaration of Helsinki [33]. In the US, all necessary institutional review board approvals were obtained, and in the EU, all necessary ethics committee approvals at a country and site level were obtained.

Aim and objectives

MEASuRE aims to collect information regarding the long-term use of metreleptin. Its primary objective is to supplement data from clinical trials by determining the real-world incidence and severity of adverse events (AEs) in patients prescribed metreleptin. As a secondary objective, MEASuRE collects available data to describe the demographic and clinical characteristics of metreleptin-treated patients and to monitor longitudinal changes in routine laboratory measurements that could be inferred as effectiveness endpoints. MEASuRE also provides the opportunity to obtain further data on the incidence rates of specific safety events and other clinical parameters involving metreleptin-treated patients where current information is sparse. The full list of primary, secondary, and exploratory endpoints of MEASuRE is presented in Table 1.

Table 1 Primary endpoints, secondary endpoints and exploratory endpoints collected for MEASuRE Governance of MEASuRE

MEASuRE is governed by its sponsor, Amryt Pharmaceuticals. The sponsor is responsible for all aspects of data collection, management and retention, data quality control, and data analysis as well as the training of staff from participating sites, as appropriate. The sponsor also provides the resources for study implementation and conducting analyses (including the preparation of scientific reports) involving data from the registry in a manner that meets regulatory and methodological standards.

A steering committee for MEASuRE has been established and includes clinicians and scientists with expertise in the areas of lipodystrophy and metabolic disease, epidemiology, endocrinology, hepatology, and biostatistics. Through collaboration with ECLip, data from EU patients are collected into MEASuRE via the ECLip registry (detailed below); thus, the MEASuRE steering committee was broadened to include ECLip registry board members not from participating EU sites, to ensure balanced communication and global representation. Steering committee members provide subject matter expertise for the MEASuRE program and are responsible for reviewing the data from the registry over time. Based on their review, the steering committee make continuous recommendations to the sponsor regarding the registry. They also assist in study design, study execution and interpretation, and in publication planning and manuscript review.

Data ownership

In the US, data ownership for MEASuRE lies with the registry sponsor. For data originating from the ECLip registry, ownership resides with the patients and their treating physicians as appropriate for a patient registry [30].

Study population

Patients eligible for inclusion in MEASuRE are those treated with at least one dose of commercially supplied metreleptin at sites in the US and in EU countries where metreleptin is reimbursed, and where their prescribing physician is a MEASuRE investigator. Eligible patients do not need to be taking metreleptin at the time of enrolment; they can be treated with at least one dose of commercial metreleptin at any time before registry participation. All treatment decisions, including visit frequency, are made at the discretion of the patient’s treating physician, and are not mandated by the MEASuRE protocol.

The inclusion criteria for MEASuRE are broad with limited exclusion criteria to best represent the population of patients taking metreleptin as per usual clinical practice. Inclusion criteria for registry enrolment are patients diagnosed with GL (US), or patients diagnosed with GL or PL (EU) who are, or who have been, treated with commercial metreleptin as part of their clinical care, and who have provided written consent before enrolment into the registry, and who have finished their participation in metreleptin clinical studies and are continuing or restarting treatment with metreleptin through commercial supply.

Patients receiving metreleptin off-label may be included in the registry, except for patients from Germany who must be treated in accordance with the EMA-approved indication for metreleptin [15]. Patients with localized and HIV-associated lipodystrophy and patients currently treated with an investigational agent as part of a clinical trial are excluded from the registry.

Prescribing physician enrolment

Physicians who prescribe metreleptin are encouraged to invite their eligible patients to participate in MEASuRE. This enables the collection and assessment of data from a heterogeneous patient population together with further information regarding treatment practices among participating sites. In the US and EU, site level institutional review board or ethics committee approval must be in place prior to the initiation of recruitment to MEASuRE. All participating physicians must receive training on the study protocol prior to recruitment.

Because of the risk of anti-metreleptin antibodies with neutralising activity and risk of lymphoma during treatment, metreleptin is available in the US only through a restricted program under a risk evaluation and mitigation strategy (REMS) [14]. As such, metreleptin is dispensed in the US through a limited number of specialty pharmacies. Prescriber information (i.e., geographic location, specialty, and medical degree) and patient demographic characteristics are collected at these specialty pharmacies. Prescriber information provided by these specialty pharmacies is used to identify physicians who have prescribed metreleptin, after which they are invited by the sponsor to enroll in the registry if they have not already done so. Information from the specialty pharmacies is also used to identify the number of patients for whom each prescriber has written a metreleptin prescription.

In the EU, only prescribing physicians from countries where metreleptin is reimbursed and commercially available are invited to contribute data to MEASuRE. As all EU MEASuRE-specific data are collected via the ECLip registry, EU prescribing physicians must be an ECLip registry member prior to contributing data to MEASuRE.

Patient enrolment and follow-up

At the time of registry enrolment, written consent is necessary for all participants per local requirements. This includes patients who can understand the requirements of the registry and provide written informed consent for themselves. For patients unable to respond on their own behalf, a parent or guardian provides consent. Pediatric patients may be included in all discussions, as appropriate.

To meet the requirements mandated by the FDA, MEASuRE endeavors to enroll at least 100 patients with GL treated with commercial metreleptin; patients enrolled from the US and EU will be used to achieve this target. All patients enrolled from the US will be followed for a minimum of ten years (i.e., from when the 100th enrolled patient reaches ten years of follow-up), unless they withdraw consent to participate in the registry, or die. EU patients will be enrolled and followed for the duration of the product lifecycle unless the patient withdraws consent or dies.

Patient categories

All patients enrolled into the registry are categorized into one of two patient cohorts, i.e., a metreleptin new user cohort or a metreleptin prevalent user cohort. These cohorts are defined as follows:

the metreleptin new user cohort includes patients who are initiating treatment with metreleptin, through commercial supply at the time of providing written consent for registry enrolment.

the metreleptin prevalent user cohort includes patients who have been, or who are, treated with metreleptin through commercial supply but initiated treatment before registry enrolment and/or patients treated with metreleptin through commercial supply but after transferring their metreleptin treatment from a non-commercial source (e.g., clinical studies, expanded access programs).

The inclusion of patients who participated in clinical trials or an expanded access program will enable continued long-term assessment of patients beyond clinical trial participation. Furthermore, patients who received metreleptin, but later discontinued treatment will also be encouraged to enroll. It is recognized that patients who initiate metreleptin after it is commercially available but discontinue shortly thereafter may not be inclined to enroll in the registry since they are no longer receiving the product. These patients could differ in demographic characteristics from those who enroll and continue in the registry and may also have a different safety profile if they discontinued treatment due to an AE; thus, efforts will be made to enroll these patients.

For the prevalent metreleptin users, data collection will include data endpoints at baseline (e.g., demographics, medical history, and comorbidities at the time of initiation of metreleptin, medication history including concomitant medications and laboratory tests) and information on any serious AEs experienced during the six months prior to registry enrolment as part of baseline assessments. This will ensure that any primary endpoints that occur shortly after treatment initiation will not be underrepresented in the study population.

Endpoints

MEASuRE collects data to determine the incidence and severity of AEs of special interest (AESIs) including pancreatic and hepatic AEs, hypoglycemia, hypersensitivity reactions, medication errors, serious and severe infections, loss of efficacy, autoimmune disorders, cancer, and deaths. MEASuRE also gathers data regarding demographic characteristics, key laboratory values and patterns of metreleptin use. Laboratory measurements (including glycated hemoglobin [HbA1c], fasting plasma glucose and serum triglycerides) will be assessed as effectiveness endpoints. Additional exploratory endpoints will assess the use of metreleptin in sub-populations and determine the effect of metreleptin on neuroendocrine, gonadal and thyroid hormones, brain development, bone metabolism, and sexual maturation. The incidence of anti-drug antibodies (ADAs) with blocking activity may be estimated using results from immunogenicity testing. A list of the endpoints assessed as part of the MEASuRE is provided in Table 1.

Data collection and storage

US data are entered directly into MEASuRE via a web-based interface managed the clinical research organization (CRO, IQVIA) acting on behalf of the registry sponsor. At each specified bi-annual data collection time point, clinical information is abstracted from all patient visits including scheduled and/or unscheduled visits since the last data collection time point.

In the EU, MEASuRE receives data from eligible patients via the ECLip registry, which collects data from participating sites through the ECLip registry portal (https://osse.epibio.uni-ulm.de/login.xhtml). Only MEASuRE-specific endpoint data collected via the ECLip registry from eligible patients who have given consent are extracted and transferred to MEASuRE; this process is supervised by ECLip registry coordinators based at Ulm University. Data are extracted on a tri-annual basis and forwarded to the CRO for integration into the global MEASuRE database, which aggregates US and EU-derived data (Fig. 1).

Fig. 1figure 1

Arrangement of data flow into MEASuRE

AE, adverse event; ECLip, European Consortium of Lipodystrophies; EDC, electronic data capture; MEASuRE, Metreleptin Efficacy And Safety Registry; EMA, European Medicines Agency; IT, information technology

Data confidentiality

To ensure patient confidentiality and to prevent data double-entry, patients are assigned a unique identifying number pseudonym for both the US and ECLip registry datasets. The key matching identification numbers with patient names are maintained by the participating sites, and only the unique identifier is recorded on the data collection forms with patient initials collected in the US (patient initials are not included in the data received via the ECLip registry). The patient identifiers are maintained if a patient is transferred to another study site post-enrolment. Upon enrolment, in localities where this is permissible, patients may be required, by their treating physician and/or site staff, to provide their name, phone and email contact information, and similar information for next of kin or guardians; however, this information is not collected in the global MEASuRE database. The treating physician and their site staff are required to securely store this information separately from other shared registry information. This information will only be used by the treating physician to obtain patient vital status and disposition if the patient becomes lost to follow-up.

In any presentations or publications of the results of the study, the patients’ identities will remain anonymous and confidential. The sponsor, its designee(s), and specific government health agencies may inspect the records of the study.

Quality control

All sites are fully trained and are monitored through routine calls and visits, where necessary, with the CRO. Data obtained from patients are checked for accuracy prior to inclusion in MEASuRE reports submitted to regulatory authorities. In the US, this is primarily managed centrally by the CRO’s data management team in collaboration with the sites. For participating EU sites, the ECLip local operation group performs data reliability and completeness checks before forwarding data, tri-annually, to the CRO for inclusion in the MEASuRE database. The prescribing physicians participating in the registry are required to retain all study records and source documents for the maximum period required by applicable laws, regulations and guidelines, or institution procedures, or for the period specified by the sponsor, whichever is longer.

Adverse event reporting

All safety information including non-serious AEs, serious AEs, AESIs (whether related to metreleptin or not), as well as pregnancies, AEs associated with maternal exposure, and pregnancy outcomes are documented in the electronic data capture system by the participating sites within 24 hours or one (1) business day of awareness to comply with local regulatory requirements.

Interim reporting to regulatory authorities and future publications

All EU- and US-derived data submitted to MEASuRE are used to generate interim reports submitted to the FDA and the EMA, as mandated by these regulatory authorities. For peer-review publications involving data submitted to MEASuRE, the registry sponsor will be guided and advised by the steering committee as and when medically significant data are available and worthy of publication and dissemination to the wider medical community. In cases where a US or EU MEASuRE investigator(s), a MEASuRE steering committee member(s), or the MEASuRE registry sponsor wish to publish US-derived data from MEASuRE, requests must be made to and approved by the MEASuRE steering committee. For publications that include EU-derived data, the authors are also obliged to notify and receive approval from the ECLip registry board.

Statistical analysis and sample size calculations

The safety analysis set for MEASuRE will contain all enrolled subjects who receive at least one commercial dose of metreleptin, regardless of the number of prior doses received. The effectiveness analysis set will contain all enrolled subjects who have at least one lab result beyond baseline lab results and received at least one commercial dose of metreleptin. Baseline data are defined as the latest available data prior to initiating metreleptin use (i.e., metreleptin naïve data).

For the US, the goal of the registry is to enroll at least 100 patients initiating treatment with metreleptin. The sample size calculation is based on patient recruitment experience in the clinical development program and published prevalence information, it is estimated that 20 patients per year will enroll in the registry. Assuming an annual loss to follow-up rate of 10%, the cumulative person-time information during the study period is 656 person-years. Given this expected number of person-years of exposure, the study would provide 95% assurance for the detection of at least one occurrence of a given, relatively rare major safety event with an incidence rate of approximately 0.46%, that is, an event that would occur approximately once in every 220 person-years of exposure. This calculation assumes independence of person-years. In addition, this sample size, on a per-person basis, would provide two-sided 95% confidence limits with a maximum width of approximately ± 8.8% for events that have a per-person incidence of 30% or less.

In the EU, patients are enrolled indefinitely for the duration of the lifecycle of the product, and as such, no power calculation was performed.

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