TOPP-2

Design and rationale of the TOPP-2 Registry

TOPP-2 is an international, clinician-driven, multi-center prospective observational registry that collected data on children and adolescents consecutively diagnosed with PH between July 2015 and December 2022. Patients underwent clinical assessments and received standard medical care, as determined by the patient's physician in centers that declared to be committed to follow the pediatric diagnostic and follow-up guidelines, as proposed at the WSPH 2013, in their daily clinical practice. Patients did not receive (experimental) intervention or treatment as a consequence of their participation in the registry.

In this real-world, observational, non-interventional study, the frequency of visits was determined by the physician and by the health care needs of the patient. Nevertheless, participating sites declared to adhere to the guidelines, proposed by the Pediatric Taskforce at the WSPH, Nice, emphasizing the importance of continuous repeat evaluation of progression of disease in children with PH. Consistent with standard care, physicians were encouraged to schedule patient visits at least once a year. All visits were documented in the registry.

Kindly refer to the TOPP-2 observational plan and the Clinicaltrials.gov entry for further details.

Patient population and inclusion criteria

The patient population documented in TOPP-2 includes:

  • Ex-incident TOPP-1 patients, meeting all inclusion criteria and who agreed to continue their registry participation by signing the TOPP-2 informed consent form upon inclusion of sites who participated in TOPP-1.
  • Children and adolescents, newly diagnosed with PH (incident pediatric PH patients), meeting the inclusion criteria as listed below. A patient was considered an incident patient if the time elapsed between the diagnostic right heart catheterization and the initial visit at the site including the patient was less than or equal to three months.

Inclusion criteria:

  • PH diagnosis confirmed by heart catheterization (HC): PAP mean ≥ 25 mmHg at rest, PVRi ≥ 3 Wood Units•m2 and mPAWP ≤ 15 mmHg. Diagnosis of CHD patients who had undergone palliative procedure or repair to close systemic to pulmonary shunt had to be confirmed by HC at least 6 months after surgery/palliative procedure.
  • Aged ≥ 3 months and < 18 years old at time of diagnosis.
  • Incident PH patient (see above) who provided written consent to participate.
  • Patients had to present with PH belonging to either Group 1, 3, 4 or 5 according to updated Nice clinical classification.

Patients underwent clinical assessments and received standard medical care, as determined by treating physicians in their daily clinical practice. The TOPP-2 follow-up case report form (CRF) was specifically designed to capture the variables that have been proposed as treatment goals in pediatric PH and the reasons for changes in treatment strategy, including clinical status, BNP/NT-proBNP levels, ECHO-cardiac assessment and initiation/change of PH-targeted therapies.

Objectives

The TOPP-2 registry aimed to:

  • Validate the observed changes in the variables proposed in Nice as treatment goals in pediatric PH and identify new treatment goals.
  • Describe the frequency of components of clinical worsening in pediatric PH.
  • Evaluate the predictive value of these components and their composite of clinical worsening in pediatric PH.
  • Identify the current drivers of treatment strategy.
  • Compare the effectiveness of treatment strategies.
  • Describe disease characteristics, diagnosis, treatment and outcome in updated Nice clinical classification of pediatric PH group 3, 4 and 5 patients.
  • Characterize PAH-CHD with regard to presentation, clinical course and treatment strategy, according to the proposed ABCD system.

The TOPP-2 registry was launched in July 2015. The inclusion period was originally foreseen to run for up to 3 years, allowing the inclusion of approximately 200 patients. The observational plan was subsequently amended to allow enrolment until 30 June 2021. At enrolment closure, 182 migrated ex-TOPP-1 patients and 382 new incident patients were enrolled in the registry. All patients were followed up for at least 18 months until registry closure on 31 December 2022.

Participating sites

Participation in the TOPP-2 registry was upon invitation by the PePH Association based on the decision of the Executive Board of the Association.

Data collection and confidentiality

A web-based electronic data capture (EDC) system was used for data entry over a secured connection. Data was encrypted when transferred over the internet and was stored in a secure database protected from unauthorized access. Access to the patient database was password-secured and restricted to authorized users.

In order to guarantee the anonymity of the patient data within TOPP-2, no names, initials or date of birth were stored within the system. When setting up a patient the site entered initials, date of birth and gender for the system to generate a unique patient identifier. Immediately thereafter, initials and date of birth were deleted from the database and could no longer be retrieved.

An audit trail was maintained by the EDC system for all data entries and changes. This trail indicated what the entries/changes were, who made them and when.

The site including patients into the registry was responsible for data entry related to this patient. If for any reason another site tried to include the same patient, the system recognized this and informed the second site that this patient had already been included and by which site. Patients could be transferred between sites only if both sites agreed to it in writing and the transfer could only be performed by the company hosting the data or the Clinical Research Organization (CRO).

The individual sites own the data entered from their patients and were able to generate analysis reports based on data from their own site. Consolidated data from all participating sites are the property of the Association for PePH and will be analyzed on a regular basis.

Financial support

The registry was made possible through a research grant from Actelion Pharmaceuticals Ltd (now Janssen Pharmaceuticals Ltd).