Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02061072 |
| Other study ID # |
13-351-D |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 2015 |
| Est. completion date |
June 2019 |
Study information
| Verified date |
March 2020 |
| Source |
McMaster University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
The aims of this trials are:
1. to collect published and unpublished individual classic pharmacokinetic data (individual
patient data from independent investigators and pharmaceutical companies)
2. to make available population pharmacokinetic models for the concentrates derived from
the data collected
3. to develop a web based application intended to use the above models to calculate
pharmacokinetic parameters for individual patients, and
4. to test the system functionality via simulation of the use of the prototype by use of
faked test data.
Description:
Setting: All the development phases (a-c) will take place at McMaster University, Hamilton,
(ON), Canada. Phase d) will involve the centers selected for the subsequent twinned protocol
but will not use real patient data. The IT system will sit on a web accessible platform
developed and run by the Health Information Research Unit (HiRU) at McMaster University.
Participants: There are no patients taking part in this development phase. Companies and
independent investigators will act as co-investigators and will provide already existing
on-file individual pharmacokinetic (PK) data. Faked test data will be used for step d).
Eligibility criteria: eligibility criteria will be applied to pre-existing datasets. Primary
investigators or companies who own original PK data of factor VIII or IX concentrates will
provide data for the model creation. No restriction as to country, language or concentrate
will be applied.
Interventions: There is no therapeutic intervention planned. The study will result in a
system to be used to produce patient level estimates potentially useful to modify the
treatment regimens of the patients. The phase 1 "activities" portion the WAPPS-Hemo project
includes the following:
1. a systematic review to identify all the existing publications reporting PK data on
factor VIII and IX. Only articles reporting individual classic PK data will be included.
The data extracted will be extracted and compiled to be used to create the population PK
(pop-PK) models. Investigators and companies, fulfilling the eligibility criteria, will
be invited to provide data and to sign a bilateral Data Transfer Agreement. Data will be
subsequently transferred to HIRU, stored in a secure database and coded as needed for
step b).
2. establishment of a pop-PK model by splitting the data in two: a modeling set, from which
the PK model will be built, and a validation set, to be used to test the model before
implementation. Initially, the pop-PH model will be built using only the modeling data
and validated using the validation set through goodness-of-fit plots, bootstrapping, and
visual prediction checks (VPC). After the model validation, the entire data set will be
used to derive the final model for prospective use.
3. integration of the pop-PH models into the WAPPS-HEMO web service. The Information
Technology Support Group at HIRU will perform extensive in-house beta-testing using
fabricated data.
4. field testing of the website by asking centers participating in the research network to
test the website with fabricated patient data. After successful registration, the
centers will be provided with this data, and asked to generate records for those
patients. We will then run Pop-PH estimates, pilot the reporting process, gather
feedback on the testing process and troubleshoot any issues that come up. As well, we
will gather focus group feed-back and modify the service accordingly.
Outcomes: The WAPPS-Hemo project will result in:
1. a repository of all published and unpublished dataset of concentration-time points for
selected population of hemophilia patients studied after administration of factor
concentrates. Published data will be summarized in a systematic review and submitted for
publication.
2. pop-PH models for the factor concentrates for which concentration-time point for
population of hemophilia patients. The model development will be described in a
scientific report. The extended version will be available as part of the study
documentation, while a synthetic version will be submitted for publication.
3. availability of the web application to be used in the phase d) of the study.
4. availability of the prototypal web application to be used in the subsequent phase 2 of
the WAPPS-Hemo protocol.
Participant timeline: We will require 12 months to gather the data, build the model, and
create the prototypal web service.
Sample size: We expect to be able to derive models for concentrates for which we have 50 or
more pre-existing individual PK data. We expect to have data available for 4 or more
different factor concentrates.
Recruitment: No patients will be recruited for this phase of the overall WAPPS program. Only
already published data or data on file will be used to derive the model and set up the
system. All the investigator of the studies identified via the literature search will be
contacted and invited to provide data. All the drug manufactures active in the hemophilia
field will be invited to provide on-file PK data.
Data collection methods: Data will be collected from the primary investigators and companies
that have agreed to provide original PK data on factor VIII and factor IX concentrates.
Website development A cluster of fully resilient HP servers (Windows web servers in Network
load balancing configuration for the hosting the site, Microsoft SQL for the database, and
Windows server for the NONMEM software), located in two different buildings, will support the
system platform. The system will also incorporate fully mirrored hard disks, and redundant
Https connection. The administrative website and backup database will be accessible only over
a virtual private network (VPN). The system will be available 24/7 with a downtime of < 0.01
of total up time. All WAPPS related url (.com, .org, .ca, etc have been blocked immediately
at project funding notification - August 2013). All the needed licenses will be acquired,
including a single site license for the Icon NONMEM pop-PH software. The website, database
access interface, back-end NONMEM interface will be programmed in dot.net.
The system will be built ready to transfer information in a format compatible with the
hypertext languages used to embed knowledge into Electronic Medical Records (e.g., Arden
syntax and SEBASTIAN framework, http://www.openclinical.org/gmmsummaries.html), to facilitate
potential interface with the electronic medical record, database, and clinical trial case
report forms at a later stage.
Data management: Data from the primary investigators and companies will be stored on a secure
McMaster University server and only the research team will be able to access it. As the data
provided to the research team will already be anonymized, there will be no need for further
anonymization. Notwithstanding in this phase of the study only already existing data from
previous publications and on-file company-owned database will be used, we are providing a
description of the data management for the subsequent phase of the study (WAPPS phase 2,
protocol: The Implementation, User Testing and Validation of the Web-based Application for
the Pop-PH Service - Hemophilia (WAPPS-HEMO)). Users will be allowed to access and use the
system only after a moderated registration process. The head of the partner research center
will need to go through a registration process, and after validation by the McMaster team,
she will receive credentials to access the website. She will subsequently be able to
authorize other users from her/his center to access the system. Each individual user will
have unique access credentials and will be authorized to manage patients from the center she
belongs to. Only authorized users will be able to create and access patient records and input
the information required for the PK assessment. The identification of patients will happen
via a combination of three different keys, a minimum of two of which should be provided in
case of subsequent access to the record. The three identifiers will be:
1. the WAPPS unique identifier, generated by the system at patient's record creation
2. the patient birthdate, in the format "YYYY-MM-DD"
3. a local patient identifier. As to c, wherever allowed by the local center privacy
regulation, we will recommend to use a string composed by
"LASTNAME,FIRSTNAME,LOCAL_CENTER_ID". For centers whose relevant regulations do not
allow the use of this information, any combination of alphanumeric codes will be
accepted. It will then be the responsibility of the local center to track the local
identifier in the patient file.
These will be provided by the user creating a record for the patient. For subsequent
re-access of any user from the same center to any specific patient record from the center,
the system will display a list of the registered patient, using the identifier provided (i.e.
a) and b) mandatorily, c) with the information provided by the center. The user will be then
able to access a specific patient record for the allowed operation (as described in the study
protocol for step 2).
Statistical methods: The NONMEM 7 version 1.0 (ICON Development Solutions, Ellicott City, MD)
will be used with an Intel Fortran compiler (version 12) for pop-PH modeling. The statistical
program R (version 2.15.0, R Foundation for Statistical Computing, Vienna, Austria) will be
used to compile the NONMEM sets and generate the graphical representations of the models.
Perl Speaks NONMEM (PsN, version 3.5.3) and PsN and Xpose 4 will be used, respectively, for
the bootstrapping and the VPC validation tests.
To estimate the pop-PH parameters, we will use a first-order conditional estimation with
interaction method (FOCEI). Exponential function will be used to model inter-individual
variability (IIV), and the inclusion of IIV terms on PK parameters will be tested in
sequential order. IIV addition with the most significant objective function value (OFV)
reduction will enter the model first. Inter-assessment variability (IAV) will also be
evaluated with baseline pharmacokinetics at first available assessment as assessment 1 and
repeat PK profiling at the subsequent available time as assessment 2. Any residual errors
found in the data will be modeled as combined additive and proportional errors.
Potential demographic or clinical factors potentially affecting the PK (including the type of
concentrates for the basic overarching model to be used for products for which
product-specific data will not be available and the characteristics of the laboratory
technique used to measure the plasma factor level concentration) will be screened using plots
of IIV versus the covariates. For continuous coovariates, scatter plots of ETA (IIV code used
in NONMEM) versus the covariates will be used to determine functional relationships. These
plots will be overlaid with a non-parametric locally weighted smoother LOESS line. For
categorical covariates, potential differences between groups will be identified using box and
whisker plots. Any possible influence by continuous covariates should be suggested by a clear
trend of positive or negative slopes and outstanding correlation coefficients. Influence from
categorical covariates will be suggested by pronounced changes between the mean values of
each group. In the covariate modeling, a full stepwise forward addition (P<0.005) and
backward elimination (P<0.001) procedure will be used.
The model selection will also be validated with goodness-of-fit plots, including observation
(OV) versus population prediction (PRED), OV versus individual prediction (IPRED),
conditional weighted residual (CWRES) versus TIME and PRED plots. Other diagnostics, such as
parameter precision, ETA, and CWRES distribution and shrinkage, will also be used to choose
the proper pop-PH model.
Data monitoring: For step I of the WAPPS protocol, there is no need to plan a data monitoring
process. Indeed, all data will be validated as part of model derivation and used as such in
the rest of the study. Congruency checks will be performed on user's input data and PK
estimations in the subsequent phase 2 of the study and subsequently in routine use of the
interface.
Harms: During the development phases (a-c), we will not offer the web application beyond the
boundaries of the developing research unit. The website will be made available to the centers
in the research network during the testing phase d) (using only fabricated data) and the
subsequent phase 2 of the protocol. We will clearly identify the prototypal and experimental
use of the system in both the Research Agreements and the website page as a "Research tool
not yet ready for clinical practice". A clear disclaimer will indicate that "Any use of the
results of the pop-PH estimates in the care of individual patients should not be considered
part of the project in this phase".
