---
title: "Vertex Pharmaceuticals Europe Limited; non-interventional registry in Germany comparing Exagamglogene autotemcel with HU/transfusions for severe SCD in 12-21-year-olds; inform G-BA benefit assessment."
sdDatePublished: "2026-09-03T13:18:00Z"
source: "https://www.g-ba.de/downloads/40-268-12911/2026-09-03_AM-RL-XII_Exagamglogen-Autotemcel_2023-AbD-001_Feststellung_Studienunterlagen.pdf"
topics:
  - name: "health"
    identifier: "medtop:07000000"
locations:
  - "Austria"
  - "Germany"
---


Vertex Pharmaceuticals Europe Limited; non-interventional registry in Germany comparing Exagamglogene autotemcel with HU/transfusions for severe SCD in 12-21-year-olds; inform G-BA benefit assessment.

Studienunterlagen Version 3.0

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TITLE PAGE

VERTEX PHARMACEUTICALS (EUROPE) LIMITED
Non-interventional Study Protocol
Routine practice data collection to compare
Exagamglogene autotemcel with patient-
individualized treatment in severe sickle cell
disease: A prospective non-interventional study
mandated by G-BA
Vertex Study Number: HEOR-24-001-028
Date of Protocol: 21-May-2026

Vertex Pharmaceuticals (Europe) Limited
2 Kingdom Street London,
W2 6BD, UK
CONFIDENTIAL
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent
of Vertex Pharmaceuticals (Europe) Limited is strictly prohibited except to the extent required under applicable laws
or regulations. Persons to whom the information is disclosed must be informed that the information is confidential and
may not be further disclosed by them.

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SUMMARY
With its resolution from 21 December 2023, effective date 15 January 2025, the Federal Joint
Committee (Gemeinsamer Bundesausschuss, G-BA) has required Vertex to conduct a routine
practice data collection (AbD) to generate comparative data for the treatment with
Exagamglogene autotemcel (Exa-cel) compared to existing treatment alternatives in the
German healthcare system. The patient population of interest comprises patients ≥12 to <21
years of age with severe sickle cell disease (SCD) with recurrent vaso-occlusive crises
(VOCs) for whom hematopoietic stem cell transplantation (HSCT) is appropriate and a
human leukocyte antigen (HLA)-matched related hematopoietic stem cell (HSC) donor is not
available.
The aim of this study is to evaluate the effectiveness and safety of Exa-cel compared with
patient-individualized treatment in patients with severe SCD. Patient-individualized treatment
is defined as hydroxycarbamide (hydroxy urea, HU) and / or chronic red blood cell (RBC)
transfusions. The two co-primary objectives are to compare the annualized VOC rate and the
proportion of VOC-free patients between both treatment groups. Further objectives relate to
comparison of mortality and safety (restricted to total rate of serious adverse events (SAE),
operationalized as adverse events leading to hospitalization or prolonging an existing
hospitalization, or result in death).
The study is a prospective, non-interventional, registry-based, comparative study. The SCD
patient registry, mandated by the Society for Pediatric Oncology and Hematology (Register
Sichelzellkrankheit der Gesellschaft für Pädiatrische Onkologie und Hämatologie, GPOH)
and set up and administrated by Heidelberg University Hospital (UKHD), will be used as the
data source. All patients will be identified in the GPOH SCD registry and must meet the
requirements for eligibility according to the currently approved EU label for Exa-cel.
Furthermore, individuals must reside and be treated for their SCD in Germany, be receiving
patient-individualized treatment with HU and / or chronic RBC transfusions at start of
observation, have provided written informed consent, and the number of VOCs must be
available in their medical records for at least 2 years prior to start of observation.

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PROTOCOL SYNOPSIS

Title
Routine practice data collection to compare Exagamglogene autotemcel with patient-
individualized treatment in severe sickle cell disease: A prospective non-interventional
registry-based study mandated by G-BA

Brief Title
Routine practice data collection of Exagamglogene autotemcel in severe sickle cell disease
in Germany

Study Type
Non-interventional, prospective, comparative registry-based study

Study
Rationale
The Federal Joint Committee (G-BA) has mandated Vertex to conduct a routine practice
data collection (AbD) comparing Exagamglogene autotemcel (Exa-cel) with patient-
individualized treatment for patients ≥12 to <21 years of age with severe sickle cell disease
(SCD) with recurrent vaso-occlusive crises (VOCs) for whom hematopoietic stem cell
transplantation (HSCT) is appropriate and a human leukocyte antigen (HLA)-matched
related HSC donor is not available. The results of the AbD will be used to support a benefit
assessment of Exa-cel according to §35a Social Code Book V.

Study
Objectives
The aim of this non-interventional study is to evaluate the effectiveness and safety of
Exa-cel compared with patient-individualized treatment in patients with severe SCD with
recurrent VOCs. In SCD, the prevention of VOCs is the main treatment goal, ideally
resulting in VOC freedom. Therefore, the co-primary objectives of this study are to
compare the annualized VOC rate and the proportion of VOC-free patients between both
treatment groups. Further objectives relate to comparison of mortality as well as safety
(total rate of serious adverse events (SAEs)).

Data
Sources
This study will use clinical data from routine patient care as available in the patients’
medical files. Data will be documented into the GPOH SCD registry and into eCRFs
specifically designed for this data collection. AbD-specific data fields will be restricted only
to treatment centers who participate in the AbD and will only be documented for patients
who have signed informed consent to be included in the AbD. The GPOH SCD registry is
an independent multicenter, clinical and epidemiological registry including patients with
SCD irrespective of disease severity in Germany.

Study
Design
The study includes a patient identification period that will start with the first index date that
can be documented in the AbD (after implementing all required changes to the registry) and
continuing for 2 years thereafter. Therapy decision for Exa-cel during this time window will
trigger each respective patient to be offered inclusion in the study. Their index date will be
set as the date of therapy decision for Exa-cel (i.e. date when written treatment consent has
been provided by the patient).
As soon as an Exa-cel patient no longer requires red blood cell (RBC) transfusions for at
least 60 days for post-transplant support (defined as time point T60 for the patient), a
follow-up period of at least 3 years begins. For each patient, the period from the index date
to T60 (or to the end of the study or to study discontinuation, whichever comes first), is
defined as period 1. The period from T60 to the end of the study (or study discontinuation)
is defined as period 2 (period 1, period 2, and T60, see figure below in this section).

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Eligible patients within the GPOH SCD registry who are on patient-individualized
treatment and have been determined sufficiently similar to any included Exa-cel patient by
use of a matching algorithm during the patient identification period will be included in the
study subject to informed consent. Their index date, T60 date, and observation periods 1
and 2 will be linked to the calendrical milestones of the respective Exa-cel patient to whom
they were matched.
Figure: Overview of Exa-cel treatment from therapy decision to end of study and time
periods relevant for the AbD at a patient level.
Modified
Active
Comparator
New-User
(MACNU)
Design
To identify eligible Standard of Care (SoC) patients who are sufficiently similar to any Exa-
cel patient and to assign meaningful index dates, a novel study design named Modified
Active Comparator New-User (MACNU) Design is proposed. The MACNU design
employs a systematic four-step process:
(1) identification of eligible SoC patients within the GPOH SCD registry,
(2) definition of exposure sets for each Exa-cel patient based on relevant clinical
characteristics,
(3) calculation of time-conditional propensity scores, and
(4) matching Exa-cel patients with SoC patients to form a balanced study cohort.
The MACNU design enables the selection of SoC patients with disease severity
characteristics similar to those of the Exa-cel patients, which is essential to ensure
comparable treatment cohorts. Hereby, similarity is defined based on the number of VOCs
in the 2 years preceding the index date, genotype and chronic RBC transfusions treatment.
Study
Population
All study patients must meet the requirements for eligibility according to the currently
approved EU label for Exa-cel and will be identified by screening patients in the GPOH
SCD registry. Eligibility of SoC patients has to be confirmed for each inclusion into an
exposure set (see section 11.4.2)
Patients are eligible to be included in the study if all of the following criteria apply:
1. Residing and treated for their SCD within Germany
2. Severe SCD with recurrent VOCs*
3. Eligible for HSCT and all aspects related to Exa-cel treatment (e.g., full
myeloablation, stem cell mobilization, apheresis) according to the assessment of
the treating physician**
4. An HLA-matched related HSC donor is not available (discretion of treating
physician)
5. ≥12 and <21 years of age at index date
6. Complete records of VOCs leading to hospitalization available in the registry
and/or patient's file for at least 2 years prior to index date

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7. Receives patient-individualized treatment with hydroxycarbamide (HU) and / or
chronic RBC transfusions at index date
8. Provided written, signed informed consent for their data to be included in the study

* As per the label of Exa-cel, severe SCD is defined by the recurrence of VOCs; “recurrent
VOCs” for the purposes of this study are aligned to the patient selection criteria for Exa-cel
proposed by the Kompetenzcentrum Onkologie (KCO, (1)), where “recurrence” is defined
as the occurrence of at least 2 VOCs per year over the course of 2 years; Of note, patients
who, due to severe previous VOCs and/or other SCD complications, are receiving chronic
RBC transfusion therapy may have none or less than 2 VOCs/year as a consequence of this
therapy; such patients are also eligible for the AbD, as per definition their disease severity is
sufficiently high to meet the Exa-cel requirements (see section 11.3.1 for further details).
** In the context of this study, “eligibility for HSCT” is defined as per the label of Exa-cel,
where a full myeloablation is required (see section 11.3.1 for further details).
Patients are excluded from the study if any of the following criteria apply:
1. Treatment with Exa-cel or any of the agents / procedures used along the Exa-cel
treatment journey is contraindicated or not recommended; this includes prior
HSCT, pregnant women, active human immunodeficiency virus (HIV)-1, HIV-2,
hepatitis B and C virus (HBV and HCV) infections, and severe
alloimmunization/transfusion reactions that preclude RBC transfusions (discretion
of treating physician)
2. Treatment (including preparation to receive treatment) with allogeneic HSCT,
alternative gene therapy or experimental therapies

Note: Treatment centers are not obliged to but may apply for patient-individual cost-
coverage prior to Exa-cel therapy decision. To be able to estimate uncertainties in
positivity, patients for whom a cost-coverage application was submitted but denied, but who
fulfill all inclusion criteria and none of the exclusion criteria, will be included in the study
but handled as a separate group for which only patient characteristics will be reported. It
will be differentiated whether the assumption of costs was rejected due to clinical or non-
clinical (other) reasons. If there are non-clinical reasons, an incl