Study Description: Multicenter, double blind, randomized, placebo-controlled, adaptive phase
II dose finding study meant to define if MSCs, administered at dosage of 80 or 160 x 10^6
cells within 48h from TBI, are safe in patients with severe TBI, and to define if MSCs,
administered at the dosage found to be safe and more promising, decrease the plasmatic
neurofilament light (NFL) biomarker of brain damage at 14 days. Patients will be recruited at
the Neurointensive Care Unit at Fondazione IRCCS San Gerardo dei Tintori, Monza, at ASST
Ospedale Papa Giovanni XXIII Bergamo and at Fondazione IRCCS Ca Granda Ospedale Maggiore
Policlinico of Milano. Collection of multiple clinical, neuroimaging and biological
parameters will describe TBI evolution.
Preclinical studies: Studies in rodent TBI models have shown that administration of MSCs
produces functional improvement with amelioration of sensorimotor and cognitive deficit,
reduction of contusion volume and neuronal loss, modulation of the inflammatory response with
decreased inflammation, stimulation of beneficial endogenous mechanisms (angiogenesis,
neurogenesis, synaptic plasticity). These results support the notion that MSCs can reprogram
the microenvironment mitigating the progression of brain damage and fostering recovery of
function. Only few clinical studies have assessed the safety, feasibility and efficacy of MSC
therapy. No adverse events (AEs) or severe adverse events (SAEs) were reported. No AEs were
associated to the intravenous route, which is the one the investigators propose for the
study.
Target Sample Size:The total number of evaluable patients to be analyzed will be 66 (27 on
the control arm, 12 in the experimental arm stopping at first step and 27 in the experimental
arm reaching the second step). In details, the total number of evaluable patients to be
analyzed will be 24 (12 patients in each experimental arm) for the safety interim analysis
and 54 for the final efficacy analysis (27 patients in both the control arm and in the
experimental arm reaching the second step).
Expecting a 13% of deaths of TBI patients in ICU, the number of patients to be randomized is
about 78 (32 in the control arm, 14 in the experimental arm stopping at first step and 32 in
the experimental arm reaching the second step). In case of the trial closure after the first
step, the number of patients to randomize will be about 42 (14 in each arm).
Statistical design and sample size:The statistical study design is conceived in 2 steps.
Step 1: An interim safety analysis will be performed to evaluate separately in each of the
two experimental dosage groups, at one-sided type I error rate of 10%, whether more than 30%
of patients experience at least one serious adverse drug reaction (SADR) within 14 days from
treatment, and at the same time at a power of 80% whether 5% or less of the patients do not
experience any SADR. Adopting the Fleming design with A'Hern's approach, 12 evaluable
patients will be analyzed in each group (36 patients overall). The maximum number of patients
experiencing at least one SADR to observe in each experimental group is 1 out of 12, since
this result is associated with an upper limit of the 80% exact confidence interval of 28.8%.
The experimental treatment will be considered as safe for this step only if none or one
patient experiment a SADR.
According to the above role:
if both experimental treatments are considered not safe, the study will be stopped for
safety issues and the step 2 of the study will not be performed
if one experimental treatment is considered safe and the other not safe, only the safe
arm will proceed with the step 2 of the study
if both the experimental dosages are safe, then the more active schedule will be
selected for the step 2 The more active schedule will be defined in terms of proportion
of patients who reaches a NFL increase at 14 days equal or lower than baseline level by
5 folds (defined as "responder patients").
This cut-off has been defined based on longitudinal quantification kindly provided by
BIO-AX-TBI collaborators, showing a median increase of 12.8-fold at 14 days compared to
baseline, with first quartile equal to 5-fold increase (see paragraph 5.4 for details). In
case of an equal number of responder patients in the two experimental arms, the cut-off
defining the response will be increased by 1 unit iteratively since a difference between the
two experimental arms will be observed. This assessment will only be performed on the MSC
treated arms; the control group will not be considered. According to Simon, Wittes and
Ellemberg randomized phase II design, the study has more than 80% probability of correctly
select the more active schedule when the proportion of responder patients is 15% higher in
the first of the two schedules of treatment.
Step 2: the primary endpoint will be the NFL at 14 days. The final efficacy analysis will be
performed by increasing the sample size to 27 evaluable patients in the experimental and
control arms. The study is designed to detect an effect size of 0.59 on logarithmic scale of
the experimental to control arm, setting a one-sided type I error rate of 10% and a power of
80%.
Data will be analysed by the study biostatistician using the software SAS 9.4 release. A full
Statistical Analysis Plan will be written prior to statistical analysis.
Deceased or lost to follow-up patients and patients with missing values will contribute to
the analysis of the secondary outcomes only for the time during which data are available.
All patients who have received the treatment will be included in the safety analysis. Each
patient will be analyzed in the arm actually received.
The assessment of safety will be mainly based on adverse reactions (ARs) and the frequency
and nature of the serious adverse events (SAEs) and will be conducted on the safety analysis
set.
Expected results: the investigators expect to prove the safety and efficacy of MSC
intravenous administration in acute and severe TBI patients. The investigators will provide a
detailed longitudinal description of the effects of MSCs on brain advanced neuroimaging
trajectories, on axonal damage and neuro-immunomodulatory changes by blood biomarker analysis
and on clinical outcome.
MSC preparation: The preparation of MSCs will be performed as detailed in the IMP brochure
according to Good Manufacturing Procedures (GMP) guidelines at Laboratorio Stefano Verri,
ASST MONZA. Laboratorio Stefano Verri has standard operating procedures in place for storage,
release, thawing, preparing and administering the MSCs.
MSCs are stored in vials containing 40 X 10^6 MSCs each in 4.5 ml of storage solution (2.5 ml
albumin 20%, 1.1 ml normal saline solution, 0.45 ml citrate-dextrose solution (ACD), 0.45 ml
Dimethyl sulfoxide (DMSO)). Vials containing 4.5 ml of storage solution only will be prepared
and stored in the same manner. The MSC injections and the placebo injections will have
identical appearance and consistency. Vials are stored in the vapor phase of liquid nitrogen
until the time of administration.
The study treatment will be prepared by qualified personnel under a class A laminar flow hood
in proximity to the ICU.
IMP will be administered acutely (within 48h after injury) within 15 minutes from the
preparation through a central venous line.
Random allocation procedure: Patients will be randomly assigned to one of the three treatment
groups (allocation ratio 1:1:1 for the first step and 1:1 for the second step). The study
biostatistician will prepare the sequence of treatments according to a randomized permuted
blocks procedure. The randomization schedule will be generated using SAS 9.4 release. The
randomized allocation of treatment will be centralized.
Upon recruitment of a patient meeting the inclusion criteria, the local investigator will
follow a randomization list (provided by the factory member's personnel) (detailed in the
Manual of Procedures) to assign the treatment to the patient in a blinded fashion manner.
Blinding: The subjects, the research coordinators and investigators, and the personnel
involved in outcomes assessments and monitoring compliance will all be blinded. Treatment
assignment will be known only to the Sponsor Data Management Team and the Cell Factory of
each center. An unblinded physician will be designated to monitor safety results.
Patient withdrawal: Patients may withdraw (or be withdrawn) from the study at any time.
Withdrawals within 14 days will be replaced.
Reasons for patient withdrawal include:
Adverse event that in the judgement of the Investigator requires study withdrawal
Patient wishes to withdraw from the study
Patient is lost to follow-up Benefit/Risk assessment: The use of MSC therapy for TBI
patients is experimental and may not result in any direct benefit to the patient.
Nevertheless, proposers strongly believe that the benefits awaited from this MSC-based
therapeutic strategy is an amelioration of the evolution of TBI pathology with a
consequent better outcome with the reduction of the long-term disabilities. MSCs are a
particularly promising cell therapy because of their availability, immunologic
properties and track record of safety and efficacy.
The risks associated with the intravenous administration procedure include bleeding, swelling
and minor pain on injection. These are self-limiting and do not pose any long-term problem.
During the first few hours from the MSC intravenous infusion: headache, fever, rush and
allergic reaction may appear. The risk of allergic reaction is mitigated by the use of human
platelet lysate instead of the fetal calf serum during the manufacturing process. This also
allows to avoid the possible transmission of still unknown zoonosis.
There is also a remote infectious risk that can be treated with appropriate antibiotics. The
infection may conduct pain, discomfort and tissue damage.
A possible risk of intravenous MSC infusion is represented by thromboembolic events. MSC
infusion could increase pulmonary vascular resistance in the presence of injured pulmonary
microcirculation, potentially by aggregating or clumping in capillaries or small arterioles.
Subsequent potential risks are acute right heart failure, impaired cardiac output and
hemodynamic instability. Additionally, infusion of MSCs could potentially worsen
ventilation-perfusion mismatch and result in further impairment of oxygenation or carbon
dioxide excretion.
Collection of Data: All data obtained during this clinical trial will be captured
electronically in a project specific programmed Electronic Data Capture (EDC) application.
For each subject, all data and trial-related visits will be recorded in the eCRF (electronic
Case Report Form). If a subject withdraws from the trial, the reason must be stated in the
eCRF.
Informed consent: It is the responsibility of the investigator/delegate to obtain informed
consent according to ICH-GCP and Declaration of Helsinki guidelines and local regulations
from each individual subject participating in this study and/or his/her legally designated
representative/proxy. If the subject is not able to provide personal consent at the time the
consent is obtained, then he/she must provide or withdraw this consent as soon as possible
once his/her clinical condition has improved to the extent that providing personal consent is
possible, unless local regulations state otherwise.
The informed consent form (ICF) will be provided in the country's local language(s).
Regulatory and Ethical Compliance: The trial will be performed in accordance with the
Declaration of Helsinki and the Good Clinical Practice. The trial obtained the Regulatory
Agency (AIFA) approval. The protocol and trial conduct will comply with the Medicines for
Human Use (Clinical Trials) Regulations 2004 and any relevant amendments. Development Safety
Update Reports will be submitted to the IEC and Regulatory Agency.
