This study has been transitioned to CTIS with ID 2024-516338-37-00 check the CTIS register for the current data. This study aims to assess the Pharmacokinetic (PK)-parameters and safety of treatment with BR-003 in humans. BR-003 is a pliable, ring-…
ID
Source
Brief title
Condition
- Nervous system, skull and spine therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective:
- Assess systemic safety by confirming that the Cmax of BR-003 when
co-implanted with a pedicle screw onto the spine, stays below the known toxic
levels of 2000ng/mL
Secondary outcome
Secondary objectives:
- To investigate additional pharmacokinetic parameters (Tmax, AUC, T1/2)
- Assess the safety of BR-003
• Incidence, classification and grading of Adverse Events
• Clinical laboratory results (blood chemistry)
• ECG data
• Wound healing
• Vital signs, neurological assessment
• Radiological assessment
Background summary
Instrumented spine surgeries are among the most painful medical procedures
overall. During surgery, instruments and surgical implants unavoidably damage
the bone of the spinal column and surrounding soft tissues. The outer bone
layer, the periosteum, is exceptionally rich in pain receptors, especially in
the spine. For several days after spine surgery, patients experience
debilitating pain that cannot be sufficiently suppressed by currently available
analgesics. Inadequately controlled pain impedes postoperative recovery,
extends hospital stays and increases healthcare expenditures. Furthermore,
acute postoperative pain is a significant predictive factor for the development
of chronic pain conditions. For these reasons, pain management is widely
regarded as an integral aspect of recovery after spine surgery.
Currently, systemic opioids are the mainstay of postoperative pain treatment.
Although they are the strongest painkillers available, opioids fail to provide
sufficient pain relief in up to 80% of surgical patients. Opioids are highly
addictive and have many debilitating side-effects impeding recovery after
surgery. Chronic opioid use is prevalent, especially after spine surgery, and
represents a substantial public health burden. There is a large unmet clinical
need for improved non-opioid pain treatments.
Local anaesthetics have long been recognized as promising alternatives. Rather
than exerting their effects in the entire body, they are injected at specific
sites to block pain signals locally. Local anesthetics have well-established
safety and efficacy profiles and are widely used to treat acute postsurgical
pain in a variety of procedures. However, even for bupivacaine, the
longest-acting agent in this drug class, its limited duration of action is a
major limiting factor. Because repeated administrations near the spinal
periosteum are challenging, uncomfortable, and undesirable due to an associated
risk of infection, local anaesthetics have limited added value in major
procedures like spine surgery. Solutions are needed that locally block pain for
the first three days after surgery, after which the most intense pain begins to
subside . If opioids can be replaced in this critical early phase, the pain
thereafter becomes manageable with conventional oral non-opioid analgesics. So
far, extended-release formulations have not been able to demonstrate clinical
superiority over their generic counterparts. These novel injectables still work
for up to 24 hours, at best, and are not kept in place near the surgical site.
To bridge the first three days and unlock their full potential, further
improved non-opioid local pain treatments are needed.
Study objective
This study has been transitioned to CTIS with ID 2024-516338-37-00 check the CTIS register for the current data.
This study aims to assess the Pharmacokinetic (PK)-parameters and safety of
treatment with BR-003 in humans. BR-003 is a pliable, ring-shaped,
biocompatible hydrogel that contains bupivacaine, a well-known and approved
local anaesthetic. Attached to the shanks of pedicle screws, BR-003 is
co-implanted locally without affecting existing surgical workflows. After
placement, BR-003 provides a targeted, sustained release of bupivacaine for at
least three days before dissolving within approximately 36 weeks (based on a
sheep study).
Primary objective:
- Assess systemic safety by confirming that the Cmax of BR-003, when
co-implanted with pedicle screws onto the spine, stays below the known toxic
levels of 2000 ng/mL
Secondary objectives:
- To investigate additional pharmacokinetic parameters (Tmax, AUC, T1/2)
- Assess the safety of BR-003
• Incidence, classification and grading of Adverse Events
• Clinical laboratory results (blood chemistry)
• ECG data
• Wound healing
• Vital signs, neurological assessment
• Radiological assessment
Study design
The study will consist of 2 cohorts with 12 patients in total. The study is
divided into two parts; the main study period, covering the first 42 days after
the day of surgery, and the follow-up period, starting after the 42 day main
study period until 12 months after the day of surgery.
In cohort I, six patients that will undergo a 1-level fusion will be included,
with 4 pedicle screws and 4 BR-003s with a dose of 36 mg per BR-003. They will
receive a cumulative dose of 144 mg bupivacaine base. Data from the main study
period of cohort I will be assessed by an independent DSMB and only when
considered safe, cohort II can start.
In cohort II, the cumulative dose will be increased to 216 mg bupivacaine base.
Six patients planned for 2-level fusions will receive a cumulative dose of 216
mg (6 BR-003s).
In both cohorts patients will be hospitalized from the day of surgery (standard
of care) until day 4 after the surgery. Thereafter the patient will visit the
hospital on day 9, 14 en 42. The follow-up period of this study consists of
two telephonic contacts at month 3 and 6 after
surgery, and a hospital visits at month 12 after the surgery. The day 9 visit
can also take place at the patients home. More details about the visits and
assessments can be found in the section *Study assessment schedule*.
Intervention
BR-003 (36mg bupivacaine base) is a medicinal product presented as an
Implantation Matrix (IM) providing sustained release of bupivacaine to manage
postoperative pain, to be administered during spinal fusion surgery,
co-implanted with a pedicle screw.
Study burden and risks
All enrolled patients will undergo elective spine surgery for a degenerative
condition. These surgical procedures carry a certain risk profile that is
discussed beforehand by the treating physician/spine surgeon. Details on the
additional burden and risks for participating in this phase Ib trial can be
found below. In the preoperative phase patients routinely undergo screening to
ensure safety during the surgical procedure. During this mandatory visit all
activities pertaining to the '*screening* part of the current study can be
completed, thereby minimising the burden on patients in terms of time
investment or discomfort. During and after surgery, patients will receive
standard of care pain treatment/management and will receive additional
monitoring for vital functions but also for items related to patient
(dis)comfort and perceived changes in well-being in relation to the reason for
the surgery. These monitoring activities will also be used to complete most of
the activities related to the current study, again minimising patient burden
and discomfort. For the assessments required for the current study that cannot
be completed during routine examinations, the patient burden and associated
risks is considered low and acceptable. The additional assessments are:
multiple ECG recordings, frequent blood sampling for PK, 3 blood chemistry
samples, wearing an accelerometer on one leg from surgery until day 14,
completing a questionnaire about pain management once and completing three
times two questionnaires on health related quality of life and the extent to
which a person*s functional level is restricted by disability.
The risks associated with participating in the current study are mainly related
to the systemic and local effects of exposure to bupivacaine. For the expected
systemic effects of bupivacaine, the applicant has extensively studied the
effects of implanting BR-003 in a large animal model and found the systemic
levels of bupivacaine to be in orders of magnitude lower than the toxic
threshold. The applicant therefore suggests the risks of adverse events caused
by systemic bupivacaine, including cardiotoxic or neurotoxic effects, to be
very low. The local effects of sustained high levels of bupivacaine in the
surgical wound has also been studied previously by the applicant in the same
large animal model. Potential adverse events may include wound healing
disturbances and compromised ingrowth at the interface of bone and implant. The
applicant has found a very low incidence of primary wound healing disturbances
and no secondary wound healing disturbances.
Woudenbergseweg 41
Austerlitz 3711AA
NL
Woudenbergseweg 41
Austerlitz 3711AA
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
1. Males and females aged between 18 years and 80 years (inclusive)
2. Planned for open or percutaneous posterior spinal stabilisation with 4 (for
cohort I) or 6 (for
cohort II) pedicle screws with a diameter of 5 to 7.5 mm (inclusive) with or
without concomitant
posterolateral fusion, vertebral augmentation, intervertebral body fusion
devices, osteotomies,
and posterior decompression. Only primary instrumented spinal surgery cases can
be included.
3. Willing and able to comply with the protocol for the duration of the study
4. Give written informed consent prior to any study-related procedure not part
of the standard
practice, with the understanding that the consent may be withdrawn by the
subject at any time
without prejudice to his/her (post-)surgery care
5. Females are eligible only if not currently pregnant, nursing, or planning to
become pregnant
during the study or within 9 months after study drug administration. Female
subjects must be surgically sterile, at least 2 years menopausal, or using an
acceptable method of birth control.
WOCBP, must have a documented negative pregnancy test within 24 hours before
surgery.
Exclusion criteria
1. Concomitant anterior/lateral procedures (e.g. anteriorly placed vertebral
cage, anterior plating,
ALIF/XLIF)
2. Use of ilium screws or use of (additional) pedicle screws, with a size <
5 mm or > 7.5 mm.
3. Indication for surgery being:
a. Active or previous (para)spinal infection
b. Metastatic, malignant or benign tumours of the spine
c. Fracture/other traumatic injury
4. Known high risk of intra-/postoperative surgical complications (e.g.
patients having previously
undergone more than 2 non-instrumented spinal surgeries at the index level)
5. Planned use of a surgical drain
6. Planned use of an epidural catheter
7. Use of local amino-amide or amino-ester anaesthetics within 5 days prior to
the scheduled
surgery (10 days in case of slow release products), peri-op and post op for the
first two weeks after the surgery.
8. Has a pre-existing concurrent acute or chronic painful physical/restrictive
condition expected to
require analgesic treatment in the postoperative period for pain that is not
strictly related to the
surgical indication and which may confound the postoperative assessments.
9. Has a medical condition such that, in the opinion of the Investigator,
participating in the study
would pose a health risk to the subject or confound the postoperative
assessments. Conditions
may include, but are not limited to, the following:
a. History of allergic reactions to bupivacaine or excipients or BR-003, or if
the
investigational product is otherwise contra-indicated
b. ASA-classification >3, as assessed during the most recent pre-operative
screening.
c. Clinically significant renal or hepatic abnormalities (defined as an AST or
ALT > 3x
Upper limit of normal (ULN), creatinine > 2x ULN)
d. History of clinically significant cardiac abnormality such as myocardial
infarction within
6 months prior to study participation, NYHA class III or IV, or clinically
significant
abnormalities on ECG
e. History of coronary artery bypass graft surgery within 12 months prior to
study
participation
10. Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in
the opinion of the
Investigator, could interfere with study assessments or compliance
11. A body mass index (BMI) > 39 kg/m2 or patients with a weight below 50 kg
12. History of, suspected, or known addiction to or abuse of illicit drug(s),
prescription medicine(s),
or alcohol
13. As per subject history and/or medical records, has active infection or is
currently undergoing
treatment for Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV)
14. Participation in another interventional study
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-516338-37-00 |
| EudraCT | EUCTR2022-001069-11-NL |
| CCMO | NL81348.056.22 |