The Galvani Splenic Neuromodulation System consists of a lead, rechargeable implantable pulse generator, external components and accessories. The system is designed to deliver electrical stimulation to the splenic NVB in patients with moderate to…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective and associated endpoints for each period of this
multipart study are:
1. To evaluate the safety and tolerability of the Galvani splenic
neuromodulation system and stimulation of the splenic NVB as assessed by:
a. Incidence, causality and severity of Adverse Events (AEs), Serious Adverse
Events (SAEs), Adverse Device Effects (ADEs) and Serious Adverse Device Effects
(SADEs).
b. Laboratory Safety Assessments (clinical chemistry and haematology).
c. Vital sign measurements (blood pressure, heart rate, respiratory rate, and
body temperature).
d. 12-Lead ECG monitoring.
Secondary outcome
Secondary objectives and endpoints are:
1. For the Randomized Control Trial (Period 1) - to evaluate the effect of
splenic NVB stimulation on the clinical signs and symptoms of RA as assessed by:
a. Change from baseline in the 28 Joint Disease Activity Score DAS28 at week 12
(end of Period 1).
2. For the Randomized Control Trial and Open Label periods (Periods 1-2) - to
evaluate the effect of splenic NVB stimulation on the change in pharmacodynamic
and response biomarkers as assessed by:
a. Changes from baseline in the levels of LPS-inducible release of TNFα, IL-6,
IL-8, and IL-17 in whole blood assay at assessment timepoints.
3. Throughout each period of this multipart study:
a. to evaluate the effect of splenic NVB stimulation on the clinical signs and
symptoms of RA as assessed by:
i. change from baseline in DAS28 at assessment timepoints
b. to evaluate the effect of splenic NVB stimulation on Patient Reported
Outcomes as assessed by:
i. change from baseline in HAQ-DI score at assessment timepoints
ii. change from baseline in physical and mental component scores as well as
domain scores of SF-36 at assessment timepoints.
c. to evaluate the usability of the clinician and patient external devices and
accessories as assessed by participants* and clinicians* feedback on the use of
CP, PR, IPG Charger, Belt and Adhesive patch using sponsor-developed
questionnaires.
d. to evaluate the participants* perception of therapy and sensation as
assessed by participants* feedback using a sponsor-developed questionnaire.
e. to evaluate the device performance as assessed by the tabulation of device
deficiencies.
Additional secondary objectives and endpoints specific to the Open Label
Treatment phase (Period 2) are:
1. For the cohort of participants on active stimulation during the RCT Phase
(i.e., Period 1) who achieve a clinical response (i.e.: > 1.2 units of
improvement on DAS28) at week 12: to determine whether this response can be
sustained and/or extended upon 12 additional weeks of active stimulation as
assessed by:
a. Change from week 12 to week 24 in DAS28.
b. Achievement of DAS28 score of < 2.6 at week 24.
2. For the cohort of participants on sham stimulation during the RCT Phase and
for participants who failed to achieve an adequate clinical response on active
stimulation during the RCT Phase at week 12: to provide active treatment with
baricitinib - an approved therapy for this patient population - and determine
response to this therapy as assessed by:
a. Change from week 12 to week 24 in DAS28.
b. Achievement of clinical response (> 1.2 units of improvement on DAS28) at
week 24 vs. week 12.
c. Achievement of DAS28 score of < 2.6 at week 24
Background summary
Rheumatoid arthritis is a chronic inflammatory disease that affects the
synovial joints of approximately 1% of the world's population (women three
times more often than men). Although treatment options and efficacy have
increased substantially in the past two decades, the disease cannot be cured or
prevented. Therefore, rheumatoid arthritis still has a considerable effect on
the quality of life of patients, not only because life-long medication is often
required, but also because residual disease activity leads to progressive loss
of function in the musculoskeletal system and extra-articular morbidity.
Despite the fact that there are many types of DMARDs available, only a minority
of patients reach the treatment goal of remission or low disease activity
(Smolen, Aletaha & McInnes, 2016). Therefore, key future goals in the
management of rheumatoid arthritis are the ability to induce long-lasting
drug-free remission in patients with the disease. In addition, there are also
patients who discontinue medication because of side effects, or because they do
not want to take chronic medication. Neuromodulation has been suggested as a
potential treatment option for patients.
Extensive evidence from small and large animal models, studies in porcine and
human tissue and immune cells, and a pilot intraoperative clinical study have
provided extensive evidence of immunomodulatory effect from Splenic Nerve
Stimulation (SpNS) and suggests it differs from biological or targeted
synthetic disease-modifying antirheumatic drugs.
Galvani bioelectronics developed a system to deliver electrical stimulation to
the splenic neurovascular bundle in patients with moderate to severe RA or
other inflammatory diseases. The implantable system is designed specifically
for laparoscopic delivery to the splenic neurovascular bundle using surgical
tools and accessories. The lead is attached to an Implantable Pulse Generator
(IPG). The lead and the IPG are referred to as the *implantable system*.
Non-implantable components of the System include a Clinician Programmer (CP), a
Patient Remote (PR) and IPG Charger, a charging belt and adhesive patches to
hold the IPG Charger over the IPG. All components of this system are considered
investigational.
Study objective
The Galvani Splenic Neuromodulation System consists of a lead, rechargeable
implantable pulse generator, external components and accessories. The system
is designed to deliver electrical stimulation to the splenic NVB in patients
with moderate to severe RA or other inflammatory diseases. This study will
evaluate the safety, tolerability, and effects of stimulating the splenic
neurovascular bundle (NVB) with an active implantable medical device system in
participants with moderate to severe RA.
Study design
Study GAL1040 (www.clinicaltrials.gov, NCT05003310) is a randomized control
trial evaluating the safety, tolerability, and effects of stimulating the
splenic NVB on the clinical signs and symptoms of RA. The study is being
conducted in a maximum of 12 centres in the US and the Netherlands with an
external Data safety Monitoring Board overseeing safety of GAL1040. A
staggered enrolment will be applied with an implant suspension for safety
analysis following 4 and again after approximately 10 participants implanted.
Safety data will be submitted to the FDA to request continuation of study at
both timepoints.
The study will consist of 4 study periods, including a Randomized Control Trial
period (Period 1), an Open Label period (Period 2), a Treat-to-target period
(Period 3), and a Long-term Follow-up period (Period 4) (see Figure 6 and 7 for
the study overview ). Participants with active rheumatoid arthritis (RA) will
receive an implantable system and following a recovery period of at least 28
days after implant of the system, will be randomly assigned at Day 1 (of Period
1) to receive either active stimulation or sham-stimulation via this system for
12 weeks (84 days). The first 4 participants will receive Open-label
stimulatie. Day 1 assessments will be used as a baseline. After the 12 weeks of
randomized stimulation, all participants will enter an open label phase (Period
2) during which participants who achieved a clinical response (DAS28
improvement of greater than 1.2 points at week 12 relative to baseline) from
active stimulation will continue active stimulation whereas participants who
received sham stimulation as well as those who did not respond to active
stimulation will be switched to baricitinib for 12 weeks.
At the 24 weeks* assessment, stimulation arm participants will have received
either 24 weeks of active stimulation or 12 weeks of active stimulation
followed by 12 weeks of baricitinib, whereas sham arm participants will have
received 12 weeks of sham stimulation followed by 12 weeks of baricitinib. At
the end of Period 2, participants who have achieved an initial clinical
response (DAS28 improvement > 1.2 points) to therapy but have failed to achieve
the treatment target (of DAS28 < 2.6) will enter the Treat-to-target period
(Period 3); others will proceed to Period 4 (a 5-year Long-term Follow-up).
During the Treat-to-Target period, participants will be treated with dual
therapy (stimulation in combination with baricitinib) for up to 24 weeks,
thereafter they will move to Period 4.The total duration for each participant
in the treatment periods (Periods 1-3) - excluding screening and implant
recovery and prior to entering Period 4 (LTFU) - is up to 48 weeks,
depending on response to therapy). Period 4 (LTFU) provides long term safety
follow up for all study participants for a period of 5 years. It also provides
an escape to rescue treatment (if needed) and standard of care therapy for
participants from previous periods experiencing uncontrolled systemic flares,
lack of efficacy or intolerance to investigational therapy. Participants who
did not receive Stim ON in the previous periods may receive Stim ON during
Period 4, subject to a favourable benefit-risk assessment in the judgement of
the treating rheumatologist.
Intervention
Participants with active rheumatoid arthritis (RA) will receive an implantable
system by a laparoscopic surgical procedure and following a recovery period of
at least 28 days after implant of the system, will be randomly assigned at Day
1 (of Period 1) to receive either active stimulation or sham-stimulation via
this system for 12 weeks (84 days). After period 1, different treatment options
are available depending on the disease activity of the patient including
stimulation or the approved RA drug baricitinib.
Study burden and risks
During this clinical trial, the patient must undergo a laparoscopic surgery to
place the implant. The patient is admitted to the hospital for 1 night to
follow the patient for safety reasons. The implant operation is performed in
the Catherina Hospital by an experienced and trained surgeon. In addition, the
patient will have to come to the hospital several times to undergo various
examinations to investigate the effect of the stimulation and the safety of the
implant and stimulation, these are described in the patient information sheet.
the examinations will consist of blood sampling, ECG, physical examination and
questionnaires. The questionnaires are lists that are more often used for
patients in RA clinical trials (SF-36 and HAD-Q) that evaluates, among other
things, the mental and physical condition of the patients. If a patient feels
uncomfortable with a question, it may be skipped. Furthermore, there are
questionnaires specifically developed by Galvani, these are about the use and
the patient's experience with the system.
During the screening, the patient undergoes a CT scan with a dye and an
abdominal X-ray after implantation. There are risks associated with these
imaging, including a small increased risk of cancer and risks associated with
the contrast agent, The doctor will look at the medical data to see if the
contrast agent is a risk for the patient. If risks are identified, the doctor
may recommend specific treatments that can help reduce the risk of receiving
the contrast agent. The participant may also feel discomfort when taking blood
or taking an ECG. The risks associated with these procedures are no greater
during the study than during routine clinical care and all examination
procedures will be carried out by fully trained and experienced staff.
The operation and use of the investigational device may cause side
effects/adverse effects. Because no patients have yet been implanted, the risks
are difficult to predict until the research apparatus is implanted and used in
more people. Although the implant procedure of the Galvani system is new, the
procedures are based on existing operations
Risks of surgery
The risks that follow are seen as possible risks based on other operations on
which the implant procedure is based:
• Bleeding from the spleen artery or other blood vessels may occur during
surgery. In the rare case that the bleeding cannot be stopped, the spleen
artery must be removed, or more invasive surgery is needed. The occurrence of
spleen artery damage during longer, more complicated surgeries, such as
operations targeting the esophagus, is low and occurs in less than 1% of
surgeries. If the spleen artery is removed, the spleen is still supplied with
sufficient blood through other veins.
• It is also possible that the splenic nerve is damaged during the operation,
or during the placement or removal of the wire. Long-term effects of splenic
nerve damage are not known, but surgeries that take place in this area do not
report problems thought to be due to damage to these nerves.
• Nerve damage can cause the stimulation not to work as expected.
• There is a very small chance that the artery wall will be damaged during
surgery, which can lead to a blood clot on the inside or around the blood
vessel (pseudoaneurysm) and result in occlusion (blockage) or stenosis
(narrowing). In all of these cases, the blood clot may move to the spleen or
slow or stop blood flow to the spleen. If blood flow through the artery is
reduced or stopped completely, it can change the way the spleen functions, but
there are other arteries that supply the spleen with blood, so it's likely that
the spleen won't need to be removed and can continue to perform its function.
* There is a small chance that other organs in the abdomen will be damaged or
bleeded by the operation. In these cases, additional medication or surgery may
be needed to repair the damage.
• It is recommended not to remove the implant, should it be decided to do so,
the explant risks are similar to the implant risks.
Risks during the use of the research apparatus
• It is possible that the patient can feel the stimulation. The settings of the
investigational device can be adjusted so that the patient is less bothered by
it.
• It is possible that the stimulation can have unexpected effects on your body,
such as change in blood pressure or heart rhythm.
• It is possible that a nearby organ (such as the pancreas) is affected by the
stimulation that causes changes in its function. Frequent blood tests will
check this.
• There is a small chance (<2%) that after the operation the area around the
wire will become infected, this can usually be treated with medication. If
these problems become severe, another operation may be needed to remove the
wire if necessary.
• The risk of infection if your IPG needs to be placed on the outside of the
muscle (in front of your abdomen) instead of in your abdominal wall is <5% This
is due to the extra cut. It is also possible that you feel the IPG under the
skin if it needs to be placed on the outside. Because the IPG is located
outside the muscle, there is a risk of erosion (breakdown of the skin).
Erosion is expected to occur rarely and the surgical procedure is designed to
reduce this risk, but if erosion occurs, it is possible that the IPG will need
to be removed.
• The wire of the investigational apparatus and the stimulation can cause
damage to tissues and organs, including the spleen nerve and the spleen artery,
and it can take time for the damage to be noticed. If the spleen artery is
damaged, the effect of the stimulation may be mixed. If the artery itself is
damaged, it can lead to gradual weakening of the artery but rarely will it lead
to bleeding.
• Damage to the artery by the wire can cause blood clots that can move towards
the spleen. If blood flow through the artery is reduced or stopped completely,
it can change the way the spleen functions, but there are other arteries that
supply the spleen with blood, so it is very likely that the spleen does not
need to be removed and can continue to perform its function.
• It is also possible for the wire or stimulator to move or break, which may
cause the investigational device to stimulate the nerve or cause the
investigational device to stimulate other areas of your body, which can lead to
pain, discomfort, change in blood pressure or changes in heart rate. This may
also prevent the investigational device from stimulating the nerve and the
stimulation not working as expected.
Movement of the IPG or wire can also cause bleeding or damage to nearby
tissues. If this happens, surgical intervention is needed to repair the
implanted examination device.
• If a woman does becomes pregnant, the stimulation is set to OFF because the
effect of stimulation on pregnancy is not known. It is also not known what the
effect of the implant during pregnancy is on other organs.
All risks related to the surgical procedure and the implant have been evaluated
according to Galvani's "risk-management process". Extensive risk analyses were
carried out and mitigations were introduced. A detailed description of
clinically relevant risks and their mitigations can be found in Table 2 of the
protocol. In addition, a complete Verification and Validation (V&V) system was
carried out in line with Galvani's ISO13485 certified quality management
system, the results of that analysis are summarized in the Investigator
brochure and IMDD. In the system V&V activities, a set of 1332 requirements
were successfully evaluated. It was concluded that the Galvani System has an
acceptable benefit/risk profile for the intended use and selected patient
population in the closely monitored clinical trial. With implementation of the
additional mitig
Gunnels Wood Road 2S126
Stevenage SG1 2NY
GB
Gunnels Wood Road 2S126
Stevenage SG1 2NY
GB
Listed location countries
Age
Inclusion criteria
1. Adult-onset RA of at least six months duration as defined by the 2010
ACR/EULAR classification criteria.
2. Male or female participants, 22-75 years of age inclusive at time of signing
the informed consent.
3. Participants must have active disease as defined by at least 4 active
swollen and at least 4 active tender joints (based on 28 joint count) and CRP >=
5.0 mg/L or DAS28-CRP>5.1. .
4. The participant must have had an Inadequate Response to at least 2 biologic
DMARDs and/or JAK-inhibitors (JAKis) including at least one TNF inhibitor.
6. Participants must be receiving treatment with standard dose(s) of
conventional synthetic DMARD(s) or the participant must have a documented
history with a csDMARD and failed treatment due to ineffectiveness or
intolerance.
7. Demonstrate, or simulate, ability to use the Galvani System components by
8. For Female Participants Only: A female participant is eligible to
participate if she is not pregnant or breastfeeding or planning on becoming
pregnant in the future, and one of the following conditions applies: Is a woman
of non-childbearing potential OR Is a woman of childbearing potential (WOCBP)
and using an acceptable contraceptive method.
Exclusion criteria
1. Prior use of baricitinib or for whom baricitinib use is not recommended
2. Inability to provide informed consent.
3. Significant psychiatric disease or substance abuse.
4. History of unilateral or bilateral vagotomy.
5. Active or latent tuberculosis.
6. Known infection with human immunodeficiency virus (HIV); current acute or
chronic hepatitis B or hepatitis C; previous hepatitis B.
7. Positive SARS COV 2 PCR screening test for COVID-19 infection (at the point
of screening for this study).
8. Currently implanted electrically active medical devices (e.g., cardiac
pacemakers, automatic implantable cardioverter-defibrillators).
9. Any prior investigational treatment (including small molecule drugs and/or
biologic therapies) must be discontinued for at least 4 weeks or 5 half-lives,
whichever is longer, prior to Day 1.
10. Patients with comorbid fibromyalgia.
11. Previous splenectomy.
12. Drug or alcohol abuse or dependence including opioid dependence or chronic
opioid use.
13. Laboratory exclusion criteria: cytopenia as characterized by - anemia
(hemoglobin < 8 g/dL), lymphopenia (ALC < 500 cells/mm3) and/or neutropenia
(ANC < 1000 cells/mm3).
14. Any finding - which in the opinion of the investigator would interfere with
the study interventions (including device implantation), study procedures
and/or assessments, or create an undue risk for the participant.
15. Exclusion criteria related to the surgery and implant procedure (Surgeon
Responsibility):
a. Patients with an epigastric abdominal wall thickness, epidermis to posterior
rectus sheath at the level of the linea alba, greater than 2 cm based on
screening ultrasound assessment and confirmed by CT-angiogram.
b. Patients with splenic artery luminal diameter greater than 7.4 mm or less
than 3.0 mm dimension on CT-angiogram.
c. Type IV hiatal hernia and any hiatal hernia that produces a significant
distortion of the local anatomy, especially the pancreas and/or splenic artery.
d. Gastric resection/mobilisation surgery with surgical access of the lesser
sac.
e. Celiac axis, aneurysms or anatomy associated with congenital anomalies of
the origin of the splenic artery.
f. Splenic artery anatomical variants - splenic artery which is entirely within
the substance of the pancreas or the presence of the splenic artery aneurysms
or pseudoaneurysms.
g. Participants who do not have a demonstrable clear plane between the pancreas
and the splenic artery, at the interface site, in the preoperative CT angiogram.
h. Findings of cirrhosis or portal hypertension.
i. Documented history of pancreatitis with significant peripancreatic
inflammation (CT evidence of necrosis, pseudocyst formation or significant
retroperitoneal calcification).
j. Pancreatic abnormalities/mass/cyst/pseudocyst/lesions.
k. Any condition per the investigator's clinical judgment that qualifies the
participant not fit for surgery.
l. BMI >= 33.
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
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 |
|---|---|
| ClinicalTrials.gov | NCT05003310 |
| CCMO | NL78487.000.21 |