The objective of this first-in-human study is to evaluate the safety, feasibility and efficacy of Re-Cellularization via Electroporation Therapy (ReCET) by the (Endogenex system) combined with (GLP-1 receptor agonist) in subjects with insulin…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Safety: Incidence rate of adverse events.
• Feasibility: Procedure time and technical success rate
• Primary efficacy: Protocol driven free of insulin at 6 months and HbA1c <= 7.5
% in the active group, compared to the control group
Secondary outcome
• Secondary efficacy:
- Time in range (flash glucose monitoring),
- liver fat fraction (MRI-PDFF) and fibrosis
- sympathovagal activity (Nexfin device).
- bloodL HbA1c, HOMA-IR, Fasting Plasma Glucose
- Weight, BMI, waist circumference
- lipid panel, liverenzymes etc.
- micro albumin
- glucoregulatory hormones (Mixed Meal Test)
- Microbiota diversity oral and fecal
- Intake registration
In the active group, compared to the control group at 6 months
Background summary
T2D is managed by lifestyle interventions and a variety of pharmacological
agents. Nevertheless, only 50% of T2D patients
achieve their treatment targets. For many patients, exogenous insulin
administration remains the final treatment option to
manage their hyperglycemia. However this approach does not treat the root
phenomenon of the disease, i.e., insulin
resistance, and the resulting hyperinsulinemia contributes to weight gain and
further deterioration of the patients metabolic health.
T2D can, however, be effectively treated by bariatric surgery. Patients
undergoing Roux-en-Y gastric bypass surgery demonstrate
major improvements in glycaemic control and metabolic and cardiovascular
health, which occur virtually immediately after surgery
and well before any significant weight loss is established. Reintroduction of
nutrients into the bypassed duodenal limb quickly
returns patients to their previous dysmetabolic state, highlighting the
importance of the duodenum in the insulin-sensitizing effect of
bariatric surgery and in the pathogenesis of the metabolic syndrome.
The important role of the duodenal mucosa is highlighted by specific endoscopic
procedures to treat T2D and concomitant
metabolic diseases. In a recent published European multicenter study that
examined patients with sub-optimally controlled T2D
(using oral glucose-lowering medication), a single duodenal mucosal resurfacing
(DMR) procedure entailing hydrothermal ablation
of the duodenal mucosa, elicited a substantial improvement glycaemia, insulin
resistance, and liver transaminases at 12 and 24
months post-procedure. A subsequent one-armed pilot study found that 69%
(11/16) of formerly insulin-dependent T2D patients,
had adequate glycemic control 6 months after their insulin was replaced by a
single DMR, GLP-1 RA and lifestyle counselling.
Moreover, the patients that were adequately controlled, experienced improved
glycemic and metabolic health, as reflected by
significant decreases in HbA1c, HOMA-IR and weight and liver fat %. These
studies strongly suggest that regeneration of
duodenal mucosa improves insulin sensitivity and glycaemic regulation similar
to bariatric surgery but trough a less invasive
procedure. However, the handling of the Revita system is very challenging and
the procedure is time consuming, which
makes upscaling of this procedure difficult. Moreover, the use of a balloon in
the DMR technique causes *patched* ablation areas,
which possibly impedes the efficacy of DMR. Overlapping ablations, or ablations
of non-lifted duodenal mucosa, have shown to be
risk factors for a post-procedural duodenal stenosis.
Re-Cellularization via Electroporation Therapy (ReCET) is a minimally invasive
endoscopic procedure that uses the
Endogenex device (Endogenex Inc., Plymouth, MN, USA) to deliver Pulsed Electric
Fields (PEF) to the duodenum. The treatment is non-thermal and does not require
mucosal lifting for protecting submucosal tissue. This The system uses a
through-the-scope design that greatly improves
technical feasibility and will reduce procedure time. PEF induces mucosal
renewal via cell apoptosis and subsequent rapid
regeneration. Data from animal and clinical studies using thermally induced DMR
suggest that this is followed by an insulinsensitizing
effect that resembles the metabolic improvements after bariatric surgery.
PEF-induced DMR may allow for a more
complete ablation with regards to the mucosal area treated and a more
controlled ablation with regards to the depth of ablation
minimizing the risk of damaging the deeper layers of the duodenal wall (i.e.
deep submucosa and muscularis propria).
In addition, ReCET uses another type of energy, e.g. electroporation, that
might restore sympathovagal balance. Many studies
have shown a functional gut-brain axis in which gut-derived peptides,
microbiota, metabolites, and neuronal feedback inform the
brain about energy status and then elicit an appropriate feeding and metabolic
response. It is thought that the gut brain-axis
modulates central control of food intake and metabolism specifically via the
production of short-chain fatty acid butyrate. Oral
butyrate supplementation affected sympathestic tone and intestinal transit
times as well as physical activity and reduced liver fat in
mice before. Therefore, ReCET could result in even bigger changes in the
neuronal feedback from the gut to the brain that
elicits improvement in metabolic health.
Study objective
The objective of this first-in-human study is to evaluate the safety,
feasibility and efficacy of Re-Cellularization via Electroporation Therapy
(ReCET) by the (Endogenex system) combined with (GLP-1 receptor agonist) in
subjects with insulin dependent
type 2 diabetes mellitus and an adequate beta cell reserve. The aimed effect is
an adequate or improved glucose
regulation without the need for insulin therapy. Secondary effects include
improved cardiovascular, hepatological en metabolic
parameters.
Study design
Randomized double blind shamcontrolled monocenter study
Intervention
ReCET or shamprocedure in combination with GLP1-RA (semaglutide)
Study burden and risks
To participate in this clinical study, subjects have to consent with 11 visits,
including blood samples drawn at every visit, physical examination (once during
screening and on indication during following visits) and potential burden
associated with undergoing MRI for liver fat fraction + fibrosis measurement
(like claustrophobia), flash blood glucose monitoring and questionnaires.
Subjects also have to consent with undergoing 2 endoscopies (including 1
follow-up endoscopy) with duodenal mucosal biopsies (cold snares). There are
risks related to any endoscopic procedure. Specific risks associated with this
procedure include: abdominal pain, bleeding, delayedgastric emptying, dental
injury, diarrhea, difficulty swallowing, fever, gastric dumping syndrome,
headache, hypoxia, infection, injuryto esophagus, nausea, non-healing ulcer,
nutritional mal-absorption, pancreatitis, perforation, pneumoperitoneum,
pulmonaryaspiration, sore throat, stomach or duodenal mucosa stricture and
obstruction, tightness and cramping and worsening diabeticsymptoms including
hypoglycemia. Many of these risks and complications associated with the
procedure are similar to thoseassociated with other commonly performed
endoscopic procedures such as duodenal biopsies and endoscopic mucosal
resection.
In addition to the risks listed above, the Endogenex system has unique risks
associated with its catheters and control consoles used to complete the
procedure. This includes risks associated with the materials selected, its
design and construction.
These risks include See section 4.4 (protocol) for more information:
The following steps have been taken to minimize risks associated with the
procedure.
The medical consequences and morbidity associated with T2D has been well
studied and documented and includes renal failure,blindness, peripheral
neuropathy, amputation, increased risk of myocardial infarctions, stroke and
peripheral vascular disease. In addition, treatment with insulin is associated
with weight gain and the risk of hypoglycemia. A successful intervention may
enable subjects to more effectively control their glycaemic levels or even
reduce or discontinue use of medications needed to treat their disease,
including insulin. This procedure potentially allows subjects to reduce
morbidity of the disease and through improvedglycaemic and metabolic health.
As noted above, there are substantial potential benefits associated with the
procedure and the risk associated with the device and procedure have been
identified and minimized where possible. Thus, the balance of potential risks
and benefits associated with the Endogenex procedure warrants clinical research
and justifies its investigation.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
1. Diagnosed with type 2 diabetes mellitus
2. 28 -75 years of age
3. On daily long acting insulin dose <= 1 U/kg
4. BMI >= 24 and <= 40 kg/m2
5. HbA1c <= 8.0% (64 mmol/mol)
6. Fasting C-peptide >= 0.2 nmol/L (0.6 ng/ml)
7. Willing to comply with study requirements and able to understand and comply
with signed informed consent
Exclusion criteria
1. Diagnosed with Type 1 Diabetes or with a history of ketoacidosis 2. Current
use of multiple daily doses insulin or insulin pump. 3. Current use of a GLP-1
analogue. 4. Known autoimmune disease, as evidenced by a positive Anti-GAD
test, including Celiac disease, or pre-existing symptoms of systemic lupus
erythematosus, scleroderma or other autoimmune connective tissue disorder 5.
Previous GI surgery that could affect the ability to treat the duodenum such as
subjects who have had a Bilroth 2, Roux-en-Y gastric bypass, or other similar
procedures or conditions 6. History of chronic or acute pancreatitis 7. Known
active hepatitis or active liver disease 8. Symptomatic gallstones or kidney
stones, acute cholecystitis or history of duodenal inflammatory diseases
including Crohn*s Disease and Celiac Disease 9. History of coagulopathy, upper
gastro-intestinal bleeding conditions such as ulcers, gastric varices,
strictures, congenital or acquired intestinal telangiectasia 10. Use of
anticoagulation therapy (such as phenprocoumon and acenocoumarol) which cannot
be discontinued for 3-5 days before and 48 hours after the procedure and novel
oral anticoagulants (such as rivaroxaban, apixaban, edoxaban and dabigatran)
which cannot be discontinued for 48 hours before and 48 hours after the
procedure in accordance with the local protocol 11. Use of P2Y12 inhibitors
(clopidogrel, pasugrel, ticagrelor) which cannot be discontinued for 5 days
before and 48 hours after the procedure in accordance with the local protocol.
Use of aspirin is allowed. 12. Unable to discontinue NSAIDs (non-steroidal
anti-inflammatory drugs) during treatment through 4 weeks post procedure phase
13. Taking corticosteroids or drugs known to affect GI motility (e.g.
Metoclopramide) 14. Receiving weight loss medications such as Meridia, Xenical,
or over the counter weight loss medications 15. Anemia, defined as Hgb < 6.2
mmol/l 16. Known history of severe permanent cardiac arrhythmia*s with clinical
symptoms 17. Significant cardiovascular disease, including known history of
valvular disease or myocardial infarction, heart failure, transient ischemic
attack, or stroke within 6 months prior to the screening visit 18. With any
implanted electronic devices or duodenal metallic implants 19. eGFR or MDRD <
30 ml/min/1.73m^2 20. Active systemic infection 21. Active malignancy within
the last 5 years 22. Not potential candidates for surgery or general anesthesia
23. Active illicit substance abuse or alcoholism 24. Pregnancy or wish getting
pregnant in next year 25. Participating in another ongoing clinical trial of an
investigational drug or device that can interfere with the current study 26.
Any other mental or physical condition which, in the opinion of the
investigator, makes the subject a poor candidate for clinical trial
participation
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 |
|---|---|
| CCMO | NL83266.000.22 |