To assess the efficacy of Revita® DMR for improving HbA1c to
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Study Endpoint:
Percentage of subjects who achieve a HbA1c <= 7.0% at Week 24 without the need
for insulin at Week 24, DMR vs Sham.
Secondary outcome
Key Secondary Efficacy Endpoints:
* Percentage of subjects who achieve HbA1c <= 7.0% at Week 24 who have 50% or
more reduction in insulin (including insulin withdrawal) at
Week 24 relative to baseline, DMR vs Sham
* Percentage of subjects who achieve HbA1C <= 7.0% at Week 24 who are also on
the same or less insulin (including insulin withdrawal) at
Week 24 relative to baseline, DMR vs Sham
Background summary
Type 2 Diabetes
An estimated 425 million people around the world suffer from Type 2 Diabetes,1
and disease incidence is increasing at an alarming rate in both developing and
developed nations. In the United States alone, there are over 30 million people
with T2D and nearly 2 million people are newly diagnosed every year2.
As a result of the significant delay in diagnosing and initiating effective
treatment for T2D, the number of diabetics requiring insulin has increased. The
total number of people with diabetes requiring insulin worldwide is estimated
to be 150-200 million2.
T2D is a complicated condition predisposed by genetics, coupled with lifestyle
factors, such as obesity, sedentary lifestyle, and diets high in fat and sugar.
Impaired glucose tolerance and insulin resistance characterize the early years
of the diabetic state, likely occurring before more overt insulin secretory
insufficiency and the onset of frank hyperglycemia.
Insulin secretion from the pancreatic beta cells initially increases to
compensate for endogenous resistance to insulin action. This maintains
normoglycemia through the early course of the disease. Physiology studies
during this time reveal insulin resistance in peripheral tissues, namely the
liver, skeletal muscle, and adipose tissue. However, as the disease progresses,
beta cells eventually can no longer compensate for the body*s resistance to
insulin and endogenous insulin secretion proves inadequate to maintain
effective glucose homeostasis.
Inadequately controlled T2D patients, over a long period of time are prone to
develop the microvascular and macrovascular complications of the condition. In
numerous large clinical and epidemiological studies, optimization of glycemia
over sustained periods has been shown to reduce or prevent the onset of
diabetes-related complications.
The current standard of care for Type 2 diabetes first involves efforts at
preventing the disease to get worse through dietary and lifestyle improvements.
Unfortunately, the vast majority of T2D do not achieve optimized glycemic
control with lifestyle changes alone. Several classes of pharmacologic therapy
are available, including drugs that increase insulin secretion from the
pancreas, drugs that enhance the sensitivity of the body to insulin, and others
that increase glycosuria. Even with modern pharmacotherapy, the majority of T2D
patients eventually require insulin therapy administered as single or multiple
daily injections. Therefore, despite aggressive efforts at prevention and
management with multiple classes of pharmacotherapy, population-level control
of T2D has proven to be an elusive target.
The management of T2D, although associated with extensive treatment modalities,
is impeded by (i) non-compliance limiting treatment success at all parts of the
disease continuum, (ii) the currently available treatments only treat the
metabolic consequence of the disease (hyperglycemia) and
not the underlying disease itself, (iii) the available treatments are unable to
safely correct hyperglycemia in a large segment of the population, and (iv)
aversion to insulin use means the individual suffer needlessly with
hyperglycemia pre-insulin use and (v) patient noncompliance exacerbated by the
multiple drugs they are on for diabetes and its comorbidities.
There is a strong need for therapy aiming at treating underlying disease and
thereby reducing the need for ADAs.
Non-Alcoholic Fatty Liver Disease (NAFLD)
Non-alcoholic fatty liver disease (NAFLD) occurs in approximately 51.8% of
people with type 2 diabetes in the USA, and in approximately 68% in people with
type 2 diabetes in Europe. This disease can progress from simple steatosis to
non-alcoholic steatohepatitis (NASH), hepatic cirrhosis and hepatocarcinoma.The
estimated global prevalence of NAFLD is 55.5% and the global prevalence of NASH
is 37.3% among patients with type 2 diabetes. NASH constitutes a serious public
health concern manifest by premature cardiovascular disease, end-stage diabetes
complications, and soon-to-be the most common cause of end-stage liver disease.
Insulin resistance is the hallmark of NASH. Some recent studies both in animals
and humans have demonstrated abnormal hyperplasia of the duodenal mucosa,
changes in enteroendocrine cell density and number, endocrine hyperplasia, and
alterations in gut hormone signaling; these observations highlight the role of
the upper intestine in glucose homeostasis and insulin sensitivity.Given these
physiological and pathophysiological features, disruption of duodenal mucosa in
both animals and humans showed an improvement in both glucose homeostasis ,
liver transaminase levels, and liver fat content, all suggesting a possible
improvement in NASH. Until now, lifestyle medication has been the only
recognized efficient treatment for fatty liver disease. Unfortunately, only a
minority of individuals with fatty liver achieve significant weight loss
through lifestyle modifications. Based on these earlier studies, duodenal
mucosal resurfacing may provide treatment for NASH in T2D.
Investigational device
The Revita® ® System is designed to mimic the metabolic benefit of the duodenal
exclusion component
of bariatric surgery and to thereby elicit an insulin-sensitizing effect. The
Revita® ® System is an
endoscopic treatment consisting of a single-use disposable catheter and a
control console designed to lift the duodenal mucosa with saline and then
perform controlled circumferential hydrothermal ablation of the mucosa. The
Revita® ® System consists of two main components: the Revita® ® Catheter and a
Console.
The exclusion of the duodenum from the passage of nutrients by surgical
diversion appears to result in weight-independent improvements in glycemia
associated with a reduction in insulin resistance.This effect is also notable
in being almost immediate in its onset (within days) and durable over time
(years). The gastrointestinal tract is now recognized to be the largest
endocrine organ in the body. It releases gastrointestinal hormones in a finely
tuned pattern to help the body achieve glucose homeostasis in the fasting and
post-prandial states, with the gastro-intestinal mucosa playing the role as a
critical sensing and secreting interface. Bypass of the proximal small bowel
appears to modify the secretion of certain
key gastrointestinal hormones that in turn lead to improvements in glucose
homeostasis. This occurs without calorie malabsorption. Rather, these changes
restore the ability of the liver to suppress endogenous glucose production in
response to insulin, a physiologic process that is otherwise impaired in
diabetes.
Study objective
To assess the efficacy of Revita® DMR for improving HbA1c to <= 7% without the
need of insulin in subjects with T2D compared to sham.
To assess the efficacy of DMR versus Sham on improvement in Glycemic, Hepatic
and Cardiovascular endpoints.
Study design
Double-blind, Randomized, Sham control; Multicenter study
Intervention
The Revita® System is an endoscopic treatment consisting of a single catheter
and console designed to lift the duodenal mucosa with saline followed by
controlled circumferential hydrothermal ablation of the mucosa.
The sham procedure will consist of placing the Revita® Catheter as described
above into the duodenum for a minimum of 30 minutes with no manipulation of the
device or activation of the catheter.
Study burden and risks
The burden and risk mainly consist out of extra time spent in comparison to
standard treatment, the DMR or sham procedure and the risks of
medical evaluation, including venapunctures and biopsy.
There are certain residual risks associated with the use of the Revita® System
and the DMR procedure.
Many of these risks are similar to those seen with other endoscopic devices
that are passed either over the wire or through an endoscope for treatment in
the esophagus, stomach or duodenum
Minimizing Study Risks
The following steps have been taken to minimize risks associated with the
procedure and the use of the
Revita® System:
* The tissue or fluid contacting materials used in the construction of the
Revita® Catheter are known medical-grade materials that are well-characterized
and have a long history of use. In addition, biocompatibility testing has
proven that the materials are safe.
* The device design uses known technologies including sub-mucosal injection and
hot fluid balloon to complete the procedure. Similar technologies are currently
in use for such accepted procedures as endoscopic mucosal resection and
treatment of menorrhagia.
* The device has been rigorously tested in the laboratory, pig models and
clinical trials to characterize its performance and confirm the safety and
performance of the procedure.
* All endoscopists and endoscopy teams receive detailed training in the use of
the Revita® System and the DMR procedure. The training includes hands-on use of
the system in a lab setting.
* The procedure has now been performed successfully on approximately 277
individuals in both sponsored and investigator-initiated studies with no major
safety concerns.
Hartwell Avenue 17
Lexington MA 02421
US
Hartwell Avenue 17
Lexington MA 02421
US
Listed location countries
Age
Inclusion criteria
1. Male; and non-pregnant, non-lactating females
2. Age between 21 and 70 years (both inclusive)
3. Subjects with type 2 diabetes on stable doses of (up to maximally approved
doses) of metformin and up to 2 ADAs (including either GLP1 or DPP-4i, and/or
thiazolidinediones [TZD]), requiring a minimum of 20 units up to a maximum of
60 units of basal insulin
4. Glycosylated Hemoglobin A1c (HbA1c) of 7.5-9.5% (both inclusive) confirmed
at the end of run-in period
5. Fasting Plasma Glucose (FPG) >=180 to <270 mg/dL (measured after overnight
8-hour fasting and 24-36 hours after the last dose of glargine at the end of at
least 3-week stable run-in period
6. Body Mass Index (BMI) >= 24 to <= 40 kg/m2
7. Women of Child-bearing potential (WOCBP) should have negative urine beta hCG
pregnancy test and must agree to use two established contraceptive methods
throughout the study duration
8. Able to sign an informed consent form and comply with study requirements.
Exclusion criteria
1. Known case of absolute insulin deficiency as indicated by clinical
assessment, and a fasting plasma C-peptide of <0.6 ng/ml
2. Any drugs or concomitant medications (such as psychoactive drugs such as
carbamazepine, phenobarbital, sympathomimetics (ephedrine etc.),
corticosteroids, anabolic steroids, and male sex hormones such as testosterone,
etc.) that can interfere with glucose metabolism
3. Subjects who either are on SGLT2i, meglitinides, sulphonylurea (SUs), short
or rapid acting insulin or any other class of ADA other than permitted baseline
ADAs at the time of consent or who have a known or documented SGLT2i and/or
metformin intolerance prior to the study
4. Recurrent or severe urinary tract or genital mycotic infections or history
of GU infection within 4 weeks prior to informed consent
5. ALT >3 times upper limit normal values unless if associated with underlying
NAFLD
6. Use of an investigational drug within 1 month or 5 half-lives (whichever is
longer) before the screening
7. Diagnosed with type 1 diabetes or with a recent history of ketoacidosis
8. Ketosis-prone T2D
9. History of non-healing diabetic ulcers or amputations
10. History of more than 1 severe hypoglycemia episode or unawareness within
past 6 months of screening
11. In case of two or more glucose alert values of <=70 mg/dL (3.9 mmol/L)
unless a clear correctable precipitating factor can be identified/clinically
significant hypoglycemia with self-
monitored or laboratory plasma glucose level < 54 mg/dL (3.0 mmol/L /
severe hypoglycemic episode requiring third party assistance occurring during
run-in period
12. Known intestinal autoimmune disease, as evidenced by either a positive
anti-glutamic acid decarboxylase (GAD) test, including Celiac disease, or
pre-existing symptoms of lupus
erythematosus, scleroderma, or other autoimmune connective tissue
disorder, which affects the small intestine
13. Secondary hypothyroidism or inadequately controlled primary hypothyroidism
(thyroid stimulating hormone (TSH) value outside the normal range at screening)
14. Known history of thyroid cancer or hyperthyroidism who have undergone
treatment within past 12 months or inadequately controlled hyperthyroidism
15. An uncontrolled endocrine condition such as multiple endocrine neoplasia
etc. (except T2D)
16. Known history of a structural or functional disorder of the esophagus,
including any swallowing disorder, esophageal chest pain disorders, or
drug-refractory esophageal reflux
symptoms, active and uncontrolled Gastroesophageal Reflux Disease
(GERD) (grade 3 esophagitis or greater)
17. Known history of a structural or functional disorder of the stomach,
including gastric ulcer, chronic gastritis, gastric varices, hiatal hernia (a
large hiatal hernia or type II and higher
paraoesophageal hernia) cancer or any other disorder of the stomach
18. Previous GI surgery that could affect the ability to treat the duodenum
such as subjects who have had a Billroth 2, Roux-en-Y gastric bypass, gastric
sleeve or other similar procedures
or conditions
19. Known history of chronic pancreatitis or a recent history of acute
pancreatitis within the past year
20. Presence of acute or chronic active hepatitis B or C (except if hepatitis C
is cured) or cirrhosis; or hepatic decompensation/acute liver disease during
the last 6 months; or alcoholic or
autoimmune chronic hepatitis
21. Symptomatic gallstones or symptomatic kidney stones, acute cholecystitis
22. Clinically active systemic infection
23. Known immunocompromised status, including but not limited to individuals
who have undergone organ transplantation, chemotherapy, or radiotherapy within
the past 12 months, who
have clinically significant leukopenia, who are positive for the human
immunodeficiency virus (HIV), who are on potential immunosuppressants or whose
immune status makes the
subject a poor candidate for clinical trial participation in the
opinion of the Investigator
24. History of active malignancy or partial remission from clinically
significant malignancy within the past 5 years (except basal or squamous cell
skin cancer or carcinoma in situ or those
received curative treatment and in complete remission for 5 years or if
subject confirmed as cancer free)
25. Known active coagulopathy, or current upper gastro-intestinal bleeding
conditions such as ulcers, gastric varices, strictures, or congenital or
acquired intestinal telangiectasia
26. Subjects with active helicobacter pylori infection (Subjects may be
enrolled if they had history of h pylori infection and were successfully
treated)
27. Known cases of anemia, thalassemia or conditions that affect red blood cell
(RBC) turnover such as recent blood transfusion within 90 days
28. Use of anticoagulation therapy (such as warfarin, coumadin, novel oral
anticoagulants [NOAC]) or anti-platelet agents (such as thienopyridine) which
cannot be discontinued for 5-7
days or 2 drug half-lives before the procedure
29. Use of systemic glucocorticoids (excluding topical or ophthalmic
application or inhaled forms) for more than 10 consecutive days within 90 days
prior to the Screening Visit
30. Use of drugs known to affect GI motility (e.g., metoclopramide)
31. History of moderate to severe chronic kidney disease (CKD), with estimated
glomerular filtration rate (eGFR) <45 mL/min/1.73m2 (estimated by Modification
of Diet in Renal Disease
[MDRD]) or end stage renal failure or on dialysis
32. History of myocardial infarction, stroke, or major event requiring
hospitalization within the last 3 months prior to screening
33. History of new or worsening signs or symptoms of coronary heart disease
(CHD) within the last 3 months
34. Known case of severe peripheral vascular disease
35. Known case of symptomatic heart failure with reduced ejection fraction
(NYHA Class II-IV) requiring pharmacologic therapy to control symptoms
36. Clinically significant electrocardiogram (ECG) findings such as new
clinically significant arrythmia or conduction disturbances that increases risk
and requires intervention as
determined by the investigator
37. Subjects who are at risk for pancreatitis particularly those with a recent
fasting triglycerides value of > 600 mg/dL value done within past 3 months
38. Actively participating in a weight loss program and is currently not in the
maintenance phase
39. General contraindications to deep or conscious sedation or general
anesthesia or high risk as determined by anesthesiologist (e.g., ASA score 4 or
higher) or contraindications to
upper GI Endoscopy
40. History of any illicit alcohol or substance abuse
41. Use of weight loss medication such as Meridia, Xenical, or over the
counterweight loss medications or other prescribed medications used
specifically for purpose of weight loss
42. Use of Dietary supplements or herbal preparations that may have unknown
effects on glycemic control, risk of bleeding
43. Participating in another ongoing clinical trial of an investigational drug
or device
44. History of non-adherence to treatment in the previous 6 months, as
determined by the investigator based on patient history, HbA1c value and/or
drug accountability
45. Any other mental or physical condition which, in the opinion of the
investigator, makes the subject a poor candidate for clinical trial
participation
46. Unwilling or unable to perform SMBG, complete the subject glycemia diary,
or comply with study visits and other study procedures as required per protocol
47. Recovered from severe COVID-19 infection (requiring hospitalization)
however still have persistent long COVID-19 symptoms (i.e., they have not
recovered for several weeks or
months since the start of symptoms that were suggestive of COVID-19,
irrespective if they are tested or not).
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 | NCT04419779 |
| CCMO | NL75986.018.20 |