Effect of Duodenal Mucosal Resurfacing (DMR) Using the Revita System in the Treatment of Type 2 Diabetes (T2D)

• Sponsor: Fractyl Laboratories, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02879383
• Collaborator: (none)
• Enrollment: 109
• Locations: 11
• Arms: 2
• Actual Duration (Months): 33.6
• Patients Per Site: 9.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to demonstrate the efficacy and safety of the Fractyl duodenal mucosal resurfacing (DMR) Procedure using the Revita System compared to a sham procedure for the treatment of uncontrolled type 2 diabetes.

Subjects randomized to the DMR procedure are followed per protocol for 48 Weeks. The Sham treatment arm will cross over to receive the DMR treatment at 24 weeks with background medications held constant from 24-48 weeks of follow up.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2; Noninsulin-Dependent Diabetes Mellitus	Procedure: DMR Procedure; Procedure: Sham Procedure	N/A

Detailed Description

The study is a multi-center, randomized, prospective, double-blinded (subject and endocrinologist) trial of type 2 diabetes patients sub-optimally controlled on 1 or more oral anti-diabetic medications comparing the Fractyl DMR procedure to sham procedure. Randomization will be 1:1 DMR treatment to sham. All subjects will participate in a 4 week oral anti-diabetic medication run-in period before the index procedure to confirm lack of blood glucose control in conjunction with medication compliance and nutritional counseling. The Sham treatment arm will cross-over to receive the DMR treatment at 24 weeks with background medications held constant 24weeks of follow up after the cross-over DMR procedure. The DMR treatment arm will be managed according to current diabetes standard of care.

Subjects randomized to the DMR procedure are followed per protocol for 48 Weeks. The Sham treatment arm will cross over to receive the DMR treatment at 24 weeks with background medications held constant from 24-48 weeks of follow up.

Study Design

• Study Type: Interventional
• Actual Enrollment: 109 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Evaluation of the Effect of Duodenal Mucosal Resurfacing (DMR) Using the Revita System in the Treatment of Type 2 Diabetes (T2D)
• Actual Study Start Date: Mar 1, 2017
• Actual Primary Completion Date: Dec 20, 2019
• Actual Study Completion Date: Dec 20, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DMR Procedure Subjects randomized to the DMR procedure are unblinded at 24 weeks and followed for an additional 24 weeks.	Procedure: DMR Procedure; The DMR procedure consists of hydrothermal ablation of the duodenum using the Revita System; Other Names: DMR Revita
Sham Comparator: Sham Procedure Subjects are unblinded at 24 Weeks. Sham subjects to cross over to receive DMR treatment at 24 Weeks and followed up for additional 24 weeks.	Procedure: Sham Procedure; The sham procedure consists of placing the Revita Catheter into the stomach for 30 minutes and then removing it from the patient.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline at 24 Weeks in Hemoglobin A1c (HbA1c), DMR vs Sham. [Baseline and 24 Weeks post-procedure]

   The primary efficacy endpoint is the change from baseline at 24 weeks in HbA1c, DMR vs Sham

2. Change From Baseline at 12 Weeks in MR-PDFF, DMR vs Sham [Baseline and 12 Weeks post-procedure]

   The absolute change from baseline at 12 weeks in MR-PDFF in patients with baseline MR-PDFF > 5% , DMR vs Sham

Eligibility Criteria

Criteria

• Ages Eligible for Study: 28 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. 28-75 years of age

2. Diagnosed with Type 2 Diabetes and evidence of preserved insulin secretion. Fasting insulin > 7 μU/ mL.

3. Glycated Hemoglobin (HbA1c) of 7.5 - 10.0% (59-86 mmol/mol)

4. Body Mass Index (BMI) ≥ 24 and ≤ 40 kg/m2

5. Currently taking one or more oral glucose lowering medications of which one must be Metformin, with no changes in dose or medication in the previous 12 Weeks prior to study entry

6. Able to comply with study requirements and understand and sign the informed consent

Exclusion Criteria:

1. Diagnosed with Type 1 Diabetes or with a history of ketoacidosis

2. Current use of Insulin

3. Current use of Glucagon-like peptide-1 (GLP-1) analogues

4. Hypoglycemia unawareness or a history of severe hypoglycemia (more than 1 severe hypoglycemic event, as defined by need for third-party-assistance, in the last year)

5. Known autoimmune disease, as evidenced by a positive Anti- Glutamic Acid Decarboxylase (GAD) test, including Celiac disease, or pre-existing symptoms of systemic lupus erythematosus, scleroderma or other autoimmune connective tissue disorder

6. Active H. pylori infection (Participants with active H. pylori may continue with the screening process if they are treated via medication and re-testing verifies the condition has resolved.)

7. 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

8. History of chronic or acute pancreatitis

9. Known active hepatitis or active liver disease

10. Symptomatic gallstones or kidney stones, acute cholecystitis or history of duodenal inflammatory diseases including Crohn's Disease and Celiac Disease

11. History of coagulopathy, upper gastro-intestinal bleeding conditions such as ulcers, gastric varices, strictures, congenital or acquired intestinal telangiectasia

12. Use of anticoagulation therapy (such as warfarin) which cannot be discontinued for 7 days before and 14 days after the procedure

13. Use of P2Y12 inhibitors (clopidogrel, pasugrel, ticagrelor) which cannot be discontinued for 14 days before and 14 days after the procedure. Use of aspirin is allowed.

14. Unable to discontinue NSAIDs (non-steroidal anti-inflammatory drugs) during treatment through 4 weeks post procedure phase

15. Taking corticosteroids or drugs known to affect GI motility (e.g. Metoclopramide)

16. Receiving weight loss medications such as Meridia, Xenical, or over the counter weight loss medications

17. Persistent Anemia, defined as Hgb<10 g/dl

18. Estimated Glomerular Filtration Rate (eGFR) or Modified of Diet in Renal Diseae (MDRD) <30 ml/min/1.73m^2

19. Active systemic infection

20. Active malignancy within the last 5 years

21. Not potential candidates for surgery or general anesthesia

22. Active illicit substance abuse or alcoholism

23. Participating in another ongoing clinical trial of an investigational drug or device

24. Any other mental or physical condition which, in the opinion of the Investigator, makes the subject a poor candidate for clinical trial participation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hopital Erasme	Brussels		Belgium	1070
2	UZ Leuven	Leuven		Belgium
3	Hospital das Clinicas da Faculdade de medicina da Universidade de São Paulo	Sao Paulo		Brazil
4	ABC Hospital	São Paulo		Brazil
5	Policlinico Gemelli (Sacro Cuore)	Rome	Lazio	Italy
6	Humanitas Research Hospital & Humanitas University Via Manzoni 56, Rozzano	Milano		Italy	20089
7	Amsterdam University Medical Center	Amsterdam		Netherlands	1105 AZ
8	Glasgow Royal Infirmary	Glasgow		United Kingdom	G4 0SF
9	University College London Hospitals	London		United Kingdom	NW1 2BU
10	King's College, Denmark Hill	London		United Kingdom
11	Queens Medical Centre campus, Nottingham University Hospitals NHS Trust, Derby Road	Nottingham		United Kingdom	NG7 2UH

Sponsors and Collaborators

• Fractyl Laboratories, Inc.

Investigators

• Principal Investigator: Geltrude Mingrone, MD, PhD, Gemelli University Hospital, Rome
• Principal Investigator: Jacques Bergman, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study Documents (Full-Text)

• Study Protocol - May 5, 2019
• Statistical Analysis Plan - May 3, 2019

More Information

Publications

None provided.

• Responsible Party: Fractyl Laboratories, Inc.
• ClinicalTrials.gov Identifier: NCT02879383
• Other Study ID Numbers: C-30000
• First Posted: Aug 25, 2016
• Last Update Posted: May 25, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Fractyl Laboratories, Inc.: Type 2 Diabetes, Revita System, DMR
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2

Study Results

Participant Flow

Pre-assignment Detail	All subjects participated in a 4-week oral antidiabetic drug (OAD) run-in period before the index procedure to confirm lack of blood glucose control in conjunction with medication compliance and nutritional counseling. All subjects were managed according to current diabetes standard of care.

Arm/Group Title	DMR Procedure (Europe)	Sham Procedure (Europe)	DMR Procedure (Brazil)	Sham Procedure (Brazil)
Arm/Group Description	Subjects randomized to the DMR procedure are unblinded at 24 weeks and followed for an additional 24 weeks. DMR Procedure: The DMR procedure consists of hydrothermal ablation of the duodenum using the Revita System	Subjects are unblinded at 24 Weeks. Sham subjects given option to cross over to receive DMR treatment at 24 Weeks and followed up for additional 24 weeks. Not all patients crossed over and received DMR treatment at 24 Weeks. Sham Procedure: The sham procedure consists of placing the Revita Catheter into the stomach for 30 minutes and then removing it from the patient.	Subjects randomized to the DMR procedure are unblinded at 24 weeks and followed for an additional 24 weeks. DMR Procedure: The DMR procedure consists of hydrothermal ablation of the duodenum using the Revita System	Subjects are unblinded at 24 Weeks. Sham subjects given option to cross over to receive DMR treatment at 24 Weeks and followed up for additional 24 weeks. Not all patients crossed over and received DMR treatment at 24 Weeks. Sham Procedure: The sham procedure consists of placing the Revita Catheter into the stomach for 30 minutes and then removing it from the patient.
Period Title: First 24 Weeks
STARTED	39	37	17	16
COMPLETED	39	36	17	16
NOT COMPLETED	0	1	0	0
Period Title: First 24 Weeks
STARTED	33	0	4	0
COMPLETED	33	0	4	0
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	DMR Procedure (Europe)	Sham Procedure (Europe)	DMR Procedure (Brazil)	Sham Procedure (Brazil)	Total
Arm/Group Description	Subjects randomized to the DMR procedure are unblinded at 24 weeks and followed for an additional 24 weeks. DMR Procedure: The DMR procedure consists of hydrothermal ablation of the duodenum using the Revita System	Subjects are unblinded at 24 Weeks. Sham subjects to cross over to receive DMR treatment at 24 Weeks and followed up for additional 24 weeks. Sham Procedure: The sham procedure consists of placing the Revita Catheter into the stomach for 30 minutes and then removing it from the patient.	Subjects randomized to the DMR procedure are unblinded at 24 weeks and followed for an additional 24 weeks. DMR Procedure: The DMR procedure consists of hydrothermal ablation of the duodenum using the Revita System	Subjects are unblinded at 24 Weeks. Sham subjects to cross over to receive DMR treatment at 24 Weeks and followed up for additional 24 weeks. Sham Procedure: The sham procedure consists of placing the Revita Catheter into the stomach for 30 minutes and then removing it from the patient.	Total of all reporting groups
Overall Participants	39	36	17	16	108
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	27 69.2%	30 83.3%	16 94.1%	13 81.3%	86 79.6%
>=65 years	12 30.8%	6 16.7%	1 5.9%	3 18.8%	22 20.4%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59	56.5	56	57.6	58
Sex: Female, Male (Count of Participants)
Female	9 23.1%	8 22.2%	8 47.1%	8 50%	33 30.6%
Male	30 76.9%	28 77.8%	9 52.9%	8 50%	75 69.4%
Race/Ethnicity, Customized (Count of Participants)
White	25 64.1%	21 58.3%	12 70.6%	13 81.3%	71 65.7%
Black	0 0%	0 0%	4 23.5%	3 18.8%	7 6.5%
Asian	0 0%	1 2.8%	1 5.9%	0 0%	2 1.9%
Other	1 2.6%	2 5.6%	0 0%	0 0%	3 2.8%
undisclosed	13 33.3%	12 33.3%	0 0%	0 0%	25 23.1%
Region of Enrollment (participants) [Number]
Netherlands	8 20.5%	9 25%	0 0%	0 0%	17 15.7%
Belgium	9 23.1%	7 19.4%	0 0%	0 0%	16 14.8%
Brazil	0 0%	0 0%	17 100%	16 100%	33 30.6%
United Kingdom	11 28.2%	12 33.3%	0 0%	0 0%	23 21.3%
Italy	11 28.2%	8 22.2%	0 0%	0 0%	19 17.6%
BMI (kg/m2) (kg/m2) [Median (Full Range) ]
Median (Full Range) [kg/m2]	31.4	30.4	32.3	31.6	31.4
Fasting Glucose (mg/dL) [Median (Full Range) ]
Median (Full Range) [mg/dL]	191	185	190	182	187
HbA1c (%) (% of glycosylated hemoglobin) [Median (Full Range) ]
Median (Full Range) [% of glycosylated hemoglobin]	8.1	8.2	8.6	8.15	8.26
MRI-PDFF (%) among subjects with baseline MRI-PDFF >5% (% of liver fat) [Median (Full Range) ]
Median (Full Range) [% of liver fat]	16.46	16.11	16.45	16.98	16.5

Outcome Measures

1. Primary Outcome

Title	Change From Baseline at 24 Weeks in Hemoglobin A1c (HbA1c), DMR vs Sham.
Description	The primary efficacy endpoint is the change from baseline at 24 weeks in HbA1c, DMR vs Sham
Time Frame	Baseline and 24 Weeks post-procedure

Outcome Measure Data

Analysis Population Description

mITT population

Arm/Group Title	DMR Procedure (Europe)	Sham Procedure (Europe)	DMR Procedure (Brazil)	Sham Procedure (Brazil)
Arm/Group Description	Subjects randomized to the DMR procedure are unblinded at 24 weeks and followed for an additional 24 weeks. DMR Procedure: The DMR procedure consists of hydrothermal ablation of the duodenum using the Revita System	Subjects are unblinded at 24 Weeks. Sham subjects to cross over to receive DMR treatment at 24 Weeks and followed up for additional 24 weeks. Sham Procedure: The sham procedure consists of placing the Revita Catheter into the stomach for 30 minutes and then removing it from the patient.	Subjects randomized to the DMR procedure are unblinded at 24 weeks and followed for an additional 24 weeks. DMR Procedure: The DMR procedure consists of hydrothermal ablation of the duodenum using the Revita System	Subjects are unblinded at 24 Weeks. Sham subjects to cross over to receive DMR treatment at 24 Weeks and followed up for additional 24 weeks. Sham Procedure: The sham procedure consists of placing the Revita Catheter into the stomach for 30 minutes and then removing it from the patient.
Measure Participants	39	36	17	16
Median (Inter-Quartile Range) [percentage change from baseline]	-0.60	-0.30	-1.85	-1.60

2. Primary Outcome

Title	Change From Baseline at 12 Weeks in MR-PDFF, DMR vs Sham
Description	The absolute change from baseline at 12 weeks in MR-PDFF in patients with baseline MR-PDFF > 5% , DMR vs Sham
Time Frame	Baseline and 12 Weeks post-procedure

Outcome Measure Data

Analysis Population Description

mITT population; not all patients from participant flow were able to undergo a MRI-PDFF. All patients who had a MRI-PDFF performed are analyzed and represented below.

Arm/Group Title	DMR Procedure (Europe)	Sham Procedure (Europe)	DMR Procedure (Brazil)	Sham Procedure (Brazil)
Arm/Group Description	Subjects randomized to the DMR procedure are unblinded at 24 weeks and followed for an additional 24 weeks. DMR Procedure: The DMR procedure consists of hydrothermal ablation of the duodenum using the Revita System	Subjects are unblinded at 24 Weeks. Sham subjects to cross over to receive DMR treatment at 24 Weeks and followed up for additional 24 weeks. Sham Procedure: The sham procedure consists of placing the Revita Catheter into the stomach for 30 minutes and then removing it from the patient.	Subjects randomized to the DMR procedure are unblinded at 24 weeks and followed for an additional 24 weeks. DMR Procedure: The DMR procedure consists of hydrothermal ablation of the duodenum using the Revita System	Subjects are unblinded at 24 Weeks. Sham subjects to cross over to receive DMR treatment at 24 Weeks and followed up for additional 24 weeks. Sham Procedure: The sham procedure consists of placing the Revita Catheter into the stomach for 30 minutes and then removing it from the patient.
Measure Participants	33	28	15	15
Median (Inter-Quartile Range) [percentage change from baseline]	-5.4	-2.24	-5.4	-6.07

Adverse Events

Time Frame	Adverse events for subjects randomized to DMR (and all training cases) were followed for up to a maximum of 56 weeks. Adverse events for subjects randomized to sham who crossed-over to DMR at 24 weeks were followed for up to a maximum of 56 weeks.
Arm/Group Title	DMR Procedure (Europe)		Sham Procedure (Europe)		DMR Procedure (Brazil)		Sham Procedure (Brazil)		Sham Crossover (Europe)		Sham Crossover (Brazil)
Arm/Group Description	Subjects randomized to the DMR procedure are unblinded at 24 weeks and followed for an additional 24 weeks. DMR Procedure: The DMR procedure consists of hydrothermal ablation of the duodenum using the Revita System		Subjects are unblinded at 24 Weeks. Sham subjects to cross over to receive DMR treatment at 24 Weeks and followed up for additional 24 weeks. Sham Procedure: The sham procedure consists of placing the Revita Catheter into the stomach for 30 minutes and then removing it from the patient.		Subjects randomized to the DMR procedure are unblinded at 24 weeks and followed for an additional 24 weeks. DMR Procedure: The DMR procedure consists of hydrothermal ablation of the duodenum using the Revita System		Subjects are unblinded at 24 Weeks. Sham subjects to cross over to receive DMR treatment at 24 Weeks and followed up for additional 24 weeks. Sham Procedure: The sham procedure consists of placing the Revita Catheter into the stomach for 30 minutes and then removing it from the patient.		Subjects that were in sham arm (Europe) until 24 weeks and then crossover to receive DMR treatment at 24 weeks and followed up for additional 24 weeks. AEs captured from time of DMR procedure through follow up to end of study.		Subjects that were in sham arm (Brazil) until 24 weeks and then crossover to receive DMR treatment at 24 weeks and followed up for additional 24 weeks. AEs captured from time of DMR procedure through follow up to end of study.
All Cause Mortality
	DMR Procedure (Europe)		Sham Procedure (Europe)		DMR Procedure (Brazil)		Sham Procedure (Brazil)		Sham Crossover (Europe)		Sham Crossover (Brazil)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/39 (0%)		0/37 (0%)		0/17 (0%)		0/16 (0%)		0/33 (0%)		0/4 (0%)
Serious Adverse Events
	DMR Procedure (Europe)		Sham Procedure (Europe)		DMR Procedure (Brazil)		Sham Procedure (Brazil)		Sham Crossover (Europe)		Sham Crossover (Brazil)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/39 (12.8%)		1/37 (2.7%)		3/17 (17.6%)		0/16 (0%)		0/33 (0%)		0/4 (0%)
Cardiac disorders
Acute myocardial infarction	1/39 (2.6%)	1	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Ear and labyrinth disorders
Ear Disorder	0/39 (0%)	0	1/37 (2.7%)	1	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Gastrointestinal disorders
Jejunal perforation	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Duodenal ulcer	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Injury, poisoning and procedural complications
Foot fracture	1/39 (2.6%)	1	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Arterial injury	1/39 (2.6%)	1	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Musculoskeletal and connective tissue disorders
back pain	1/39 (2.6%)	1	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Neck pain	1/39 (2.6%)	1	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Intervertebral disc protrusion	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	2	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Other (Not Including Serious) Adverse Events
	DMR Procedure (Europe)		Sham Procedure (Europe)		DMR Procedure (Brazil)		Sham Procedure (Brazil)		Sham Crossover (Europe)		Sham Crossover (Brazil)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/39 (79.5%)		26/37 (70.3%)		16/17 (94.1%)		14/16 (87.5%)		26/33 (78.8%)		4/4 (100%)
Blood and lymphatic system disorders
Iron Deficiency anaemia	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
anaemia	0/39 (0%)	0	0/37 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/33 (0%)	0	0/4 (0%)	0
Gastrointestinal disorders
Abdominal pain	7/39 (17.9%)	7	4/37 (10.8%)	4	5/17 (29.4%)	5	0/16 (0%)	0	3/33 (9.1%)	5	0/4 (0%)	0
Abdominal pain upper	3/39 (7.7%)	4	2/37 (5.4%)	2	3/17 (17.6%)	4	2/16 (12.5%)	2	8/33 (24.2%)	9	0/4 (0%)	0
constipation	1/39 (2.6%)	1	1/37 (2.7%)	1	1/17 (5.9%)	1	2/16 (12.5%)	2	1/33 (3%)	1	0/4 (0%)	0
Diarrhoea	1/39 (2.6%)	1	6/37 (16.2%)	8	2/17 (11.8%)	2	1/16 (6.3%)	1	5/33 (15.2%)	7	1/4 (25%)	1
Dyspepsia	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	2	1/16 (6.3%)	1	1/33 (3%)	1	0/4 (0%)	0
duodenitis	4/39 (10.3%)	4	4/37 (10.8%)	4	0/17 (0%)	0	0/16 (0%)	0	1/33 (3%)	1	0/4 (0%)	0
Oesophagitis	3/39 (7.7%)	3	2/37 (5.4%)	2	2/17 (11.8%)	2	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
vomiting	2/39 (5.1%)	2	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	2/33 (6.1%)	2	0/4 (0%)	0
Gastritis Erosive	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Hematochezia	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
haemorrhoids	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Nausea	1/39 (2.6%)	1	1/37 (2.7%)	1	3/17 (17.6%)	3	0/16 (0%)	0	3/33 (9.1%)	3	0/4 (0%)	0
Toothache	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
abdominal Discomfort	0/39 (0%)	0	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	2/33 (6.1%)	2	0/4 (0%)	0
General disorders
asthenia	0/39 (0%)	0	0/37 (0%)	0	2/17 (11.8%)	2	0/16 (0%)	0	2/33 (6.1%)	2	0/4 (0%)	0
polyp	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
fatigue	2/39 (5.1%)	2	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/33 (3%)	1	0/4 (0%)	0
Oedema peripheral	2/39 (5.1%)	2	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Immune system disorders
food allergy	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Infections and infestations
Cystitis	3/39 (7.7%)	3	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Ear infection	2/39 (5.1%)	2	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Influenza	2/39 (5.1%)	2	2/37 (5.4%)	2	1/17 (5.9%)	1	1/16 (6.3%)	1	0/33 (0%)	0	0/4 (0%)	0
Gastroenteritis	0/39 (0%)	0	1/37 (2.7%)	1	1/17 (5.9%)	1	0/16 (0%)	0	1/33 (3%)	1	0/4 (0%)	0
Infection	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Nasopharyngitis	5/39 (12.8%)	6	5/37 (13.5%)	6	0/17 (0%)	0	0/16 (0%)	0	5/33 (15.2%)	5	0/4 (0%)	0
Pharyngitis	1/39 (2.6%)	1	0/37 (0%)	0	1/17 (5.9%)	2	0/16 (0%)	0	1/33 (3%)	1	0/4 (0%)	0
pneumonia	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Respiratory tract infection	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Subcutaneous abscess	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Upper respiratory tract infection	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	2/16 (12.5%)	2	0/33 (0%)	0	1/4 (25%)	1
Urinary tract infection	4/39 (10.3%)	4	1/37 (2.7%)	1	1/17 (5.9%)	1	1/16 (6.3%)	1	0/33 (0%)	0	0/4 (0%)	0
conjunctivitis	1/39 (2.6%)	1	1/37 (2.7%)	1	0/17 (0%)	0	1/16 (6.3%)	1	0/33 (0%)	0	0/4 (0%)	0
Oral Herpes	0/39 (0%)	0	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	1/4 (25%)	1
Injury, poisoning and procedural complications
fall	0/39 (0%)	0	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	1/4 (25%)	1
limb injury	0/39 (0%)	0	1/37 (2.7%)	1	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	1/4 (25%)	1
ligament sprain	0/39 (0%)	0	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	2/33 (6.1%)	2	0/4 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Hypoglycaemia	7/39 (17.9%)	16	7/37 (18.9%)	13	11/17 (64.7%)	106	12/16 (75%)	107	4/33 (12.1%)	10	2/4 (50%)	16
Hyperglycaemia	5/39 (12.8%)	36	4/37 (10.8%)	11	0/17 (0%)	0	0/16 (0%)	0	6/33 (18.2%)	11	0/4 (0%)	0
vitamin D deficiency	0/39 (0%)	0	0/37 (0%)	0	0/17 (0%)	0	3/16 (18.8%)	3	0/33 (0%)	0	0/4 (0%)	0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Musculoskeletal pain	2/39 (5.1%)	3	0/37 (0%)	0	1/17 (5.9%)	1	1/16 (6.3%)	1	0/33 (0%)	0	0/4 (0%)	0
back pain	5/39 (12.8%)	5	3/37 (8.1%)	3	0/17 (0%)	0	0/16 (0%)	0	2/33 (6.1%)	2	0/4 (0%)	0
Pain in extremity	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	1/16 (6.3%)	1	0/33 (0%)	0	0/4 (0%)	0
Myalgia	0/39 (0%)	0	0/37 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/33 (0%)	0	0/4 (0%)	0
Nervous system disorders
Diabetic neuropathy	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	1/16 (6.3%)	1	0/33 (0%)	0	0/4 (0%)	0
Headache	3/39 (7.7%)	4	1/37 (2.7%)	2	3/17 (17.6%)	3	2/16 (12.5%)	2	0/33 (0%)	0	0/4 (0%)	0
Dizziness	1/39 (2.6%)	1	1/37 (2.7%)	1	0/17 (0%)	0	1/16 (6.3%)	1	0/33 (0%)	0	0/4 (0%)	0
facial paralysis	0/39 (0%)	0	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	1/4 (25%)	2
Psychiatric disorders
Generalised anxiety disorder	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Renal and urinary disorders
Nephrolithiasis	0/39 (0%)	0	0/37 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/33 (0%)	0	0/4 (0%)	0
Renal Cyst	0/39 (0%)	0	0/37 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/33 (0%)	0	0/4 (0%)	0
Urinary Incontinence	0/39 (0%)	0	0/37 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/33 (0%)	0	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	2/39 (5.1%)	2	2/37 (5.4%)	2	0/17 (0%)	0	1/16 (6.3%)	1	1/33 (3%)	1	0/4 (0%)	0
asthma	0/39 (0%)	0	2/37 (5.4%)	2	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
cough	0/39 (0%)	0	0/37 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	4/33 (12.1%)	4	0/4 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Pruritus	2/39 (5.1%)	2	1/37 (2.7%)	1	0/17 (0%)	0	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Surgical and medical procedures
Hydrocele operation	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Inguinal hernia repair	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/33 (0%)	0	0/4 (0%)	0
Vascular disorders
Orthostatic hypotension	0/39 (0%)	0	0/37 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	1/33 (3%)	1	0/4 (0%)	0

Limitations/Caveats

Results from prespecified interaction testing and clinical parameter assessment showed heterogeneity between European (DMR N=39; sham N=37) and Brazilian (DMR N=17; sham N=16) populations, therefore, results were stratified by region. Limitations of this feasibility study include the relatively small patient population and heterogeneity between European and Brazilian populations.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.