Phase 3 Gene Therapy for Painful Diabetic Neuropathy

• Sponsor: Helixmith Co., Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02427464
• Collaborator: (none)
• Enrollment: 507
• Locations: 25
• Arms: 2
• Duration (Months): 36
• Patients Per Site: 20.3
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the safety and efficacy of bilateral intramuscular injections of VM202 versus placebo in the treatment of painful diabetic peripheral neuropathy.

A total of 507 of 477 planned participants were randomized in a 2:1 ratio to one of two treatment groups. Note that 500 participants received IP treatment, whereas 7 participants did not receive IP treatment.

Treatments - Engensis (VM202) - 336 Engensis of 318 planned participants

Control - Placebo (VM202 vehicle) - 164 Placebo of 159 planned participants

Randomization were stratified by current use of gabapentin and/or pregabalin.

Condition or Disease	Intervention/Treatment	Phase
Painful Diabetic Neuropathy; Diabetic Neuropathy, Painful	Biological: Engensis (VM202); Other: placebo	Phase 3

Detailed Description

Peripheral neuropathy is a serious complication of diabetes. This form of neuropathy carries a high risk of pain, trophic changes, and autonomic dysfunction. Current treatments of diabetic peripheral neuropathy (DPN) are based on either pathogenetic mechanisms or symptomatic relief. A number of clinical trials have established symptomatic treatment but for pathogenetic mechanisms, the only proven treatment strategy is strict glycemic control. Clearly, it would be desirable to prevent, impede, or reverse the disrupting and often life-threatening manifestations of peripheral neuropathy by stimulating growth or regeneration of peripheral nerve axons.

Study Design

• Study Type: Interventional
• Actual Enrollment: 507 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety and Efficacy of VM202 in Participants With Painful Diabetic Peripheral Neuropathy
• Study Start Date: Apr 1, 2016
• Actual Primary Completion Date: Apr 1, 2019
• Actual Study Completion Date: Apr 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Engensis (VM202) Subjects randomized to the Engensis (VM202) treatment arm received the following intramuscular injections in each calf: Day 0 - 16 injections of 0.5mL of VM202 / calf Day 14 - 16 injections of 0.5mL of VM202 / calf Day 90 - 16 injections of 0.5mL of VM202 / calf Day 104 - 16 injections of 0.5mL of VM202 / calf	Biological: Engensis (VM202); gene therapy
Placebo Comparator: Placebo Subjects in the placebo control group received the following intramuscular injections in each calf: Day 0 - 16 injections of 0.5mL of VM202 vehicle / calf Day 14 - 16 injections of 0.5mL of VM202 vehicle / calf Day 90 - 16 injections of 0.5mL of VM202 vehicle / calf Day 104 - 16 injections of 0.5mL of VM202 vehicle / calf	Other: placebo

Outcome Measures

Primary Outcome Measures

1. Change in the Average 24 Hour Pain Score From Baseline to Day 90 [The Pain and Sleep Interference diary was completed by participants for at least 5 assessments during a 7-day period at Screening (the mean 24-hour score was the reference/baseline score) and within 14 days prior to Day 90 visit.]

   Participants rated their 24-hour average daily pain intensity score using an 11-point numerical rating scale from 0 (no pain) to 10 (worst possible pain) in a Daily Pain and Sleep Interference Diary

2. Participants With at Least at 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 90 [Baseline to Day 90]

   Number of participants with at least a 50 percent reduction in average 24-hour pain score, using an 11-point numerical rating scale from 0 (no pain) to 10 (worst possible pain) in the Daily Pain and Sleep Interference Diary

3. Number of Participants With Treatment-emergent Adverse Events. [Baseline to Day 270]

   Number of Participants with at least one treatment-emergent adverse events.

Secondary Outcome Measures

1. Change in the Average 24-hour Pain Score From Baseline to Day 180 [Baseline to Day 180]

   Participants rated their 24-hour average daily pain intensity score using an 11-point numerical rating scale from 0 (no pain) to 10 (worst possible pain) in the Daily Pain and Sleep Interference Diary

2. Participants With at Least a 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 180 [Baseline to Day 180]

   The number of participants with at least a 50% reduction in average 24-hour pain score using an 11-point numerical rating scale from 0 (no pain) to 10 (worst possible pain) in the Daily Pain and Sleep Interference Diary

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age ≥ 18 years to ≤ 75 years

2. Documented history of type I or II diabetes with current treatment control (HbA1c of ≤ 10.0% at Screening) and currently on medication for diabetes (oral, injectable, and/or insulin)

3. No significant changes anticipated in diabetes medication regimen

4. No new symptoms associated with diabetes within the last 3 months prior to study entry

5. Diagnosis of painful diabetic peripheral neuropathy in both lower extremities

6. Lower extremity pain for at least 6 months

7. Visual analog scale (VAS) score of ≥ 40 mm at Initial Screening (0 mm = no pain - 100 mm very severe pain)

8. Symptoms from the Brief Pain Neuropathy Screening (BPNS) is ≤ 5 point difference between legs at Initial Screening

9. The average daily pain intensity score of the Daily Pain and Sleep Interference Diary completed after medication wash-out is ≥ 4 with a standard deviation ≤ 2

10. The physical examination component of the Michigan Neuropathy Screening Instrument Score (MNSI) is ≥ 3 at Screening

11. Subjects on gabapentin (Neurontin), pregabalin (Lyrica), duloxetine (Cymbalta) for painful DPN at study entry must be on stable regimen of these treatments for at least 3 months prior to study entry

12. If female of childbearing potential, negative urine pregnancy test at screening and using acceptable method of birth control during the study

Exclusion Criteria:

1. Peripheral neuropathy caused by condition other than diabetes

2. Other pain more severe than neuropathic pain that would prevent assessment of DPN

3. Progressive or degenerative neurological disorder

4. Myopathy

5. Inflammatory disorder of the blood vessels (inflammatory angiopathy, such as Buerger's disease)

6. Active infection

7. Chronic inflammatory disease (e.g., Crohn's disease, rheumatoid arthritis)

8. Positive HIV or HTLV at Screening

9. Active Hepatitis B or C as determined by Hepatitis B core antibody (HBcAb), antibody to Hepatitis B surface antigen (IgG and IgM; HBsAb), Hepatitis B surface antigen (HBsAg), and Hepatitis C antibodies (Anti HCV) at Screening

10. Subjects with known immunosuppression or currently receiving immunosuppressive drugs, chemotherapy, or radiation therapy

11. Stroke or myocardial infarction within last 3 months

12. Specific laboratory values at Screening including: Hemoglobin < 8.0 g/dL, WBC < 3,000 cells per microliter, platelet count <75,000/mm3, Creatinine > 2.0 mg/dL; AST and/or ALT > 3 times the upper limit of normal or any other clinically significant lab abnormality which in the opinion of the investigator should be exclusionary

13. Ophthalmologic conditions pertinent to proliferative retinopathy or conditions that preclude standard ophthalmologic examination

14. Uncontrolled hypertension defined as sustained systolic blood pressure (SBP) > 200 mmHg or diastolic BP (DBP) > 110 mmHg at Screening

15. Subjects with a recent history (< 5 years) of or new screening finding of malignant neoplasm except basal cell carcinoma or squamous cell carcinoma of the skin (if excised and no evidence of recurrence for one year); subjects with family history of colon cancer in any first degree relative are excluded unless they have undergone a colonoscopy in the last 12 months with negative findings

16. Use of the following drugs / therapeutics is prohibited. Subjects may participate in the study if they are willing to discontinue use of these drugs / therapeutics 7 days prior to starting the 7 Day Daily Pain and Sleep Interference Diary. Subjects must refrain from taking these drugs or undergoing these therapies for the duration of the study

• skeletal muscle relaxants, opioids, benzodiazepines (except for stable bedtime dose),

• capsaicin, local anesthetic creams (except for lidocaine cream prior to IM injection) and patches, isosorbide dinitrate (ISDN) spray,

• transcutaneous electrical nerve stimulation (TENS), acupuncture

1. If not using gabapentin (Neurontin) or pregabalin (Lyrica), subjects must agree not to start these drugs for the first 180 days of the study. Subjects on these medications at study entry must maintain a stable dose until Day 180 of the study;

2. If not using duloxetine (Cymbalta), any antidepressants (e.g., amitriptyline and venlafaxine), any other antiepileptics (e.g., valproic acid, carbamazepine, vigabatrin), subjects must agree not to start these drugs for the first 6 months of the study.

Subjects on these medications at study entry must maintain a stable dose until Day 180 of the study

1. Subjects requiring > 81 mg daily of acetylsalicylic acid; subjects may be enrolled if willing/able to switch to ≤ 81 mg daily of acetylsalicylic acid or to another medication

2. Subjects requiring regular COX-2 inhibitor drug(s) or non-specific COX-1/COX-2 inhibiting drugs, or high dose steroids (except inhaled steroids or ocular steroids) subjects may be enrolled if willing/able to undergo medication wash-out prior to the first dosing and to refrain from taking these drugs until Day 180 of the study

3. Major psychiatric disorder within the last 180 days that would interfere with study participation

4. Body mass index (BMI) > 45 kg/m2 at Screening

5. Any lower extremity amputation due to diabetic complications

6. Use of an investigational drug or treatment in past 6 months, or prior participation in any study of Engensis (VM202)

7. Unable or unwilling to give informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Research Center	Phoenix	Arizona	United States	85023
2	Clinical Trials, Inc.	Little Rock	Arkansas	United States	72205
3	Richard S. Cherlin, MD	Los Gatos	California	United States	95032
4	Northern California Research	Sacramento	California	United States	95821
5	Center for Clinical Research	San Francisco	California	United States	94115
6	Neurological Research Institute	Santa Monica	California	United States	90404
7	Diablo Clinical Research, Inc.	Walnut Creek	California	United States	94598
8	Associated Neurologists of Southern Connecticut, PC	Fairfield	Connecticut	United States	06824
9	Innovative Research of West Florida	Clearwater	Florida	United States	33756
10	University of Florida McKnight Brain Institute	Gainesville	Florida	United States	32611
11	UF Health College of Med, Jacksonville	Jacksonville	Florida	United States	32207
12	Compass Research, LLC	Orlando	Florida	United States	32806
13	Clinical Research of West Florida	Tampa	Florida	United States	33603
14	Northwestern University	Chicago	Illinois	United States	60611
15	University of Kansas Medical Center Research Institute	Kansas City	Kansas	United States	66160
16	The Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
17	University of Minnesota	Minneapolis	Minnesota	United States	55455
18	Columbia University Medical Center Department of Neurology	New York	New York	United States	10032
19	Raleigh Neurology Associates, P.A.	Raleigh	North Carolina	United States	27607
20	Martin Foot and Ankle	York	Pennsylvania	United States	17402
21	Nerve and Muscle Center of Texas	Houston	Texas	United States	77030
22	University of Utah -Neurology	Salt Lake City	Utah	United States	84132
23	EVMS (Eastern Virginia Medical School)	Norfolk	Virginia	United States	23510
24	Western Washington Medical Group	Everett	Washington	United States	98208
25	Rainier Clinical Research Center, Inc.	Renton	Washington	United States	98057

Sponsors and Collaborators

• Helixmith Co., Ltd.

Investigators

• Principal Investigator: John A Kessler, MD, Northwestern University

Study Documents (Full-Text)

• Study Protocol - Sep 5, 2019
• Statistical Analysis Plan - Sep 5, 2019

More Information

Additional Information:

• Clin Transl Sci. 2021;00:1-9

Publications

None provided.

• Responsible Party: Helixmith Co., Ltd.
• ClinicalTrials.gov Identifier: NCT02427464
• Other Study ID Numbers: VMDN-003
• First Posted: Apr 28, 2015
• Last Update Posted: Aug 22, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Helixmith Co., Ltd.: diabetic; peripheral neuropathy; shooting pain; burning pain; pins and needles pain; foot pain; ViroMed
• Additional relevant MeSH terms: Peripheral Nervous System Diseases; Diabetic Neuropathies; Pain

Study Results

Participant Flow

Recruitment Details	Participants recruited using standard methods were randomized 2:1 to Engensis or Placebo and stratified by gabapentinoid use versus non-gabapentinoid concomitant medications.

Arm/Group Title	Engensis (VM202)	Placebo
Arm/Group Description	Participants randomized to the Engensis (VM202) treatment arm received the following intramuscular injections in each calf: Day 0 - 16 injections of 0.5mL of VM202 / calf Day 14 - 16 injections of 0.5mL of VM202 / calf Day 90 - 16 injections of 0.5mL of VM202 / calf Day 104 - 16 injections of 0.5mL of VM202 / calf Engensis (VM202): gene therapy	Participants randomized to the Placebo treatment arm received the following intramuscular injections in each calf Day 0 - 16 injections of 0.5mL of VM202 vehicle / calf Day 14 - 16 injections of 0.5mL of VM202 vehicle / calf Day 90 - 16 injections of 0.5mL of VM202 vehicle / calf Day 104 - 16 injections of 0.5mL of VM202 vehicle / calf placebo
Period Title: Overall Study
STARTED	338	169
Intent-to-Treat Population	336	164
COMPLETED	288	145
NOT COMPLETED	50	24

Baseline Characteristics

Arm/Group Title	Engensis (VM202)	Placebo	Total
Arm/Group Description	Subjects randomized to the Engensis (VM202) treatment arm received the following intramuscular injections in each calf: Day 0 - 16 injections of 0.5mL of VM202 / calf Day 14 - 16 injections of 0.5mL of VM202 / calf Day 90 - 16 injections of 0.5mL of VM202 / calf Day 104 - 16 injections of 0.5mL of VM202 / calf Engensis (VM202): gene therapy	Subjects in the placebo control group received the following intramuscular injections in each calf: Day 0 - 16 injections of 0.5mL of VM202 vehicle / calf Day 14 - 16 injections of 0.5mL of VM202 vehicle / calf Day 90 - 16 injections of 0.5mL of VM202 vehicle / calf Day 104 - 16 injections of 0.5mL of VM202 vehicle / calf placebo	Total of all reporting groups
Overall Participants	336	164	500
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.8 (9.09)	61.6 (9.09)	61.0 (9.09)
Sex: Female, Male (Count of Participants)
Female	143 42.6%	45 27.4%	188 37.6%
Male	193 57.4%	119 72.6%	312 62.4%
Race/Ethnicity, Customized (Count of Participants)
White	247 73.5%	125 76.2%	372 74.4%
Black or African American	71 21.1%	29 17.7%	100 20%
Asian	11 3.3%	4 2.4%	15 3%
American Indian or Alaska Native	1 0.3%	1 0.6%	2 0.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Other	5 1.5%	4 2.4%	9 1.8%
Unknown	1 0.3%	1 0.6%	2 0.4%
Region of Enrollment (participants) [Number]
United States	336 100%	164 100%	500 100%

Outcome Measures

1. Primary Outcome

Title	Change in the Average 24 Hour Pain Score From Baseline to Day 90
Description	Participants rated their 24-hour average daily pain intensity score using an 11-point numerical rating scale from 0 (no pain) to 10 (worst possible pain) in a Daily Pain and Sleep Interference Diary
Time Frame	The Pain and Sleep Interference diary was completed by participants for at least 5 assessments during a 7-day period at Screening (the mean 24-hour score was the reference/baseline score) and within 14 days prior to Day 90 visit.

Outcome Measure Data

Analysis Population Description

Overall number of Intent-to-Treat population with available data for this assessment

Arm/Group Title	Engensis (VM202)	Placebo
Arm/Group Description	Participants randomized to the Engensis (VM202) treatment arm received the following intramuscular injections in each calf: Day 0 - 16 injections of 0.5mL of VM202 / calf Day 14 - 16 injections of 0.5mL of VM202 / calf Day 90 - 16 injections of 0.5mL of VM202 / calf Day 104 - 16 injections of 0.5mL of VM202 / calf Engensis (VM202): gene therapy	Participants randomized to the Placebo treatment arm received the following intramuscular injections in each calf Day 0 - 16 injections of 0.5mL of VM202 vehicle / calf Day 14 - 16 injections of 0.5mL of VM202 vehicle / calf Day 90 - 16 injections of 0.5mL of VM202 vehicle / calf Day 104 - 16 injections of 0.5mL of VM202 vehicle / calf placebo
Measure Participants	312	154
Mean (Standard Deviation) [units on a scale]	-1.80 (2.05)	-1.57 (2.07)

2. Primary Outcome

Title	Participants With at Least at 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 90
Description	Number of participants with at least a 50 percent reduction in average 24-hour pain score, using an 11-point numerical rating scale from 0 (no pain) to 10 (worst possible pain) in the Daily Pain and Sleep Interference Diary
Time Frame	Baseline to Day 90

Outcome Measure Data

Analysis Population Description

Intent-to-Treat population

Arm/Group Title	Engensis (VM202)	Placebo
Arm/Group Description	Participants randomized to the Engensis (VM202) treatment arm received the following intramuscular injections in each calf: Day 0 - 16 injections of 0.5mL of VM202 / calf Day 14 - 16 injections of 0.5mL of VM202 / calf Day 90 - 16 injections of 0.5mL of VM202 / calf Day 104 - 16 injections of 0.5mL of VM202 / calf Engensis (VM202): gene therapy	Participants randomized to the Placebo treatment arm received the following intramuscular injections in each calf Day 0 - 16 injections of 0.5mL of VM202 vehicle / calf Day 14 - 16 injections of 0.5mL of VM202 vehicle / calf Day 90 - 16 injections of 0.5mL of VM202 vehicle / calf Day 104 - 16 injections of 0.5mL of VM202 vehicle / calf placebo
Measure Participants	336	164
Count of Participants [Participants]	69 20.5%	28 17.1%

3. Primary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events.
Description	Number of Participants with at least one treatment-emergent adverse events.
Time Frame	Baseline to Day 270

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Engensis (VM202)	Placebo
Arm/Group Description	Participants randomized to the Engensis (VM202) treatment arm received the following intramuscular injections in each calf: Day 0 - 16 injections of 0.5mL of VM202 / calf Day 14 - 16 injections of 0.5mL of VM202 / calf Day 90 - 16 injections of 0.5mL of VM202 / calf Day 104 - 16 injections of 0.5mL of VM202 / calf Engensis (VM202): gene therapy	Participants randomized to the Placebo treatment arm received the following intramuscular injections in each calf Day 0 - 16 injections of 0.5mL of VM202 vehicle / calf Day 14 - 16 injections of 0.5mL of VM202 vehicle / calf Day 90 - 16 injections of 0.5mL of VM202 vehicle / calf Day 104 - 16 injections of 0.5mL of VM202 vehicle / calf placebo
Measure Participants	332	161
Count of Participants [Participants]	241 71.7%	111 67.7%

4. Secondary Outcome

Title	Change in the Average 24-hour Pain Score From Baseline to Day 180
Description	Participants rated their 24-hour average daily pain intensity score using an 11-point numerical rating scale from 0 (no pain) to 10 (worst possible pain) in the Daily Pain and Sleep Interference Diary
Time Frame	Baseline to Day 180

Outcome Measure Data

Analysis Population Description

Intent-to-Treat population

Arm/Group Title	Engensis (VM202)	Placebo
Arm/Group Description	Participants randomized to the Engensis (VM202) treatment arm received the following intramuscular injections in each calf: Day 0 - 16 injections of 0.5mL of VM202 / calf Day 14 - 16 injections of 0.5mL of VM202 / calf Day 90 - 16 injections of 0.5mL of VM202 / calf Day 104 - 16 injections of 0.5mL of VM202 / calf Engensis (VM202): gene therapy	Participants randomized to the Placebo treatment arm received the following intramuscular injections in each calf Day 0 - 16 injections of 0.5mL of VM202 vehicle / calf Day 14 - 16 injections of 0.5mL of VM202 vehicle / calf Day 90 - 16 injections of 0.5mL of VM202 vehicle / calf Day 104 - 16 injections of 0.5mL of VM202 vehicle / calf placebo
Measure Participants	336	164
Mean (Standard Deviation) [units on a scale]	-2.59 (2.38)	-2.14 (2.36)

5. Secondary Outcome

Title	Participants With at Least a 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 180
Description	The number of participants with at least a 50% reduction in average 24-hour pain score using an 11-point numerical rating scale from 0 (no pain) to 10 (worst possible pain) in the Daily Pain and Sleep Interference Diary
Time Frame	Baseline to Day 180

Outcome Measure Data

Analysis Population Description

Intent-to-Treat population

Arm/Group Title	Engensis (VM202)	Placebo
Arm/Group Description	Participants randomized to the Engensis (VM202) treatment arm received the following intramuscular injections in each calf: Day 0 - 16 injections of 0.5mL of VM202 / calf Day 14 - 16 injections of 0.5mL of VM202 / calf Day 90 - 16 injections of 0.5mL of VM202 / calf Day 104 - 16 injections of 0.5mL of VM202 / calf Engensis (VM202): gene therapy	Participants randomized to the Placebo treatment arm received the following intramuscular injections in each calf Day 0 - 16 injections of 0.5mL of VM202 vehicle / calf Day 14 - 16 injections of 0.5mL of VM202 vehicle / calf Day 90 - 16 injections of 0.5mL of VM202 vehicle / calf Day 104 - 16 injections of 0.5mL of VM202 vehicle / calf placebo
Measure Participants	336	164
Count of Participants [Participants]	113 33.6%	42 25.6%

Adverse Events

Time Frame	270 days
Adverse Event Reporting Description	All-Cause Mortality, Serious and Other Adverse Events were monitored for the Safety Population
Arm/Group Title	Engensis (VM202)		Placebo
Arm/Group Description	Participants randomized to the Engensis (VM202) treatment arm received the following intramuscular injections in each calf: Day 0 - 16 injections of 0.5mL of VM202 / calf Day 14 - 16 injections of 0.5mL of VM202 / calf Day 90 - 16 injections of 0.5mL of VM202 / calf Day 104 - 16 injections of 0.5mL of VM202 / calf Engensis (VM202): gene therapy		Participants randomized to the Placebo treatment arm received the following intramuscular injections in each calf Day 0 - 16 injections of 0.5mL of VM202 vehicle / calf Day 14 - 16 injections of 0.5mL of VM202 vehicle / calf Day 90 - 16 injections of 0.5mL of VM202 vehicle / calf Day 104 - 16 injections of 0.5mL of VM202 vehicle / calf placebo
All Cause Mortality
	Engensis (VM202)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/332 (0%)		1/161 (0.6%)
Serious Adverse Events
	Engensis (VM202)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/332 (9.6%)		16/161 (9.9%)
Cardiac disorders
Acute coronary syndrome	1/332 (0.3%)		1/161 (0.6%)
Acute myocardial infarction	1/332 (0.3%)		1/161 (0.6%)
Angina pectoris	2/332 (0.6%)		0/161 (0%)
Coronary artery disease	2/332 (0.6%)		0/161 (0%)
Angina unstable	1/332 (0.3%)		0/161 (0%)
Atrial fibrillation	1/332 (0.3%)		0/161 (0%)
Atrioventricular block complete	0/332 (0%)		1/161 (0.6%)
Cardiac failure acute	1/332 (0.3%)		0/161 (0%)
Cardiac failure congestive	0/332 (0%)		1/161 (0.6%)
Myocardial infarction	1/332 (0.3%)		0/161 (0%)
Ear and labyrinth disorders
Vertigo	0/332 (0%)		1/161 (0.6%)
Eye disorders
Vitreous haemorrhage	1/332 (0.3%)		0/161 (0%)
Gastrointestinal disorders
Melaena	1/332 (0.3%)		0/161 (0%)
Oesophageal varices haemorrhage	0/332 (0%)		1/161 (0.6%)
Pancreatitis	1/332 (0.3%)		0/161 (0%)
General disorders
Chest pain	2/332 (0.6%)		0/161 (0%)
Hepatobiliary disorders
Cholecystitis	0/332 (0%)		1/161 (0.6%)
Infections and infestations
Cellulitis	2/332 (0.6%)		0/161 (0%)
Appendicitis	0/332 (0%)		1/161 (0.6%)
Cellulitis of male external genital organ	0/332 (0%)		1/161 (0.6%)
Cholecystitis infective	0/332 (0%)		1/161 (0.6%)
Diverticulitis	1/332 (0.3%)		0/161 (0%)
Infected bite	0/332 (0%)		1/161 (0.6%)
Infected skin ulcer	0/332 (0%)		1/161 (0.6%)
Influenza	1/332 (0.3%)		0/161 (0%)
Post procedural cellulitis	1/332 (0.3%)		0/161 (0%)
Pyelonephritis	1/332 (0.3%)		0/161 (0%)
Sepsis	1/332 (0.3%)		0/161 (0%)
Urinary tract infection	1/332 (0.3%)		0/161 (0%)
Injury, poisoning and procedural complications
Hand fracture	0/332 (0%)		1/161 (0.6%)
Head injury	1/332 (0.3%)		0/161 (0%)
Humerus fracture	1/332 (0.3%)		0/161 (0%)
Joint dislocation	0/332 (0%)		1/161 (0.6%)
Lumbar vertebral fracture	0/332 (0%)		1/161 (0.6%)
Post procedural haematoma	0/332 (0%)		1/161 (0.6%)
Road traffic accident	1/332 (0.3%)		0/161 (0%)
Investigations
Influenza A virus test positive	1/332 (0.3%)		0/161 (0%)
Lipase increased	1/332 (0.3%)		0/161 (0%)
Metabolism and nutrition disorders
Diabetic ketoacidosis	1/332 (0.3%)		0/161 (0%)
Hyperglycaemia	1/332 (0.3%)		0/161 (0%)
Hypoglycaemia	1/332 (0.3%)		0/161 (0%)
Hypokalaemia	0/332 (0%)		1/161 (0.6%)
Lactic acidosis	0/332 (0%)		1/161 (0.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/332 (0.3%)		2/161 (1.2%)
Neuropathic arthropathy	1/332 (0.3%)		0/161 (0%)
Osteoarthritis	0/332 (0%)		1/161 (0.6%)
Osteochondrosis	1/332 (0.3%)		0/161 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	1/332 (0.3%)		0/161 (0%)
Invasive ductal breast carcinoma	1/332 (0.3%)		0/161 (0%)
Rectal cancer	1/332 (0.3%)		0/161 (0%)
Nervous system disorders
Cerebral infarction	0/332 (0%)		1/161 (0.6%)
Diabetic hyperosmolar coma	0/332 (0%)		1/161 (0.6%)
Encephalopathy	0/332 (0%)		1/161 (0.6%)
Hypertensive encephalopathy	1/332 (0.3%)		0/161 (0%)
Metabolic encephalopathy	0/332 (0%)		1/161 (0.6%)
Mononeuropathy	1/332 (0.3%)		0/161 (0%)
Transient ischaemic attack	1/332 (0.3%)		0/161 (0%)
Psychiatric disorders
Schizoaffective disorder	0/332 (0%)		1/161 (0.6%)
Renal and urinary disorders
Acute kidney injury	1/332 (0.3%)		0/161 (0%)
Hydronephrosis	1/332 (0.3%)		0/161 (0%)
Ureterolithiasis	1/332 (0.3%)		0/161 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/332 (0%)		1/161 (0.6%)
Chronic obstructive pulmonary disease	1/332 (0.3%)		0/161 (0%)
Respiratory failure	0/332 (0%)		1/161 (0.6%)
Vascular disorders
Hypertensive emergency	1/332 (0.3%)		0/161 (0%)
Orthostatic hypotension	0/332 (0%)		1/161 (0.6%)
Peripheral artery stenosis	1/332 (0.3%)		0/161 (0%)
Other (Not Including Serious) Adverse Events
	Engensis (VM202)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	237/332 (71.4%)		102/161 (63.4%)
Eye disorders
Diabetic retinopathy	7/332 (2.1%)		10/161 (6.2%)
Cataract	9/332 (2.7%)		3/161 (1.9%)
Gastrointestinal disorders
Diarrhoea	9/332 (2.7%)		3/161 (1.9%)
Nausea	9/332 (2.7%)		2/161 (1.2%)
General disorders
Oedema peripheral	9/332 (2.7%)		2/161 (1.2%)
Infections and infestations
Upper respiratory tract infection	22/332 (6.6%)		12/161 (7.5%)
Nasopharyngitis	17/332 (5.1%)		4/161 (2.5%)
Bronchitis	9/332 (2.7%)		2/161 (1.2%)
Injury, poisoning and procedural complications
Fall	7/332 (2.1%)		8/161 (5%)
Injection Site Reaction (Grade 1 or 2)	46/332 (13.9%)		18/161 (11.2%)
Metabolism and nutrition disorders
Hyperglycaemia	9/332 (2.7%)		2/161 (1.2%)
Hypoglycaemia	9/332 (2.7%)		2/161 (1.2%)
Musculoskeletal and connective tissue disorders
Pain in extremity	18/332 (5.4%)		5/161 (3.1%)
Arthralgia	14/332 (4.2%)		7/161 (4.3%)
Muscle spasms	10/332 (3%)		10/161 (6.2%)
Back pain	12/332 (3.6%)		5/161 (3.1%)
Nervous system disorders
Headache	14/332 (4.2%)		3/161 (1.9%)
Skin and subcutaneous tissue disorders
Skin ulcer	7/332 (2.1%)		4/161 (2.5%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Investigator Agreement .....