Trial Outcomes & Findings for RISE Adult Medication Study (NCT NCT01779362)
NCT ID: NCT01779362
Last Updated: 2023-05-11
Results Overview
Clamp measures of ß-cell response, co-primary outcomes
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
267 participants
Primary outcome timeframe
3-months after medication washout (Month 15)
Results posted on
2023-05-11
Participant Flow
Participant milestones
| Measure |
Metformin Alone
Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). Participants randomized to the metformin-alone arm will be blinded to treatment.
Metformin: Titrated to 1000 mg BID
|
Glargine Followed by Metformin
Basal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 80-90 mg/dl, followed by open-label metformin (titrated up to 2000 mg/day) for 9 months.
Metformin: Titrated to 1000 mg BID
Glargine: Titrated to target fasting glucose \<90 mg/dl
|
Placebo
Placebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin.
Placebo: Matching to metformin 1000 mg BI
|
Liraglutide + Metformin
Liraglutide + open-label Metformin. Liraglutide will be titrated to the maximum dose tolerated (up to 1.8 mg/day) after which metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day).
Metformin: Titrated to 1000 mg BID
Liraglutide: Titrated to 1.8 mg/day
|
|---|---|---|---|---|
|
Overall Study
STARTED
|
65
|
67
|
67
|
68
|
|
Overall Study
COMPLETED
|
56
|
65
|
58
|
53
|
|
Overall Study
NOT COMPLETED
|
9
|
2
|
9
|
15
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
RISE Adult Medication Study
Baseline characteristics by cohort
| Measure |
Metformin Alone
n=65 Participants
Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). Participants randomized to the metformin-alone arm will be blinded to treatment.
Metformin: Titrated to 1000 mg BID
|
Glargine Followed by Metformin
n=67 Participants
Basal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 80-90 mg/dl, followed by open-label metformin (titrated up to 2000 mg/day) for 9 months.
Metformin: Titrated to 1000 mg BID
Glargine: Titrated to target fasting glucose \<90 mg/dl
|
Placebo
n=67 Participants
Placebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin.
Placebo: Matching to metformin 1000 mg BI
|
Liraglutide + Metformin
n=68 Participants
Liraglutide + open-label Metformin. Liraglutide will be titrated to the maximum dose tolerated (up to 1.8 mg/day) after which metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day).
Metformin: Titrated to 1000 mg BID
Liraglutide: Titrated to 1.8 mg/day
|
Total
n=267 Participants
Total of all reporting groups
|
|---|---|---|---|---|---|
|
Age, Continuous
|
55.2 years
STANDARD_DEVIATION 8.2 • n=5 Participants
|
53.5 years
STANDARD_DEVIATION 9.3 • n=7 Participants
|
52.8 years
STANDARD_DEVIATION 10.0 • n=5 Participants
|
54.0 years
STANDARD_DEVIATION 8.1 • n=4 Participants
|
53.9 years
STANDARD_DEVIATION 8.9 • n=21 Participants
|
|
Sex: Female, Male
Female
|
37 Participants
n=5 Participants
|
23 Participants
n=7 Participants
|
25 Participants
n=5 Participants
|
29 Participants
n=4 Participants
|
114 Participants
n=21 Participants
|
|
Sex: Female, Male
Male
|
28 Participants
n=5 Participants
|
44 Participants
n=7 Participants
|
42 Participants
n=5 Participants
|
39 Participants
n=4 Participants
|
153 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
Race/Ethnicity · Non-Hispanic White
|
34 Participants
n=5 Participants
|
37 Participants
n=7 Participants
|
30 Participants
n=5 Participants
|
40 Participants
n=4 Participants
|
141 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
Race/Ethnicity · Black
|
19 Participants
n=5 Participants
|
21 Participants
n=7 Participants
|
21 Participants
n=5 Participants
|
20 Participants
n=4 Participants
|
81 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
Race/Ethnicity · Hispanic
|
6 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
11 Participants
n=5 Participants
|
6 Participants
n=4 Participants
|
28 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
Race/Ethnicity · All other
|
6 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
5 Participants
n=5 Participants
|
2 Participants
n=4 Participants
|
17 Participants
n=21 Participants
|
|
Body mass index (BMI)
|
35.0 kg/m^2
STANDARD_DEVIATION 5.1 • n=5 Participants
|
35.0 kg/m^2
STANDARD_DEVIATION 5.9 • n=7 Participants
|
34.4 kg/m^2
STANDARD_DEVIATION 5.9 • n=5 Participants
|
35.6 kg/m^2
STANDARD_DEVIATION 5.8 • n=4 Participants
|
35.0 kg/m^2
STANDARD_DEVIATION 5.7 • n=21 Participants
|
|
HbA1c
|
5.77 % of glycosylated hemoglobin
STANDARD_DEVIATION 0.40 • n=5 Participants
|
5.80 % of glycosylated hemoglobin
STANDARD_DEVIATION 0.33 • n=7 Participants
|
5.73 % of glycosylated hemoglobin
STANDARD_DEVIATION 0.43 • n=5 Participants
|
5.69 % of glycosylated hemoglobin
STANDARD_DEVIATION 0.39 • n=4 Participants
|
5.75 % of glycosylated hemoglobin
STANDARD_DEVIATION 0.39 • n=21 Participants
|
|
Fasting glucose
|
6.21 mmol/L
STANDARD_DEVIATION 0.67 • n=5 Participants
|
6.22 mmol/L
STANDARD_DEVIATION 0.74 • n=7 Participants
|
6.08 mmol/L
STANDARD_DEVIATION 0.58 • n=5 Participants
|
6.11 mmol/L
STANDARD_DEVIATION 0.50 • n=4 Participants
|
6.15 mmol/L
STANDARD_DEVIATION 0.63 • n=21 Participants
|
|
2-hour OGTT glucose
|
10.1 mmol/L
STANDARD_DEVIATION 2.4 • n=5 Participants
|
10.3 mmol/L
STANDARD_DEVIATION 2.4 • n=7 Participants
|
10.1 mmol/L
STANDARD_DEVIATION 2.3 • n=5 Participants
|
9.9 mmol/L
STANDARD_DEVIATION 2.2 • n=4 Participants
|
10.1 mmol/L
STANDARD_DEVIATION 2.3 • n=21 Participants
|
PRIMARY outcome
Timeframe: 3-months after medication washout (Month 15)Population: Primary analysis was on all participants who attended their M15 visit.
Clamp measures of ß-cell response, co-primary outcomes
Outcome measures
| Measure |
Metformin Alone
n=56 Participants
Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). Participants randomized to the metformin-alone arm will be blinded to treatment.
Metformin: Titrated to 1000 mg BID
|
Glargine Followed by Metformin
n=65 Participants
Basal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 80-90 mg/dl, followed by open-label metformin (titrated up to 2000 mg/day) for 9 months.
Metformin: Titrated to 1000 mg BID
Glargine: Titrated to target fasting glucose \<90 mg/dl
|
Placebo
n=58 Participants
Placebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin.
Placebo: Matching to metformin 1000 mg BI
|
Liraglutide + Metformin
n=53 Participants
Liraglutide + open-label Metformin. Liraglutide will be titrated to the maximum dose tolerated (up to 1.8 mg/day) after which metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day).
Metformin: Titrated to 1000 mg BID
Liraglutide: Titrated to 1.8 mg/day
|
|---|---|---|---|---|
|
ß-cell Response Measured by Hyperglycemic Clamp
Steady State C-peptide
|
3.65 nmol/L
Interval 1.94 to 6.87
|
3.58 nmol/L
Interval 1.68 to 8.33
|
3.60 nmol/L
Interval 1.72 to 7.53
|
3.73 nmol/L
Interval 1.87 to 7.44
|
|
ß-cell Response Measured by Hyperglycemic Clamp
ACPRmax
|
4.61 nmol/L
Interval 2.0 to 10.66
|
4.32 nmol/L
Interval 1.58 to 11.8
|
4.45 nmol/L
Interval 1.56 to 12.71
|
4.58 nmol/L
Interval 2.21 to 9.48
|
PRIMARY outcome
Timeframe: 3-months after a medication washoutPopulation: All participants with a Month 15 visit
Clamp measure of insulin sensitivity
Outcome measures
| Measure |
Metformin Alone
n=56 Participants
Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). Participants randomized to the metformin-alone arm will be blinded to treatment.
Metformin: Titrated to 1000 mg BID
|
Glargine Followed by Metformin
n=65 Participants
Basal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 80-90 mg/dl, followed by open-label metformin (titrated up to 2000 mg/day) for 9 months.
Metformin: Titrated to 1000 mg BID
Glargine: Titrated to target fasting glucose \<90 mg/dl
|
Placebo
n=58 Participants
Placebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin.
Placebo: Matching to metformin 1000 mg BI
|
Liraglutide + Metformin
n=53 Participants
Liraglutide + open-label Metformin. Liraglutide will be titrated to the maximum dose tolerated (up to 1.8 mg/day) after which metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day).
Metformin: Titrated to 1000 mg BID
Liraglutide: Titrated to 1.8 mg/day
|
|---|---|---|---|---|
|
Insulin Sensitivity, M/I
|
3.53 x 10-5 mmol/kg/min per pmol/L
Interval 0.67 to 18.49
|
3.38 x 10-5 mmol/kg/min per pmol/L
Interval 0.61 to 18.84
|
3.63 x 10-5 mmol/kg/min per pmol/L
Interval 0.95 to 13.84
|
3.49 x 10-5 mmol/kg/min per pmol/L
Interval 0.9 to 13.54
|
SECONDARY outcome
Timeframe: 3-months after a medication washoutPopulation: Analysis was on all participants able to have a M15 visit.
First phase response from the hyperglycemic clamp
Outcome measures
| Measure |
Metformin Alone
n=56 Participants
Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). Participants randomized to the metformin-alone arm will be blinded to treatment.
Metformin: Titrated to 1000 mg BID
|
Glargine Followed by Metformin
n=65 Participants
Basal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 80-90 mg/dl, followed by open-label metformin (titrated up to 2000 mg/day) for 9 months.
Metformin: Titrated to 1000 mg BID
Glargine: Titrated to target fasting glucose \<90 mg/dl
|
Placebo
n=58 Participants
Placebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin.
Placebo: Matching to metformin 1000 mg BI
|
Liraglutide + Metformin
n=53 Participants
Liraglutide + open-label Metformin. Liraglutide will be titrated to the maximum dose tolerated (up to 1.8 mg/day) after which metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day).
Metformin: Titrated to 1000 mg BID
Liraglutide: Titrated to 1.8 mg/day
|
|---|---|---|---|---|
|
ACPRg
|
1.68 nmol/L
Interval 0.84 to 3.34
|
1.68 nmol/L
Interval 0.91 to 3.09
|
1.68 nmol/L
Interval 0.86 to 3.26
|
1.68 nmol/L
Interval 0.99 to 2.83
|
SECONDARY outcome
Timeframe: Secondary analysis was on all participants with a Month 12 visit.Population: Secondary analysis was on all participants with a Month 12 visit.
Participants had 12-months of active therapy. Secondary results at the end of active intervention.
Outcome measures
| Measure |
Metformin Alone
n=56 Participants
Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). Participants randomized to the metformin-alone arm will be blinded to treatment.
Metformin: Titrated to 1000 mg BID
|
Glargine Followed by Metformin
n=65 Participants
Basal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 80-90 mg/dl, followed by open-label metformin (titrated up to 2000 mg/day) for 9 months.
Metformin: Titrated to 1000 mg BID
Glargine: Titrated to target fasting glucose \<90 mg/dl
|
Placebo
n=58 Participants
Placebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin.
Placebo: Matching to metformin 1000 mg BI
|
Liraglutide + Metformin
n=53 Participants
Liraglutide + open-label Metformin. Liraglutide will be titrated to the maximum dose tolerated (up to 1.8 mg/day) after which metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day).
Metformin: Titrated to 1000 mg BID
Liraglutide: Titrated to 1.8 mg/day
|
|---|---|---|---|---|
|
ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12
ACRPg
|
1.93 nmol/L
Interval 1.09 to 3.4
|
1.88 nmol/L
Interval 1.06 to 3.22
|
1.69 nmol/L
Interval 0.89 to 3.22
|
2.68 nmol/L
Interval 1.28 to 5.6
|
|
ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12
Steady State C-peptide
|
11.7 nmol/L
Interval 5.6 to 24.3
|
11.6 nmol/L
Interval 5.6 to 24.3
|
10.8 nmol/L
Interval 5.1 to 22.7
|
21.2 nmol/L
Interval 9.3 to 48.3
|
|
ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12
ACRPmax
|
13.4 nmol/L
Interval 5.9 to 30.7
|
14.1 nmol/L
Interval 5.8 to 34.3
|
13.6 nmol/L
Interval 5.1 to 36.1
|
10.1 nmol/L
Interval 3.5 to 28.5
|
Adverse Events
Metformin Alone
Serious events: 5 serious events
Other events: 29 other events
Deaths: 0 deaths
Glargine Followed by Metformin
Serious events: 2 serious events
Other events: 28 other events
Deaths: 0 deaths
Placebo
Serious events: 3 serious events
Other events: 23 other events
Deaths: 0 deaths
Liraglutide + Metformin
Serious events: 7 serious events
Other events: 30 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Metformin Alone
n=65 participants at risk
Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). Participants randomized to the metformin-alone arm will be blinded to treatment.
Metformin: Titrated to 1000 mg BID
|
Glargine Followed by Metformin
n=67 participants at risk
Basal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 80-90 mg/dl, followed by open-label metformin (titrated up to 2000 mg/day) for 9 months.
Metformin: Titrated to 1000 mg BID
Glargine: Titrated to target fasting glucose \<90 mg/dl
|
Placebo
n=67 participants at risk
Placebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin.
Placebo: Matching to metformin 1000 mg BI
|
Liraglutide + Metformin
n=68 participants at risk
Liraglutide + open-label Metformin. Liraglutide will be titrated to the maximum dose tolerated (up to 1.8 mg/day) after which metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day).
Metformin: Titrated to 1000 mg BID
Liraglutide: Titrated to 1.8 mg/day
|
|---|---|---|---|---|
|
Cardiac disorders
Chest pain
|
0.00%
0/65 • 15 months
|
3.0%
2/67 • Number of events 3 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/68 • 15 months
|
|
Renal and urinary disorders
Kidney Stone
|
0.00%
0/65 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/67 • 15 months
|
1.5%
1/68 • Number of events 1 • 15 months
|
|
Nervous system disorders
Spinal decompression
|
0.00%
0/65 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/67 • 15 months
|
1.5%
1/68 • Number of events 1 • 15 months
|
|
Nervous system disorders
Vertigo
|
0.00%
0/65 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/67 • 15 months
|
1.5%
1/68 • Number of events 1 • 15 months
|
|
Musculoskeletal and connective tissue disorders
Head injury
|
0.00%
0/65 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/67 • 15 months
|
1.5%
1/68 • Number of events 1 • 15 months
|
|
Gastrointestinal disorders
Cholelithiasis
|
0.00%
0/65 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/67 • 15 months
|
1.5%
1/68 • Number of events 1 • 15 months
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
0.00%
0/65 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/67 • 15 months
|
1.5%
1/68 • Number of events 1 • 15 months
|
|
Infections and infestations
Sepsis
|
0.00%
0/65 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/67 • 15 months
|
1.5%
1/68 • Number of events 1 • 15 months
|
|
Musculoskeletal and connective tissue disorders
Arthroplasty
|
1.5%
1/65 • Number of events 1 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/68 • 15 months
|
|
Injury, poisoning and procedural complications
Food poisoning
|
1.5%
1/65 • Number of events 1 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/68 • 15 months
|
|
Infections and infestations
Infection
|
1.5%
1/65 • Number of events 1 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/68 • 15 months
|
|
Ear and labyrinth disorders
Earache
|
1.5%
1/65 • Number of events 1 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/68 • 15 months
|
|
Musculoskeletal and connective tissue disorders
Carpal tunnel
|
1.5%
1/65 • Number of events 1 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/67 • 15 months
|
0.00%
0/68 • 15 months
|
|
Musculoskeletal and connective tissue disorders
Reduced ability to walk
|
0.00%
0/65 • 15 months
|
0.00%
0/67 • 15 months
|
1.5%
1/67 • Number of events 1 • 15 months
|
0.00%
0/68 • 15 months
|
|
Respiratory, thoracic and mediastinal disorders
Asthma
|
0.00%
0/65 • 15 months
|
0.00%
0/67 • 15 months
|
1.5%
1/67 • Number of events 1 • 15 months
|
0.00%
0/68 • 15 months
|
|
Musculoskeletal and connective tissue disorders
Arthritis
|
0.00%
0/65 • 15 months
|
0.00%
0/67 • 15 months
|
1.5%
1/67 • Number of events 1 • 15 months
|
0.00%
0/68 • 15 months
|
Other adverse events
| Measure |
Metformin Alone
n=65 participants at risk
Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). Participants randomized to the metformin-alone arm will be blinded to treatment.
Metformin: Titrated to 1000 mg BID
|
Glargine Followed by Metformin
n=67 participants at risk
Basal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 80-90 mg/dl, followed by open-label metformin (titrated up to 2000 mg/day) for 9 months.
Metformin: Titrated to 1000 mg BID
Glargine: Titrated to target fasting glucose \<90 mg/dl
|
Placebo
n=67 participants at risk
Placebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin.
Placebo: Matching to metformin 1000 mg BI
|
Liraglutide + Metformin
n=68 participants at risk
Liraglutide + open-label Metformin. Liraglutide will be titrated to the maximum dose tolerated (up to 1.8 mg/day) after which metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day).
Metformin: Titrated to 1000 mg BID
Liraglutide: Titrated to 1.8 mg/day
|
|---|---|---|---|---|
|
Endocrine disorders
Any low blood sugar
|
4.6%
3/65 • Number of events 3 • 15 months
|
11.9%
8/67 • Number of events 8 • 15 months
|
7.5%
5/67 • Number of events 5 • 15 months
|
1.5%
1/68 • Number of events 1 • 15 months
|
|
Skin and subcutaneous tissue disorders
Skin rash
|
4.6%
3/65 • Number of events 3 • 15 months
|
9.0%
6/67 • Number of events 6 • 15 months
|
6.0%
4/67 • Number of events 4 • 15 months
|
1.5%
1/68 • Number of events 1 • 15 months
|
|
Gastrointestinal disorders
GI Symptoms
|
35.4%
23/65 • Number of events 23 • 15 months
|
17.9%
12/67 • Number of events 12 • 15 months
|
14.9%
10/67 • Number of events 10 • 15 months
|
41.2%
28/68 • Number of events 28 • 15 months
|
|
Endocrine disorders
Diabetes symptoms
|
0.00%
0/65 • 15 months
|
3.0%
2/67 • Number of events 2 • 15 months
|
6.0%
4/67 • Number of events 4 • 15 months
|
0.00%
0/68 • 15 months
|
Additional Information
Sharon Edelstein, Lead Research Scientist
George Washington University Biostatistics Center
Phone: 301-881-9260
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place