Trial Outcomes & Findings for RISE Pediatric Medication Study (NCT NCT01779375)

NCT ID: NCT01779375

Last Updated: 2023-04-14

Results Overview

Clamp measures of ß-cell response, co-primary outcomes

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 91 participants
• Primary outcome timeframe: 3-months after medication washout (Month 15)
• Results posted on: 2023-04-14

Participant Flow

Participant milestones

Measure	Metformin Alone Metformin was titrated beginning at 500 mg/day to the maximum dose tolerated (up to 2000 mg/day).	Glargine Followed by Metformin Basal insulin glargine was titrated to achieve a morning fasting blood glucose of 85-95 mg/dl and continued through 3 months after which metformin was titrated as in the Metformin alone arm and continued for 9 months.
Overall Study STARTED	47	44
Overall Study COMPLETED	45	41
Overall Study NOT COMPLETED	2	3

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

RISE Pediatric Medication Study

Baseline characteristics by cohort

Measure	Metformin Alone n=47 Participants Metformin was titrated beginning at 500 mg/day to the maximum dose tolerated (up to 2000 mg/day).	Glargine Followed by Metformin n=44 Participants Basal insulin glargine was titrated to achieve a morning fasting blood glucose of 85-95 mg/dl and continued through 3 months after which metformin was titrated as in the Metformin alone arm and continued for 9 months.	Total n=91 Participants Total of all reporting groups
Age, Categorical <=18 years	47 Participants n=5 Participants	42 Participants n=7 Participants	89 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	13.9 Years STANDARD_DEVIATION 2.1 • n=5 Participants	14.9 Years STANDARD_DEVIATION 2.0 • n=7 Participants	14.4 Years STANDARD_DEVIATION 2.1 • n=5 Participants
Sex: Female, Male Female	38 Participants n=5 Participants	27 Participants n=7 Participants	65 Participants n=5 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	17 Participants n=7 Participants	26 Participants n=5 Participants
Race/Ethnicity, Customized Non-hispanic white	12 Participants n=5 Participants	13 Participants n=7 Participants	25 Participants n=5 Participants
Race/Ethnicity, Customized Black	9 Participants n=5 Participants	14 Participants n=7 Participants	23 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	20 Participants n=5 Participants	14 Participants n=7 Participants	34 Participants n=5 Participants
Race/Ethnicity, Customized All othe	6 Participants n=5 Participants	3 Participants n=7 Participants	9 Participants n=5 Participants
BMI	36.9 kg/m^2 STANDARD_DEVIATION 6.4 • n=5 Participants	36.5 kg/m^2 STANDARD_DEVIATION 6.4 • n=7 Participants	36.7 kg/m^2 STANDARD_DEVIATION 6.4 • n=5 Participants
HbA1c	5.7 % of glycosylated hemoglobin STANDARD_DEVIATION 0.6 • n=5 Participants	5.7 % of glycosylated hemoglobin STANDARD_DEVIATION 0.6 • n=7 Participants	5.7 % of glycosylated hemoglobin STANDARD_DEVIATION 0.6 • n=5 Participants
Fasting glucose	109.2 mg/dl STANDARD_DEVIATION 19.7 • n=5 Participants	107.5 mg/dl STANDARD_DEVIATION 14.1 • n=7 Participants	108.3 mg/dl STANDARD_DEVIATION 17.1 • n=5 Participants
2-hour OGTT glucose	184.2 mg/dl STANDARD_DEVIATION 50.2 • n=5 Participants	183.5 mg/dl STANDARD_DEVIATION 44.5 • n=7 Participants	183.9 mg/dl STANDARD_DEVIATION 47.3 • n=5 Participants

PRIMARY outcome

Timeframe: 3-months after medication washout (Month 15)

Population: Primary analysis was on all participants able to have a M15 visit. 2 participants in the metformin alone arm decompensated at M12 and were unable to remain off treatment until M15. A sensitivity analysis including these 2 participants using 1/2 of the worst value among all other participants did not alter the results.

Clamp measures of ß-cell response, co-primary outcomes

Outcome measures

Measure	Metformin Alone n=43 Participants Metformin was titrated beginning at 500 mg/day to the maximum dose tolerated (up to 2000 mg/day).	Glargine Followed by Metformin n=41 Participants Basal insulin glargine was titrated to achieve a morning fasting blood glucose of 85-95 mg/dl and continued through 3 months after which metformin was titrated as in the Metformin alone arm and continued for 9 months.
ß-cell Response Measured by Hyperglycemic Clamp Steady State C-peptide	4.82 nmol/L Interval 2.07 to 11.23	4.18 nmol/L Interval 1.74 to 10.08
ß-cell Response Measured by Hyperglycemic Clamp ACPRmax	6.92 nmol/L Interval 2.81 to 17.03	5.95 nmol/L Interval 2.17 to 16.37

PRIMARY outcome

Timeframe: 3-months after a medication washout

Population: All participants with a Month 15 visit

Clamp measure of insulin sensitivity

Outcome measures

Measure	Metformin Alone n=43 Participants Metformin was titrated beginning at 500 mg/day to the maximum dose tolerated (up to 2000 mg/day).	Glargine Followed by Metformin n=41 Participants Basal insulin glargine was titrated to achieve a morning fasting blood glucose of 85-95 mg/dl and continued through 3 months after which metformin was titrated as in the Metformin alone arm and continued for 9 months.
M/I	1.48 x 10-5 mmol/kg/min per pmol/L Interval 0.29 to 7.63	1.70 x 10-5 mmol/kg/min per pmol/L Interval 0.25 to 11.54

SECONDARY outcome

Timeframe: 3-months after a medication washout

Population: Primary analysis was on all participants able to have a M15 visit.

First phase response

Outcome measures

Measure	Metformin Alone n=43 Participants Metformin was titrated beginning at 500 mg/day to the maximum dose tolerated (up to 2000 mg/day).	Glargine Followed by Metformin n=41 Participants Basal insulin glargine was titrated to achieve a morning fasting blood glucose of 85-95 mg/dl and continued through 3 months after which metformin was titrated as in the Metformin alone arm and continued for 9 months.
ACPRg	1.11 nmol/L Interval 0.14 to 8.56	1.12 nmol/L Interval 0.15 to 8.35

SECONDARY outcome

Timeframe: End of active intervention (Month 12).

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=45 Participants Metformin was titrated beginning at 500 mg/day to the maximum dose tolerated (up to 2000 mg/day).	Glargine Followed by Metformin n=41 Participants Basal insulin glargine was titrated to achieve a morning fasting blood glucose of 85-95 mg/dl and continued through 3 months after which metformin was titrated as in the Metformin alone arm and continued for 9 months.
ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 Steady State C-peptide	4.78 nmol/L Interval 2.09 to 10.94	4.37 nmol/L Interval 1.75 to 10.94
ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 ACPRmax	6.95 nmol/L Interval 3.16 to 15.28	5.79 nmol/L Interval 2.49 to 13.46
ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 ACPRg	1.06 nmol/L Interval 0.1 to 11.33	1.03 nmol/L Interval 0.05 to 21.73

SECONDARY outcome

Timeframe: End of active intervention (Month 12)

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=45 Participants Metformin was titrated beginning at 500 mg/day to the maximum dose tolerated (up to 2000 mg/day).	Glargine Followed by Metformin n=41 Participants Basal insulin glargine was titrated to achieve a morning fasting blood glucose of 85-95 mg/dl and continued through 3 months after which metformin was titrated as in the Metformin alone arm and continued for 9 months.
Clamp Measure of Insulin Sensitivity	1.52 x 10-5 mmol/kg/min per pmol/L Interval 0.17 to 13.48	1.93 x 10-5 mmol/kg/min per pmol/L Interval 0.3 to 12.5

OTHER_PRE_SPECIFIED outcome

Timeframe: After 12 months of active treatment, and 3 and 9 months of washout

Measures derived the OGTT at the end of the 12 month active intervention period, and following a 3-month and 9-month washout.

Outcome measures

Outcome data not reported

Adverse Events

Metformin Alone

Serious events: 5 serious events

Other events: 30 other events

Deaths: 0 deaths

Glargine Followed by Metformin

Serious events: 2 serious events

Other events: 30 other events

Deaths: 0 deaths

Serious adverse events

Measure	Metformin Alone n=47 participants at risk Metformin was titrated beginning at 500 mg/day to the maximum dose tolerated (up to 2000 mg/day).	Glargine Followed by Metformin n=44 participants at risk Basal insulin glargine was titrated to achieve a morning fasting blood glucose of 85-95 mg/dl and continued through 3 months after which metformin was titrated as in the Metformin alone arm and continued for 9 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer	0.00% 0/47 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit	2.3% 1/44 • Number of events 1 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit
Psychiatric disorders Mental health hospitalization	2.1% 1/47 • Number of events 1 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit	0.00% 0/44 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit
General disorders Appendicitis	0.00% 0/47 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit	2.3% 1/44 • Number of events 1 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit
Ear and labyrinth disorders Otitis externa	2.1% 1/47 • Number of events 1 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit	0.00% 0/44 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit
Ear and labyrinth disorders Tonsillectomy & Adenoidectomy	4.3% 2/47 • Number of events 2 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit	0.00% 0/44 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit
Infections and infestations Pnemonia	2.1% 1/47 • Number of events 1 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit	0.00% 0/44 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit

Other adverse events

Measure	Metformin Alone n=47 participants at risk Metformin was titrated beginning at 500 mg/day to the maximum dose tolerated (up to 2000 mg/day).	Glargine Followed by Metformin n=44 participants at risk Basal insulin glargine was titrated to achieve a morning fasting blood glucose of 85-95 mg/dl and continued through 3 months after which metformin was titrated as in the Metformin alone arm and continued for 9 months.
Endocrine disorders Low blood sugar	0.00% 0/47 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit	36.4% 16/44 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit
Skin and subcutaneous tissue disorders Skin rash	12.8% 6/47 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit	13.6% 6/44 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit
Gastrointestinal disorders GI Discomfort	34.0% 16/47 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit	38.6% 17/44 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit
Endocrine disorders Polyuria or polydipsia	23.4% 11/47 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit	25.0% 11/44 • Throughout the 21 month study period AEs were captured at quarterly clinical visits and SAEs were captured as they occur or when reported at a subsequent clinical visit

Additional Information

Sharon Edelstein

George Washington University Biostatistics Center

Phone: 3018819260

Email: sharone@bsc.gwu.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place