Trial Outcomes & Findings for Metformin for Overweight & OBese ChILdren and Adolescents With BDS Treated With SGAs (NCT NCT02515773)

Last Updated: 2025-01-14

Results Overview

Raw body mass index (BMI) is calculated as (weight(kg)/ height(m)2). This raw BMI value is converted to a normalized BMI z-score, adjusted for age and sex using US Centers for Disease Control and Prevention growth charts. A z-score equal to 0 indicates the population mean and larger z-scores are heavier weights and worse outcomes.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

1565 participants

Primary outcome timeframe

Baseline to Month 6

Results posted on

2025-01-14

Participant Flow

1633 participants were screened. 68 did not meet criteria. Of the 1565 randomized patients, 228 patients did not have a visit after baseline and 38 patients, in the MET+LIFE group, did not start metformin per protocol by study day 137 post-randomization. These 266 patients were not included in the modified intent-to-treat (ITT) sample and results, giving an ITT sample size of 1299.

Participant milestones

Participant milestones
Measure	MET and LIFE Participants randomized to this group will receive both Metformin and lifestyle intervention.Participants randomized to treatment with MET will start at a dose of 500 mg orally at night and slowly titrated in 2-week intervals to ensure that each patient achieves maximum insulin-sensitizing effects of the drug while minimizing the chance of side effects. Investigators will also recommend that MET be taken with food to minimize side effects. If a participant's BMI percentile \<5% (=underweight) his/her treatment with MET will be discontinued. Although the risk of low vitamin B12 while taking MET is associated with age \> 50 years and having type II diabetes, Investigator will monitor B12 levels and a CBC throughout study participation. Metformin: Metformin - to achieves maximum insulin-sensitizing effects healthy lifestyle intervention (LIFE): Healthy Life style intervention	Healthy Lifestyle Intervention (LIFE) Participants randomized to this group will receive just lifestyle intervention alone.This healthy lifestyle intervention (LIFE) consists of counseling participants and families regarding a healthy eating plan, physical activity and sedentary activities. Prior to study initiation, clinical site staff will participate in a live (or taped) training session from a dietician to lean to administer LIFE. A trained site staff member (e.g. medical assistant or case manager) will meet with participants and their families for a 15-20 minute session at baseline that will focus on nutritional issues using the Traffic Light Plan (TLP). healthy lifestyle intervention (LIFE): Healthy Life style intervention
Overall Study STARTED	579	720
Overall Study Followed Randomized Treatment (Per-protocol Sample)	558	686
Overall Study COMPLETED	360	454
Overall Study NOT COMPLETED	219	266

Reasons for withdrawal

Reasons for withdrawal
Measure	MET and LIFE Participants randomized to this group will receive both Metformin and lifestyle intervention.Participants randomized to treatment with MET will start at a dose of 500 mg orally at night and slowly titrated in 2-week intervals to ensure that each patient achieves maximum insulin-sensitizing effects of the drug while minimizing the chance of side effects. Investigators will also recommend that MET be taken with food to minimize side effects. If a participant's BMI percentile \<5% (=underweight) his/her treatment with MET will be discontinued. Although the risk of low vitamin B12 while taking MET is associated with age \> 50 years and having type II diabetes, Investigator will monitor B12 levels and a CBC throughout study participation. Metformin: Metformin - to achieves maximum insulin-sensitizing effects healthy lifestyle intervention (LIFE): Healthy Life style intervention	Healthy Lifestyle Intervention (LIFE) Participants randomized to this group will receive just lifestyle intervention alone.This healthy lifestyle intervention (LIFE) consists of counseling participants and families regarding a healthy eating plan, physical activity and sedentary activities. Prior to study initiation, clinical site staff will participate in a live (or taped) training session from a dietician to lean to administer LIFE. A trained site staff member (e.g. medical assistant or case manager) will meet with participants and their families for a 15-20 minute session at baseline that will focus on nutritional issues using the Traffic Light Plan (TLP). healthy lifestyle intervention (LIFE): Healthy Life style intervention
Overall Study Withdrawal by Subject	12	2
Overall Study Lost to Follow-up	119	126
Overall Study Discharged from Clinic Services	53	84
Overall Study Censored (study ended before participant could complete)	18	24
Overall Study Follow-up at non-study site	8	16
Overall Study Moved from area	9	14

Baseline Characteristics

Metformin for Overweight & OBese ChILdren and Adolescents With BDS Treated With SGAs

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	MET and LIFE n=579 Participants Participants randomized to this group will receive both Metformin and lifestyle intervention.Participants randomized to treatment with MET will start at a dose of 500 mg orally at night and slowly titrated in 2-week intervals to ensure that each patient achieves maximum insulin-sensitizing effects of the drug while minimizing the chance of side effects. Investigators will also recommend that MET be taken with food to minimize side effects. If a participant's BMI percentile \<5% (=underweight) his/her treatment with MET will be discontinued. Although the risk of low vitamin B12 while taking MET is associated with age \> 50 years and having type II diabetes, Investigator will monitor B12 levels and a CBC throughout study participation. Metformin: Metformin - to achieves maximum insulin-sensitizing effects healthy lifestyle intervention (LIFE): Healthy Life style intervention	Healthy Lifestyle Intervention (LIFE) n=720 Participants Participants randomized to this group will receive just lifestyle intervention alone.This healthy lifestyle intervention (LIFE) consists of counseling participants and families regarding a healthy eating plan, physical activity and sedentary activities. Prior to study initiation, clinical site staff will participate in a live (or taped) training session from a dietician to lean to administer LIFE. A trained site staff member (e.g. medical assistant or case manager) will meet with participants and their families for a 15-20 minute session at baseline that will focus on nutritional issues using the Traffic Light Plan (TLP). healthy lifestyle intervention (LIFE): Healthy Life style intervention	Total n=1299 Participants Total of all reporting groups
Age, Continuous	14.0 Years STANDARD_DEVIATION 2.8 • n=5 Participants	13.8 Years STANDARD_DEVIATION 2.9 • n=7 Participants	13.9 Years STANDARD_DEVIATION 2.9 • n=5 Participants
Sex: Female, Male Female	273 Participants n=5 Participants	341 Participants n=7 Participants	614 Participants n=5 Participants
Sex: Female, Male Male	306 Participants n=5 Participants	379 Participants n=7 Participants	685 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	60 Participants n=5 Participants	96 Participants n=7 Participants	156 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	517 Participants n=5 Participants	624 Participants n=7 Participants	1141 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) Asian	11 Participants n=5 Participants	13 Participants n=7 Participants	24 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Black or African American	98 Participants n=5 Participants	124 Participants n=7 Participants	222 Participants n=5 Participants
Race (NIH/OMB) White	399 Participants n=5 Participants	472 Participants n=7 Participants	871 Participants n=5 Participants
Race (NIH/OMB) More than one race	50 Participants n=5 Participants	78 Participants n=7 Participants	128 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	17 Participants n=5 Participants	29 Participants n=7 Participants	46 Participants n=5 Participants
BMI Z-Score	1.90 Z-score STANDARD_DEVIATION 0.48 • n=5 Participants	1.85 Z-score STANDARD_DEVIATION 0.46 • n=7 Participants	1.87 Z-score STANDARD_DEVIATION 0.47 • n=5 Participants
Obesity	385 Participants n=5 Participants	474 Participants n=7 Participants	859 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to Month 6

Population: Modified intention-to-treat (ITT) sample consisting of patients who initiated randomized treatment and had at least one post-baseline assessment.

Outcome measures

Outcome measures
Measure	MET and LIFE n=565 Participants Participants randomized to this group will receive both Metformin and lifestyle intervention.Participants randomized to treatment with MET will start at a dose of 500 mg orally at night and slowly titrated in 2-week intervals to ensure that each patient achieves maximum insulin-sensitizing effects of the drug while minimizing the chance of side effects. Investigators will also recommend that MET be taken with food to minimize side effects. If a participant's BMI percentile \<5% (=underweight) his/her treatment with MET will be discontinued. Although the risk of low vitamin B12 while taking MET is associated with age \> 50 years and having type II diabetes, Investigator will monitor B12 levels and a CBC throughout study participation. Metformin: Metformin - to achieves maximum insulin-sensitizing effects healthy lifestyle intervention (LIFE): Healthy Life style intervention	Healthy Lifestyle Intervention (LIFE) n=687 Participants Participants randomized to this group will receive just lifestyle intervention alone.This healthy lifestyle intervention (LIFE) consists of counseling participants and families regarding a healthy eating plan, physical activity and sedentary activities. Prior to study initiation, clinical site staff will participate in a live (or taped) training session from a dietician to lean to administer LIFE. A trained site staff member (e.g. medical assistant or case manager) will meet with participants and their families for a 15-20 minute session at baseline that will focus on nutritional issues using the Traffic Light Plan (TLP). healthy lifestyle intervention (LIFE): Healthy Life style intervention
Change in BMI Z-score From Baseline to Month 6 in ITT Sample	-0.08 Z-score Standard Deviation 0.29	0.00 Z-score Standard Deviation 0.29

PRIMARY outcome

Timeframe: Baseline to Month 24

Population: Modified intention-to-treat (ITT) sample consisting of patients who initiated randomized treatment and had at least one post-baseline assessment.

Outcome measures

Outcome measures
Measure	MET and LIFE n=579 Participants Participants randomized to this group will receive both Metformin and lifestyle intervention.Participants randomized to treatment with MET will start at a dose of 500 mg orally at night and slowly titrated in 2-week intervals to ensure that each patient achieves maximum insulin-sensitizing effects of the drug while minimizing the chance of side effects. Investigators will also recommend that MET be taken with food to minimize side effects. If a participant's BMI percentile \<5% (=underweight) his/her treatment with MET will be discontinued. Although the risk of low vitamin B12 while taking MET is associated with age \> 50 years and having type II diabetes, Investigator will monitor B12 levels and a CBC throughout study participation. Metformin: Metformin - to achieves maximum insulin-sensitizing effects healthy lifestyle intervention (LIFE): Healthy Life style intervention	Healthy Lifestyle Intervention (LIFE) n=720 Participants Participants randomized to this group will receive just lifestyle intervention alone.This healthy lifestyle intervention (LIFE) consists of counseling participants and families regarding a healthy eating plan, physical activity and sedentary activities. Prior to study initiation, clinical site staff will participate in a live (or taped) training session from a dietician to lean to administer LIFE. A trained site staff member (e.g. medical assistant or case manager) will meet with participants and their families for a 15-20 minute session at baseline that will focus on nutritional issues using the Traffic Light Plan (TLP). healthy lifestyle intervention (LIFE): Healthy Life style intervention
Change in BMI Z-score From Baseline to Month 24 in ITT Sample	-0.19 Z-score Standard Deviation 1.00	-0.11 Z-score Standard Deviation 0.87

PRIMARY outcome

Timeframe: Baseline to Month 6

Population: Per protocol sample consisting of patients who had continuously followed their randomized treatment through month 6

Outcome measures

Outcome measures
Measure	MET and LIFE n=547 Participants Participants randomized to this group will receive both Metformin and lifestyle intervention.Participants randomized to treatment with MET will start at a dose of 500 mg orally at night and slowly titrated in 2-week intervals to ensure that each patient achieves maximum insulin-sensitizing effects of the drug while minimizing the chance of side effects. Investigators will also recommend that MET be taken with food to minimize side effects. If a participant's BMI percentile \<5% (=underweight) his/her treatment with MET will be discontinued. Although the risk of low vitamin B12 while taking MET is associated with age \> 50 years and having type II diabetes, Investigator will monitor B12 levels and a CBC throughout study participation. Metformin: Metformin - to achieves maximum insulin-sensitizing effects healthy lifestyle intervention (LIFE): Healthy Life style intervention	Healthy Lifestyle Intervention (LIFE) n=656 Participants Participants randomized to this group will receive just lifestyle intervention alone.This healthy lifestyle intervention (LIFE) consists of counseling participants and families regarding a healthy eating plan, physical activity and sedentary activities. Prior to study initiation, clinical site staff will participate in a live (or taped) training session from a dietician to lean to administer LIFE. A trained site staff member (e.g. medical assistant or case manager) will meet with participants and their families for a 15-20 minute session at baseline that will focus on nutritional issues using the Traffic Light Plan (TLP). healthy lifestyle intervention (LIFE): Healthy Life style intervention
Change in BMI Z-score From Baseline to Month 6 in Per Protocol Sample	-0.09 Z-score Standard Deviation 0.46	0.00 Z-score Standard Deviation 0.42

PRIMARY outcome

Timeframe: Baseline to Month 24

Population: Per protocol sample consisting of patients who had continuously followed their randomized treatment through month 24

Outcome measures

Outcome measures
Measure	MET and LIFE n=558 Participants Participants randomized to this group will receive both Metformin and lifestyle intervention.Participants randomized to treatment with MET will start at a dose of 500 mg orally at night and slowly titrated in 2-week intervals to ensure that each patient achieves maximum insulin-sensitizing effects of the drug while minimizing the chance of side effects. Investigators will also recommend that MET be taken with food to minimize side effects. If a participant's BMI percentile \<5% (=underweight) his/her treatment with MET will be discontinued. Although the risk of low vitamin B12 while taking MET is associated with age \> 50 years and having type II diabetes, Investigator will monitor B12 levels and a CBC throughout study participation. Metformin: Metformin - to achieves maximum insulin-sensitizing effects healthy lifestyle intervention (LIFE): Healthy Life style intervention	Healthy Lifestyle Intervention (LIFE) n=686 Participants Participants randomized to this group will receive just lifestyle intervention alone.This healthy lifestyle intervention (LIFE) consists of counseling participants and families regarding a healthy eating plan, physical activity and sedentary activities. Prior to study initiation, clinical site staff will participate in a live (or taped) training session from a dietician to lean to administer LIFE. A trained site staff member (e.g. medical assistant or case manager) will meet with participants and their families for a 15-20 minute session at baseline that will focus on nutritional issues using the Traffic Light Plan (TLP). healthy lifestyle intervention (LIFE): Healthy Life style intervention
Change in BMI Z-score From Baseline to Month 24 in Per Protocol Sample	-0.21 Z-score Standard Deviation 1.11	-0.12 Z-score Standard Deviation 1.01

Adverse Events

MET and LIFE

Serious events: 12 serious events

Other events: 352 other events

Deaths: 0 deaths

Healthy Lifestyle Intervention (LIFE)

Serious events: 25 serious events

Other events: 339 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	MET and LIFE n=558 participants at risk；n=579 participants at risk Participants randomized to this group will receive both Metformin and lifestyle intervention.Participants randomized to treatment with MET will start at a dose of 500 mg orally at night and slowly titrated in 2-week intervals to ensure that each patient achieves maximum insulin-sensitizing effects of the drug while minimizing the chance of side effects. Investigators will also recommend that MET be taken with food to minimize side effects. If a participant's BMI percentile \<5% (=underweight) his/her treatment with MET will be discontinued. Although the risk of low vitamin B12 while taking MET is associated with age \> 50 years and having type II diabetes, Investigator will monitor B12 levels and a CBC throughout study participation. Metformin: Metformin - to achieves maximum insulin-sensitizing effects healthy lifestyle intervention (LIFE): Healthy Life style intervention	Healthy Lifestyle Intervention (LIFE) n=686 participants at risk；n=720 participants at risk Participants randomized to this group will receive just lifestyle intervention alone.This healthy lifestyle intervention (LIFE) consists of counseling participants and families regarding a healthy eating plan, physical activity and sedentary activities. Prior to study initiation, clinical site staff will participate in a live (or taped) training session from a dietician to lean to administer LIFE. A trained site staff member (e.g. medical assistant or case manager) will meet with participants and their families for a 15-20 minute session at baseline that will focus on nutritional issues using the Traffic Light Plan (TLP). healthy lifestyle intervention (LIFE): Healthy Life style intervention
Gastrointestinal disorders Nausea	21.0% 117/558 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	10.1% 69/686 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
Gastrointestinal disorders Diarrhea	18.8% 105/558 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	5.8% 40/686 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
Gastrointestinal disorders Vomiting	12.5% 70/558 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	4.7% 32/686 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
Gastrointestinal disorders Stomach Cramps	19.7% 110/558 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	8.3% 57/686 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
Gastrointestinal disorders Flatulence	14.9% 83/558 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	7.7% 53/686 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders Increased Appetite	10.0% 56/558 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	13.3% 91/686 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders Sedation	3.6% 20/558 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	6.0% 41/686 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders Headache	4.3% 24/558 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	4.5% 31/686 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders Somnolence	2.5% 14/558 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	2.9% 20/686 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders Fatigue	2.0% 11/558 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	3.1% 21/686 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.

Additional Information

Casey Moore

University of Cincinnati

Phone: 513-558-6307

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	MET and LIFE n=558 participants at risk；n=579 participants at risk Participants randomized to this group will receive both Metformin and lifestyle intervention.Participants randomized to treatment with MET will start at a dose of 500 mg orally at night and slowly titrated in 2-week intervals to ensure that each patient achieves maximum insulin-sensitizing effects of the drug while minimizing the chance of side effects. Investigators will also recommend that MET be taken with food to minimize side effects. If a participant's BMI percentile \<5% (=underweight) his/her treatment with MET will be discontinued. Although the risk of low vitamin B12 while taking MET is associated with age \> 50 years and having type II diabetes, Investigator will monitor B12 levels and a CBC throughout study participation. Metformin: Metformin - to achieves maximum insulin-sensitizing effects healthy lifestyle intervention (LIFE): Healthy Life style intervention	Healthy Lifestyle Intervention (LIFE) n=686 participants at risk；n=720 participants at risk Participants randomized to this group will receive just lifestyle intervention alone.This healthy lifestyle intervention (LIFE) consists of counseling participants and families regarding a healthy eating plan, physical activity and sedentary activities. Prior to study initiation, clinical site staff will participate in a live (or taped) training session from a dietician to lean to administer LIFE. A trained site staff member (e.g. medical assistant or case manager) will meet with participants and their families for a 15-20 minute session at baseline that will focus on nutritional issues using the Traffic Light Plan (TLP). healthy lifestyle intervention (LIFE): Healthy Life style intervention
General disorders abdominal pain	0.86% 5/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.14% 1/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders refractory headaches	0.35% 2/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.00% 0/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders complications of tonsillectomy	0.35% 2/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.28% 2/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders neck dystonia	0.17% 1/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.00% 0/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders seizures	0.17% 1/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.28% 2/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders hypoglycemia	0.17% 1/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.00% 0/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders pneumonia	0.00% 0/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.42% 3/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders pyelonephritis	0.00% 0/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.42% 3/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders urethral/kidney stone	0.00% 0/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.42% 3/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders infection	0.00% 0/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.42% 3/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders hepatitis	0.00% 0/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.14% 1/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders allergic reaction	0.00% 0/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.28% 2/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders fractures due to motor vehicle accident	0.00% 0/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.14% 1/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders thyroidectomy	0.00% 0/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.14% 1/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders leukemia	0.00% 0/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.14% 1/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders sickle-cell crisis	0.00% 0/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.14% 1/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.
General disorders Sydenham's Chorea	0.00% 0/579 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.	0.14% 1/720 • 30 months Other non-serious adverse events are reported for the per protocol sample, consisting of patients who had followed their randomized treatment.