Cochrane Central Register of Controlled Trials (Cochrane Register of Studies)

Part I: Obesity

1. MESH DESCRIPTOR Obesity

2. MESH DESCRIPTOR Obesity, Morbid

3. MESH DESCRIPTOR Obesity, Abdominal

4. MESH DESCRIPTOR Pediatric Obesity

5. MESH DESCRIPTOR Overweight

6. MESH DESCRIPTOR Weight Loss

7. (adipos* or obes*):TI,AB,KY

8. (overweight* or over weight*):TI,AB,KY

9. (weight adj2 (reduc* or los* or control* or gain*)):TI,AB,KY

10. #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9

Part II: Anti‐obesity drugs

11. MESH DESCRIPTOR Anti‐Obesity Agents

12. MESH DESCRIPTOR Appetite Depressants

13. ((anti obes* or antiobes* or weight loss) adj3 (agent* or drug* or medicine* or pharmac*)):TI,AB,KY

14. (appetite adj3 (suppress* or depress*)):TI,AB,KY

15. ((anorexi* or anorectic*) adj3 (agent* or drug*)):TI,AB,KY

16. anorectics:TI,AB,KY

17. metformin*:TI,AB,KY

18. exenatide*:TI,AB,KY

19. liraglutid*:TI,AB,KY

20. dulaglutid*:TI,AB,KY

21. albiglutid*:TI,AB,KY

22. taspoglutid*:TI,AB,KY

23. lixisenatid*:TI,AB,KY

24. semaglutid*:TI,AB,KY

25. orlistat*:TI,AB,KY

26. cetilistat*:TI,AB,KY

27. sibutramin*:TI,AB,KY

28. fluoxetin*:TI,AB,KY

29. rimonabant*:TI,AB,KY

30. lorcaserin*:TI,AB,KY

31. benzphetamin*:TI,AB,KY

32. diethylpropion*:TI,AB,KY

33. phendimetrazin*:TI,AB,KY

34. mazindol*:TI,AB,KY

35. (phentermin* or chlorphentermin* or mephentermin*):TI,AB,KY

36. (phentermin* adj3 topiramat*):TI,AB,KY

37. (bupropion* adj3 naltrexon*):TI,AB,KY

38. (bupropion* adj3 zonisamid*):TI,AB,KY

39. beloranib*:TI,AB,KY

40. velneperit*:TI,AB,KY

41. tesofensin*:TI,AB,KY

42. #11 or #12 or #13 or #14 or #15 or#16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41

Part III: Part I + Part II

43. #10 and #42

44. MESH DESCRIPTOR Obesity WITH QUALIFIERS DT

45. MESH DESCRIPTOR Obesity, Morbid WITH QUALIFIERS DT

46. MESH DESCRIPTOR Weight Loss WITH QUALIFIERS DT

47. MESH DESCRIPTOR Overweight WITH QUALIFIERS DT

48. #43 or #44 or #45 or #46 or #47

Part IV: Population

49. MESH DESCRIPTOR Adolescent

50. MESH DESCRIPTOR Child

51. MESH DESCRIPTOR Pediatrics

52. minors:TI,AB,KY

53. (boy or boys or boyhood):TI,AB,KY

54. girl*:TI,AB,KY

55. (kid or kids):TI,AB,KY

56. (child* or schoolchild*):TI,AB,KY

57. adolescen*:TI,AB,KY

58. juvenil*:TI,AB,KY

59. youth*:TI,AB,KY

60. (teen* or preteen*):TI,AB,KY

61. (underage* or under age*):TI,AB,KY

62. pubescen*:TI,AB,KY

63. p?ediatric*:TI,AB,KY

64. #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57 or #58 or #59 or #60 or #61 or #62 or #63

Part V: Part III AND IV

65. #48 and #64

66. MESH DESCRIPTOR Pediatric Obesity WITH QUALIFIERS DT

67. #65 or #66

MEDLINE (OvidSP)

Part I: Obesity

1 Obesity/

2 Obesity, Morbid/

3 Obesity, Abdominal/

4 Pediatric Obesity/

5 Overweight/

6 Weight Loss/

7 (adipos* or obes*).tw.

8 (overweight* or over weight*).tw.

9 (weight adj2 (reduc* or los* or control* or gain*)).tw.

10 or/1‐9

Part II: Anti‐obesity drugs

11 Anti‐Obesity Agents/

12 Appetite Depressants/

13 ((anti obes* or antiobes* or weight loss) adj3 (agent* or drug* or medicine* or pharmac*)).tw.

14 (appetite adj3 (suppress* or depress*)).mp.

15 ((anorexi* or anorectic*) adj (agent* or drug*)).tw.

16 anorectics.tw.

17 metformin*.mp.

18 exenatide*.mp.

19 liraglutid*.mp.

20 dulaglutid*.mp.

21 albiglutid*.mp.

22 taspoglutid*.mp.

23 lixisenatid*.mp.

24 semaglutid*.mp.

25 orlistat*.mp.

26 cetilistat*.mp.

27 sibutramin*.mp.

28 fluoxetin*.mp.

29 rimonabant*.mp.

30 lorcaserin*.mp.

31 benzphetamin*.mp.

32 diethylpropion*.mp.

33 phendimetrazin*.mp.

34 mazindol*.mp.

35 (phentermin* or chlorphentermin* or mephentermin*).mp.

36 ((phentermin* adj3 topiramat*) or phentermine?topiramat*).mp.

37 ((bupropion* adj3 naltrexon*) or bupropion?naltrexon*).mp.

38 ((bupropion* adj3 zonisamid*) or bupropion?zonisamid*).mp.

39 beloranib*.mp.

40 velneperit*.mp.

41 tesofensin*.mp.

42 or/11‐41

Part III: Part I + Part II and additional MeSH/subheading combination

43 10 and 42

44 Obesity/dt [drug therapy]

45 Obesity, Morbid/dt [drug therapy]

46 Weight Loss/dt [drug therapy]

47 Overweight/dt [drug therapy]

48 or/43‐47

Part IV: Population [based on Leclercq 2013]

49 Adolescent/

50 Child/

51 Pediatrics/

52 minors.tw.

53 (boy or boys or boyhood).tw.

54 girl*.tw.

55 (kid or kids).tw.

56 (child* or schoolchild*).tw.

57 adolescen*.tw.

58 juvenil*.tw.

59 youth*.tw.

60 (teen* or preteen*).tw.

61 (underage* or under age*).tw.

62 pubescen*.tw.

63 p?ediatric*.tw.

64 or/49‐63

Part V: Part III AND IV and additional MeSH/subheading combination

65 48 and 64

66 Pediatric Obesity/dt

67 65 or 66

Part VI: Study filter [Cochrane Handbook 2008 RCT filter ‐ sensitivity max. version]

68 randomized controlled trial.pt.

69 controlled clinical trial.pt.

70 randomi?ed.ab.

71 placebo.ab.

72 drug therapy.fs.

73 randomly.ab.

74 trial.ab.

75 groups.ab.

76 or/68‐75

77 exp animals/ not humans/

78 76 not 77

Part VII: Part V + Part VI

79 67 and 78

Embase (OvidSP)

Part I: Obesity

1 obesity/

2 morbid obesity/

3 abdominal obesity/

4 childhood obesity/

5 weight reduction/

6 (adipos* or obes*).tw.

7 (overweight* or over weight*).tw.

8 (weight adj2 (reduc* or los* or control* or gain*)).tw.

9 or/1‐8

Part II: Anti‐obesity drugs

10 antiobesity agent/

11 anorexigenic agent/

12 ((anti obes* or antiobes* or weight loss) adj3 (agent* or drug* or medicine* or pharmac*)).tw.

13 (appetite adj3 (suppress* or depress*)).tw.

14 ((anorexi* or anorectic*) adj (agent* or drug*)).tw.

15 anorectics.tw.

16 metformin*.mp.

17 exenatide*.mp.

18 liraglutid*.mp.

19 dulaglutid*.mp.

20 albiglutid*.mp.

21 taspoglutid*.mp.

22 lixisenatid*.mp.

23 semaglutid*.mp.

24 orlistat*.mp.

25 cetilistat*.mp.

26 sibutramin*.mp.

27 fluoxetin*.mp.

28 rimonabant*.mp.

29 lorcaserin*.mp.

30 benzphetamin*.mp.

31 diethylpropion*.mp.

32 phendimetrazin*.mp.

33 mazindol*.mp.

34 (phentermin* or chlorphentermin* or mephentermin*).mp.

35 ((phentermin* adj3 topiramat*) or phentermine?topiramat*).mp.

36 ((bupropion* adj3 naltrexon*) or bupropion?naltrexon*).mp.

37 ((bupropion* adj3 zonisamid*) or bupropion?zonisamid*).mp.

38 beloranib*.mp.

39 velneperit*.mp.

40 tesofensin*.mp.

41 or/10‐40

Part III: Part I + Part II and additional MeSH/subheading combination

42 9 and 41

43 obesity/dt [drug therapy]

44 morbid obesity/dt [drug therapy]

45 weight reduction/dt [drug therapy]

46 or/42‐45

Part IV: Population [adapted from Leclercq 2013]

47 juvenile/

48 adolescent/

49 child/

50 preschool child/

51 schoolchild/

52 pediatrics/

53 minors.tw.

54 (boy or boys or boyhood).tw.

55 girl*.tw.

56 (kid or kids).tw.

57 (child* or schoolchild*).tw.

58 adolescen*.tw.

59 juvenil*.tw.

60 youth*.tw.

61 (teen* or preteen*).tw.

62 (underage* or under age*).tw.

63 pubescen*.tw.

64 p?ediatric*.tw.

65 or/47‐64

Part V: Part III AND IV and additional MeSH/subheading combination

66 46 and 65

67 childhood obesity/dt

68 66 or 67

Part VI: Study filter [ Wong 2006afilter – BS version]

69 random*.tw. or clinical trial*.mp. or exp health care quality/

Part VII: Part V + Part VI

70 68 and 69

71 limit 70 to embase

LILACS (IAHx)

((MH:"Obesity" OR MH:"Obesity, Morbid" OR MH:"Obesity, Abdominal" OR MH:"Pediatric Obesity" OR MH:"Overweight" OR MH:"Weight Loss" OR adipos$ OR obes$ OR overweight$ OR "over weight" OR sobrepes$ OR "exceso de peso" OR "excesso de peso" OR "weight reduction" OR "weight loss" OR "weight control") AND (MH:"Obesity/drug therapy" OR MH:"Obesity, Morbid/drug therapy" OR MH:"Overweight/drug therapy" OR MH:"Weight Loss/drug therapy" OR MH:"Anti‐Obesity Agents" OR MH:"Appetite Depressants" OR "farmacos antiobesidad" OR "farmacos antiobesidade" OR "depresores del apetito" OR "depressores do apetite" OR metformin$ OR exenatide$ OR liraglutid$ OR dulaglutid$ OR albiglutid$ OR taspoglutid$ OR lixisenatid$ OR semaglutid$ OR orlistat$ OR cetilistat$ OR sibutramin$ OR fluoxetin$ OR rimonabant$ OR lorcaserin$ OR benzphetamin$ OR diethylpropion$ OR phendimetrazin$ OR mazindol$ OR phentermin$ or chlorphentermin$ or mephentermin$ OR (phentermin$ AND topiramat$) OR (bupropion$ AND (naltrexon$ OR zonisamid$)) OR beloranib$ OR velneperit$ OR tesofensin$) AND (MH:"Adolescent" OR MH:"Child" OR MH:"Pediatrics" OR minors OR boy OR boys OR girl$ OR kid OR kids OR child$ OR schoolchild$ OR escolar$ OR adolescen$ OR preadolescen$ OR juvenil$ OR juventud$ OR youth$ OR teen$ OR preteen$ OR underage$ OR pubescen$ OR paediatri$ OR pediatri$ OR joven$ OR jovem$ OR niños OR niñas OR crianca$ OR menin$ OR "menor de edad" OR "menores de edad" OR "menor de idade" OR "menores de idade") OR MH:"Pediatric Obesity/drug therapy")

+ Controlled Clinical Trial

PubMed (only subsets not available on Ovid)

#1 Part I: Obesity

adipos*[tw] OR obes*[tw] OR overweight*[tw] OR over weight*[tw] OR weight reduc*[tw] OR weight los*[tw] OR weight control*[tw] OR weight gain*[tw]

#2 Part II: Antiobesity drugs

anti obesity agent*[tw] OR antiobesity agent*[tw] OR anti obesity drug*[tw] OR antiobesity drug*[tw] OR weight loss agent[tw] OR weight loss drug[tw] OR appetite suppress*[tw] OR appetite depress*[tw] OR anorexigenic agent*[tw] OR anorexigenic drug*[tw] OR anorectics[tw] OR metformin*[tw] OR exenatide*[tw] OR liraglutid*[tw] OR dulaglutid*[tw] OR albiglutid*[tw] OR taspoglutid*[tw] OR lixisenatid*[tw] OR semaglutid*[tw] OR orlistat*[tw] OR cetilistat*[tw] OR sibutramin*[tw] OR fluoxetin*[tw] OR rimonabant*[tw] OR lorcaserin*[tw] OR benzphetamin*[tw] OR diethylpropion*[tw] OR phendimetrazin*[tw] OR mazindol*[tw] OR phentermin*[tw] OR chlorphentermin*[tw] OR mephentermin*[tw] OR topiramat*[tw] OR bupropion*[tw] OR naltrexon*[tw] OR zonisamid*[tw] OR beloranib*[tw] OR velneperit*[tw] OR tesofensin*[tw]

#3 Part III: Part I + Part II

#1 AND #2

#4 Part IV: Population

minors[tw] OR boy[tw] OR boys[tw] OR boyhood[tw] OR girl*[tw] OR kid[tw] OR kids[tw] OR child*[tw] OR schoolchild*[tw] OR adolescen*[tw] OR juvenil*[tw] OR youth*[tw] OR teen*[tw] OR preteen*[tw] OR underage*[tw] OR under age*[tw] OR pubescen*[tw] OR paediatric*[tw] OR pediatric*[tw]

#5 Part V: Part III AND IV

#3 AND #4

#6 Part VI: Limiting to subsets not available on Ovid

#5 not medline[sb] not pmcbook

ICTRP Search Portal (Standard search)

obes* AND child* OR

obes* AND schoolchild* OR

obes* AND adolesc* OR

obes* AND young* OR

obes* AND pediatric* OR

obes* AND teen* OR

obes* AND preteen* OR

obes* AND juvenil* OR

obes* AND minors OR

obes* AND boy* OR

obes* AND girl* OR

obes* AND kids OR

obes* AND youth* OR

obes* AND underage* OR

obes* AND pube* OR

overweight* AND child* OR

overweight* AND schoolchild* OR

overweight* AND adolesc* OR

overweight* AND young* OR

overweight* AND pediatric* OR

overweight* AND teen* OR

overweight* AND preteen* OR

overweight* AND juvenil* OR

overweight* AND minors OR

overweight* AND boy* OR

overweight* AND girl* OR

overweight* AND kids OR

overweight* AND youth* OR

overweight* AND underage* OR

overweight* AND pube*

ClinicalTrials.gov (Expert search)

( obese OR overweight OR obesity ) [DISEASE] AND ( drug or drugs OR agent OR agents OR appetite OR metformin OR exenatide OR liraglutide OR dulaglutide OR albiglutide OR taspoglutide OR lixisenatide OR semaglutide OR orlistat OR cetilistat OR sibutramine OR fluoxetine OR rimonabant OR lorcaserin OR benzphetamine OR diethylpropion OR phendimetrazine OR mazindol OR phentermine OR chlorphentermine OR mephentermine OR topiramate OR bupropion OR naltrexone OR zonisamide OR beloranib OR velneperit OR tesofensine ) [TREATMENT] AND INFLECT EXACT "Child" [AGE‐GROUP]

Trial

Intervention(s): drug component (route, frequency, total dose/day), behaviour changing component

Comparator(s): drug component (route, frequency, total dose/day), behaviour changing component

Atabek 2008

Metformin: oral, twice daily, 500 mg x 2 (1 g)/d, 6 months

Diet and physical activity advice: individual consultation sessions with a nutritionist, completed food diary at beginning and end of trial, advised to perform 30 min of aerobic physical activity per day, 6 months

Placebo: oral, twice daily, 2 tablets/d, 6 months

Diet and physical activity advice: same as the intervention group

Berkowitz 2003

Sibutramine: oral, 1 dose per day, placebo (week 1) 5 mg/d sibutramine (week 2) 10 mg/d (weeks 3 to 6) 15 mg/d (week 7 to month 6), length = 6 months (plus an open‐label phase for additional 6 months)

Behavioural programme: in phase 1 (drug‐placebo phase) participants attended 13 weekly group sessions while in phase 2 (drug, open label) group sessions were held biweekly then monthly. Parents met separately from participants. Instructed to consume 1200 kcal/d to 1500 kcal/d and to engage in 120 min of walking or similar activity per week. Eating and activity logs kept daily. Length = 12 months

Placebo: oral, 1 dose per day, (months 1 to 6), 6 months

Behavioural programme: same as intervention group

Berkowitz 2006

Sibutramine: oral, 1 dose per day, 10 mg/d (baseline to month 6), 15 mg/d from month 6 in participants who had not lost more than 10% of their initial BMI, 12 months

Behavioural therapy programme: each individual centre implemented flexible lifestyle modification approaches that were specific to participants' needs. This included self‐monitoring of eating habits and physical activity, stress management, stimulus control, problem solving, contingency management, cognitive restructuring and social support. Participants were given counselling at each visit and nutritional counselling. Length = 12 months

Placebo: oral, 1 dose per day, placebo (baseline to month 6), uptitrated after 6 months in participants who had not lost more than 10% of their initial BMI, 12 months

Behavioural therapy programme: same as intervention group

Chanoine 2005

Orlistat: oral, dose 3 times per day, 120 mg x 3 (360 mg)/d, 1 year

Behavioural therapy: participants were prescribed a nutritionally balanced, hypocaloric diet and at each trial visit the dietitian spoke about compliance. Behavioural modification involved techniques to limit calorie and fat intake, eating more slowly, avoiding snacks and avoiding overeating. Guidelines were given to encourage regular physical activity and reduce sedentary behaviour; compliance was monitored by a behavioural psychologist at each visit. Length = 54 weeks

Placebo: oral, dose 3 times per day, 1 year

Behavioural therapy: same as intervention group

Clarson 2009

Metformin: oral, 3 times daily, 500 mg x 3 (1.5 g), 6 months

Behaviour changing intervention: monthly individual visits and 2 group sessions. Fitness specialist supervised participants in an individual 30‐min exercise sessions every 2 months. Diet advice and physical activity advice given. Progress monitored by weekly telephone calls and monthly visits. Length = 6 months

No placebo (N/A)

Behaviour changing intervention: same as intervention group

Franco 2014

Sibutramine: oral, once daily, 10 mg, 6 months

Dietary guidance: the dietary guideline proposal was of a low‐calorie diet with restriction of 25% of the total recommended calories for a teenager

Placebo: oral, once daily, 10 mg, 6 months

Dietary guidance: same as intervention group

Freemark 2001

Metformin: oral, 2 doses per day, 500 mg x 2 (1g)/d, 6 months

No behaviour changing intervention

Placebo: oral, 2 doses per day, 6 months

No behaviour changing intervention

Garcia‐Morales 2006

Sibutramine: oral, 1 dose per day, 10 mg/d, 6 months

Diet + exercise: diet and exercise advice was tailored to each participant. Advice was given on recommended food portions and possible combinations, and all participants were advised to perform at least 30 min of aerobic physical activity per day. Each participant also attended individual consultation sessions with a registered paediatric nutritionist. A detailed food consumption questionnaire was completed at the beginning and end of trial medication period. Length = 6 months

Placebo: oral, 1 dose per day, 6 months

Diet + exercise: same as intervention group

Godoy‐Matos 2005

Sibutramine: oral, 1 dose per day, 10 mg/d, 6 months

Hypocaloric diet + exercise: participants were given dietary counselling to achieve an energy deficit of 500 kcal/d at the start of the run‐in phase (no further visits after). Physical activity instructions were delivered by the attendant doctors in a brief written protocol aimed to obtain mainly aerobic moderate exercises for at least 30 min/d. A lifestyle intervention was not given during 6‐month trial

Placebo: oral, 1 dose per day, 6 months

Hypocaloric diet + exercise: same as intervention group

Kendall 2013

Metformin: oral, twice daily, 500 mg x 2 + 500 mg (1.5 g), 6 months

Healthy lifestyle advice: participants provided with a standardised healthy lifestyle advice at the start in a 1‐to‐1 sessions, including a healthy diet advice sheet and increased levels of exercise (available upon request). A lifestyle intervention was not given during the 6‐month trial

Placebo: oral, twice daily, 2 + 1 (3) tablets/d, 6 months

Healthy lifestyle advice : same as intervention group

Maahs 2006

Orlistat: oral, 3 doses per day, 120 mg x 3 (360 mg)/d, 6 months

Diet + exercise therapy: the goal caloric intake was calculated using the Harris‐Benedict equation with ambulating activity factor (500 calories was subtracted from the final number to obtain daily calorie level). Participants were instructed to increase activity using a paediatric activity pyramid and encouraged to exercise for at least 30 min, 3 times per week. Monthly follow‐up visits with a dietitian reinforced this advice. Log sheets and diet records were also completed. Length = 6 months

Placebo: oral, 3 doses per day, 6 months

Diet + exercise therapy: same as intervention group

Mauras 2012

Metformin: oral, twice daily, 500 mg or 1000 mg (dependent on age), 6 months

Diet + exercise intervention: dietary counselling provided with recommended decrease of 250 calories/d to 500 calories/d. Intense follow‐up provided by dietitian. Participants given free membership to YMCA or gym. Encouraged to exercise at least 3 times per week for 30 min per sessions. Activity diary kept and pedometer worn. Length = 6 months

No placebo

Diet + exercise intervention: same as intervention group

NCT00001723

Orlistat: 120 mg 3 times daily for 6 months

Behavioural weight loss programme: 12‐week intensive programme

Placebo: 120 mg 3 times daily for 6 months

Behavioural weight loss programme: same as intervention group

Ozkan 2004

Orlistat: oral, 3 doses per day, 120 mg x 3 (360 mg)/d, mean 11.7 months ‐ length of treatment was not consistent across participants

Conventional treatment: the lifestyle modification programme included reducing daily calories. Was administered by a team comprising of a paediatric endocrinologist, paediatrician and a dietitian. Participants seen by dietitian monthly and in the outpatient clinic every 2 months. Length = between 6 and 17 months

No placebo

Conventional treatment: same as intervention group; length between 6 and 17 months

Prado 2012

Metformin: oral, once daily, 500 mg, 3 months

Nutritional guide and exercise programme: according to pattern 1500 kcal/d. Exercise classes once per week and exercise guide to be practiced twice per week. Length = 3 months

Placebo: oral, once daily, 3 months

Nutritional guide and exercise programme: same as intervention group

Rezvanian 2010

Metformin: oral, once daily, 1500 mg/d, 12 weeks

Healthy eating and physical activity advice: physical activity advice included reducing sedentary time and taking part in 30 min of enjoyable, moderate‐intensity physical activity per day. A registered dietitian conducted a nutrition education session with recommendations on diet such as increasing consumption of fruit and vegetables and not using hydrogenated fat

Placebo: oral, once daily, 12 weeks

Healthy eating and physical activity advice: same as intervention group

Fluoxetine: oral, once daily, 20 mg/d, 12 weeks

Healthy eating and physical activity advice: same as the other intervention groups

Metformin + fluoxetine: oral, once daily, dosage not given, 12 weeks

Healthy eating and physical activity advice: same as the other intervention groups

Srinivasan 2006

Metformin: oral, 2 doses per day, dose gradually built up to 1g x 2 (2 g)/d, 6 months

"Standardised information on healthy eating and exercise": no further information given

Placebo: oral, 2 doses per day, dose gradually built up to 1 g x 2 (2 g)/d, 6 months

"Standardised information on healthy eating and exercise": same as intervention group

Van Mil 2007

Sibutramine: oral, once daily, 5 mg/d, 12 weeks

Energy‐restricted diet and exercise plan: the energy prescription calculated from measured basal metabolic rate multiplied by an estimated physical activity level minus 500 kcal. Physical activity prescribed based on individual preferences and information obtained by physical activity questionnaire. It contained a daily bout of exercise of at least 30 min. Length = 12 weeks

Placebo: oral, once daily, 5 mg/d, 12 weeks

Energy‐restricted diet and exercise plan: same as intervention group

Wiegand 2010

Metformin: oral, twice daily, 2 x 500 mg (1 g)/d, 6 months

Multiprofessional behaviour changing intervention: an interview was performed before randomisation to determine 1 to 3 individually chosen tasks (goals). Multiprofessional reinforcement sessions took place every 4 to 8 weeks. Regarding physical activity, participants and their families attended specialised sport classes (2 sport classes per week, 45 min each, was recommended) in addition to regular sport classes at school. Length = 6 months

Placebo: oral, twice daily, 6 months

Multiprofessional behaviour changing intervention: same as intervention group

Wilson 2010

Metformin: oral, 4 times daily, 4 x 500 mg (2 g)/d, 48 weeks

Behaviour changing intervention: used the Weigh of Life LITE programme developed at Texas Children's Hospital, Houston. There were 10 individualised "intensive" sessions at weekly intervals and monthly follow‐up sessions for the reminder of the trial. Sessions led by trained health specialist and parent/guardians were invited. Length = 48 weeks

Placebo: oral, 4 times daily, 48 weeks

Behaviour changing intervention: same as intervention group

Yanovski 2011

Metformin: oral, twice daily, 2 x 1000 mg (2000 mg)/d, 6 months

Dietitian‐administered weight‐reduction programme: each participant and parent/guardian met with a dietitian monthly, who promoted a reduced‐energy diet, increased physical activity and decreased inactivity. Participants trained to completed a 7‐day food diary which was used to prescribe a "traffic light" style 500 kcal/d deficit diet, and exercise was encouraged for 30 min/d, monitored by pedometers readings. Length = 6 months

Placebo: oral, twice daily, 6 months

Dietitian‐administered weight‐reduction programme: same as intervention group

"‐" denotes not reported.

BMI: body mass index; /d: per day; kcal: kilocalories; min: minute; N/A: not applicable; YMCA: Young Men's Christian Association.

Trial

Intervention(s) and comparator(s)

Duration of intervention
(duration of follow‐up)

Description of participants

Trial period
(year to year)

Country

Setting

Ethnic groups
(%)

Duration of obesity
(mean years (SD))

Atabek 2008

I: metformin + diet and physical activity advice

6 months (6 months)

Obese adolescents with hyperinsulinaemia

‐

Turkey

Hospital in/outpatient clinic/other based in University School of Medicine

‐

‐

C: placebo + diet and physical activity advice

Berkowitz 2003

I: behavioural programme + sibutramine

6 months (6 months)

Obese adolescent boys and postmenarchal girls

March 1999 to August 2002

USA

University of Pennsylvania School of Medicine

White 49, black 49, other 2

‐

C: behavioural programme + placebo

White 62, black 33, other 5

Berkowitz 2006

I: behavioural therapy programme + sibutramine

12 months (12 months)

Obese adolescents

July 2000 to February 2002

USA

33 weight loss clinics and outpatient clinic based in a University School of Medicine

White 56, African‐American 22, Hispanic or Mexican American 16, other 6

‐

C: behavioural therapy programme + placebo

White 59, African‐American 19, Hispanic or Mexican‐American 14, other 9

Chanoine 2005

I: orlistat + diet + exercise + behavioural therapy

54 weeks (54 weeks)

Obese adolescents

August 2000 to October 2002

USA and Canada

32 clinical centres

White 75, black 19, other 6

‐

C: placebo + diet + exercise + behavioural therapy

White 78, black 14, other 8

Clarson 2009

I: metformin + lifestyle intervention

6 months (6 months)

Obese adolescents with insulin resistance

Enrolled 2005 to 2007

Canada

Participants assessed in community clinic and there were monthly visits to clinic during intervention. Intervention carried out in community ‐ at adolescent's home ‐ unclear where group sessions took place

‐

‐

C: lifestyle intervention only

Franco 2014

I: sibutramine + dietary guidance

6 months (6 months)

Obese adolescents

‐

Brazil

Paediatric endocrinology outpatient clinic in childhood obesity group of the Instituto da Crianca do Hospital das Clinicas de Faculdade de Medicina de Universidade de Sao Paulo

‐

‐

C: placebo + dietary guidance

Freemark 2001

I: metformin

6 months (6 months)

Obese adolescents with fasting hyperinsulinaemia and a family history of type 2 diabetes

‐

USA

Inpatient and outpatient clinic of a university

White 64, black 36

‐

C: placebo

White 47, black 53

Garcia‐Morales 2006

I: sibutramine + diet + exercise

6 months (6 months)

Obese Mexican adolescents

August 2001 to August 2003

Mexico

Outpatients attending the endocrinology department of the Federico Gomez Children's Hospital of Mexico

‐

‐

C: placebo + diet + exercise

Godoy‐Matos 2005

I: sibutramine + hypocaloric diet + exercise

7 months (7 months)

Obese adolescents

January 2002 to April 2003

Brazil

Regular clinical setting

‐

‐

C: placebo + hypocaloric diet + exercise

Kendall 2013

I: metformin + healthy lifestyle advice

6 months (6 months)

Obese children and adolescents with hyperinsulinaemia or impaired fasting glucose or impaired glucose tolerance (or both)

‐

UK

UK paediatric endocrine centres

White 80, Asian 19, Afro‐Caribbean 11

‐

C: placebo + healthy lifestyle advice

White 72, Asian 26, Afro‐Caribbean 1

Maahs 2006

I: orlistat + diet and exercise therapy

26 weeks (26 weeks)

Obese adolescents

December 2002 to September 2003

USA

General clinical research centre at University of New Mexico Hospital

Hispanic 60

‐

C: placebo + diet and exercise therapy

Hispanic 65

Mauras 2012

I: metformin + diet/exercise intervention

6 months (6 months)

Obese children with normal glucose tolerance but elevated hsCRP or fibrinogen concentrations (or both)

‐

USA

‐

White 51, African‐American 37, other 11

Uncomplicated (exogenous) obesity for < 5 years

C: diet/exercise intervention

White 39, African‐American 42, other 19

NCT00001723

I: orlistat + behavioural weight loss programme

6 months (6 months)

Obese children and adolescents with obesity‐related diseases

RCT began in 1999 and ended in 2008

USA

National Institutes of Health Clinical Center

Non‐Hispanic black 63,

non‐Hispanic white 37

‐

C: placebo + behavioural weight loss programme

Non‐Hispanic black 60,

non‐Hispanic whites 40

Ozkan 2004

I: conventional treatment + orlistat

Intervention group was followed for 5 to 15 months (mean duration of treatment 11.7, SD 3.7 months)

Adolescents with severe exogenous obesity

‐

Turkey

Outpatient clinic

‐

‐

C: conventional treatment

Control group was followed for 6 to 17 months (mean 10.2, SD 3.7 months)

Prado 2012

I: metformin + nutritional guide and exercise programme

3 months (6 months)

Obese female adolescents at risk of developing type 2 diabetes

June 2009 to July 2010

Chile

Conducted at Center of Adolescent Health Serjoven

‐

‐

C: placebo + nutritional guide and exercise programme

Rezvanian 2010

I1: metformin + healthy eating and physical activity advice

12 weeks (24 weeks)

Obese children and adolescents

‐

Iran

Pediatric Obesity and Metabolic Syndrome Research Clinic of the Pediatric Preventive Cardiology Department, Isfahan Cardiovascular Research Center

‐

‐

I2: fluoxetine + healthy eating and physical activity advice

I3: metformin and fluoxetine + healthy eating and physical activity advice

C: placebo + healthy eating and physical activity advice

Srinivasan 2006

I: metformin first then placebo + standardised information on healthy eating and exercise

6 months (12 months)

Obese children and adolescents (aged 9 to 18) with suspected insulin resistance

‐

Australia

Outpatient clinic of a tertiary paediatric hospital (university teaching hospital)

64% were from ethnic backgrounds with high prevalence of insulin resistance and the metabolic syndrome (e.g. Indian subcontinent, Pacific Islands), 25% were from a northern European background, and 11% were from a mixed background

‐

C: placebo first then metformin + standardised information on healthy eating and exercise

Van Mil 2007

I: sibutramine + energy‐restricted diet and exercise plan

12 weeks (24 weeks)

Obese adolescents

‐

The Netherlands

Outpatient clinic

‐

‐

C: placebo + energy‐restricted diet and exercise plan

Wiegand 2010

I: metformin + multiprofessional lifestyle intervention

6 months (6 months)

Obese insulin‐resistant adolescents

May 2006 to December 2006

Germany and Switzerland

Paediatric obesity centre

White 87, other 13

‐

C: placebo + multiprofessional lifestyle intervention

White 92, other 9

Wilson 2010

I: metformin + lifestyle intervention programme

52 weeks (100 weeks)

Obese adolescents

October 2003 to August 2007

USA

6 Glaser paediatric research centres

White 56, African‐American 21, Asian 8, other 15, Hispanic ethnicity 18

‐

C: placebo + lifestyle intervention programme

White 71, African‐American 16, Asian 0, other 13, Hispanic ethnicity 29

Yanovski 2011

I: metformin + dietitian‐administered weight‐reduction programme

6 months (12 months)

Obese insulin‐resistant children

September 2000 to August 2008

USA

Trial took place at the NIH clinical research centre

Non‐Hispanic white 42, Non‐Hispanic black 42, Hispanic white 11, other 5

‐

‐

C: placebo + dietitian‐administered weight‐reduction programme

Non‐Hispanic white 49, Non‐Hispanic black 38, Hispanic white 11, other 2

"‐" denotes not reported.

C: comparator; hsCRP: high sensitivity C‐reactive protein; I: intervention; RCT: randomised controlled trial; SD: standard deviation.

Trial

Intervention(s) and comparator(s)

Sex
(female %)

Age
(mean years (SD))

HbA1c
(mean % (SD))

BMI
(mean kg/m² (SD))

Bodyweight
(mean kg (SD))

Comedications/cointerventions

Comorbidities

Atabek 2008

I: metformin + diet and physical activity advice

50

11.8 (2.8)

‐

28.5 (3.4)

67.16 (16.8)

Diet and physical activity advice. Individual consultation sessions with a registered paediatric nutritionist

All participants had hyperinsulinaemia

C: placebo + diet and physical activity advice

50

11.6 (2.7)

‐

28.0 (3.4)

66.27 (16.9)

Berkowitz 2003

I: behavioural programme + sibutramine

72

14.1 (1.3)

‐

37.5 (4.0)

102 (14.7)

Behavioural therapy

‐

C: behavioural programme + placebo

62

14.1 (1.2)

‐

38.0 (3.6)

105.3 (16.2)

Berkowitz 2006

I: behavioural therapy programme + sibutramine

66

13.6 (1.3)

‐

35.9 (4.1)

97.9 (14.7)

Behavioural therapy

50.5% had dyslipidaemia, 1.4% had hypertension

C: behavioural therapy programme + placebo

62

13.7 (1.3)

‐

36.1 (3.8)

97.8 (14.6)

57.4% had dyslipidaemia, 2.3% had hypertension

Chanoine 2005

I: orlistat + diet + exercise + behavioural therapy

65

13.6 (1.3)

‐

35.7 (4.2)

97.7 (15.0)

Behavioural modification + diet + exercise counselling

In the orlistat group, 14 participants had a baseline abnormality revealed by gallbladder ultrasound, including 8 participants with fatty liver infiltration or hepatomegaly and 3 participants with gallstones; 25.3% of participants had the metabolic syndrome at baseline

C: placebo + diet + exercise + behavioural therapy

71

13.5 (1.2)

‐

35.4 (4.1)

95.1 (14.2)

‐

Clarson 2009

I: metformin + lifestyle intervention

‐

13.1

‐

36.4 (1.8)

‐

Lifestyle intervention

All participants insulin resistant. 15 participants had acanthosis nigricans

C: lifestyle intervention only

‐

13.1

‐

33.9 (1.1)

‐

Franco 2014

I: sibutramine + dietary guidance

56

13.3 (1.8)

‐

33.9 (7.2)

85.5 (23.2)

Dietary guidance

‐

C: placebo + dietary guidance

12.3 (1.7)

‐

32.8 (5.8)

83.1 (19.6)

Freemark 2001

I: metformin

79

14.4 (0.6)

5.6 (0.1)

41.5 (0.9)

‐

‐

All participants had fasting hyperinsulinaemia. 8 participants had acanthosis nigricans

C: placebo

46

15.4 (0.5)

5.5 (0.1)

38.7 (1.3)

‐

Garcia‐Morales 2006

I: sibutramine + diet + exercise

61

15.2 (1.3)

‐

35.1 (5.3)

92.6 (14.6)

Diet and exercise advice

8.7% high blood pressure, 8.7% glucose, 43.5% high triglycerides, 8.7% high cholesterol, 4.3% high LDL, 13% high HDL

C: placebo + diet + exercise

52

14.7 (1.1)

‐

36.6 (5.2)

98.9 (22.7)

30.4% high blood pressure, 8.7% glucose, 52.2% high triglycerides, 34.8% high cholesterol, 17.4% high LDL

Godoy‐Matos 2005

I: sibutramine + hypocaloric diet + exercise

83

Females: 15.9 (1.1) Males: 16.7 (0.6)

‐

Females: 37.5 (3.8)

Males: 37.6 (4.3)

Females: 100.5 (14.2)

Males: 117.1 (11.7)

Exercise advice

‐

C: placebo + hypocaloric diet + exercise

80

Females: 16.3 (1.2) Males: 16.7 (0.6)

‐

Females: 35.8 (4.2)

Males: 37.4 (1.9)

Females: 94.0 (13.6) Males: 113.4 (10.0)

‐

Kendall 2013

I: metformin + healthy lifestyle advice

66

13.7 (2.3)

‐

37.1 (6.4)

100.3 (24.1)

Standardised healthy lifestyle advice

All participants had hyperinsulinaemia or impaired fasting glucose or impaired glucose tolerance (or both)

C: placebo + healthy lifestyle advice

69

13.6 (2.2)

‐

36 (6.3)

96.4 (21.8)

Maahs 2006

I: orlistat + diet and exercise therapy

60

15.8 (1.5)

5.4 (0.1)

39.2 (5.3)

111.1 (22.9)

Dietary and exercise counselling

‐

C: placebo + diet and exercise therapy

75

15.8 (1.4)

5.4 (0.1)

41.7 (11.7)

114.3 (38.4)

‐

Mauras 2012

I: metformin + diet/exercise intervention

57

12.3 (0.5)

‐

32 (1)

‐

Dietary counselling and free membership to a sports club/gym

Elevated hsCRP or fibrinogen (or both) concentrations

C: diet/exercise intervention

52

12.0 (0.4)

‐

33.2 (0.7)

‐

NCT00001723

I: orlistat + behavioural weight loss programme

65

14.65 (1.38)

‐

41.7 (0.6)

‐

Behavioural therapy and a multivitamin for 6 months

All participants had at least 1 of the following: systolic or diastolic hypertension (determined by age‐specific charts); frank type 2 diabetes, impaired glucose tolerance assessed by oral glucose tolerance testing; hyperinsulinaemia (defined as a fasting insulin > 15 IU/mL); significant hyperlipidaemia (total cholesterol > 200 mg/dL, LDL cholesterol > 129 mg/dL or fasting triglycerides > 200 mg/dL); hepatic steatosis (ALT or AST above normal range with negative hepatitis studies) or sleep apnoea documented by a sleep trial

C: placebo + behavioural weight loss programme

66

14.52 (1.46)

‐

‐

Ozkan 2004

I: conventional treatment + orlistat

67

12.9 (2.4)

‐

32.5

82.1 (20.9)

Daily oral multivitamin preparation, lifestyle modification programme

‐

C: conventional treatment

12.5 (2.2)

‐

31.2

73.9 (15.3)

Lifestyle modification programme

‐

Prado 2012

I: metformin + nutritional guide and exercise programme

100

15.6 (1.9)

‐

33.6

‐

Nutritional guide and exercise programme

30% of participants had psychiatric comorbidities

C: placebo + nutritional guide and exercise programme

100

‐

33.3

‐

11.1% of participants had psychiatric comorbidities

Rezvanian 2010

I1: metformin + healthy eating and physical activity advice

‐

13.1 (1.4)

‐

26.4 (0.5)

‐

Physical activity advice; nutritional education session and dietary advice

‐

I2: fluoxetine + healthy eating and physical activity advice

‐

13.5 (1.2)

‐

26.5 (0.7)

‐

‐

I3: metformin and fluoxetine + healthy eating and physical activity advice

‐

13.7 (1.1)

‐

26.6 (0.8)

‐

‐

C: placebo + healthy eating and physical activity advice

‐

13.4 (1.4)

‐

26.2 (0.6)

‐

‐

Srinivasan 2006

I: metformin first then placebo + standardised information on healthy eating and exercise

54

12.5 (2.2)

‐

‐

‐

Information on healthy eating and exercise

Suspicion of insulin resistance; 89% participants had acanthosis nigricans

C: placebo first then metformin + standardised information on healthy eating and exercise

‐

‐

‐

Van Mil 2007

I: sibutramine + energy‐restricted diet and exercise plan

45

14.1 (1.0)

‐

30.1 (4.5)

80.8 (15.6)

Diet and exercise plan

‐

C: placebo + energy‐restricted diet and exercise plan

58

13.8 (1.5)

‐

33.3 (5.0)

89.2 (16.4)

‐

Wiegand 2010

I: metformin + multiprofessional lifestyle intervention

72

15.1

‐

34.3 (5)

‐

Lifestyle intervention

All had risk factors for developing type 2 diabetes: acanthosis nigricans, signs of the metabolic syndrome, impaired fasting glucose, and positive family history of type 2 diabetes, or with impaired glucose tolerance

C: placebo + multiprofessional lifestyle intervention

62

15

‐

35.5 (5.8)

‐

Wilson 2010

I: metformin + lifestyle intervention programme

67

14.8 (1.3)

5.4 (0.3)

35.9 (5.7)

95.9 (16.6)

Lifestyle intervention given during run‐in period and follow‐up sessions provided monthly for the remainder of the trial; a multivitamin tablet and calcium carbonate 1000 mg was taken daily

‐

C: placebo + lifestyle intervention programme

66

15.0 (1.5)

5.3 (0.3)

35.9 (4.7)

101.8 (15.7)

‐

Yanovski 2011

I: metformin + dietitian‐administered weight‐reduction programme

57

10.1 (1.6)

‐

34.2 (6.8)

76.4 (23.1)

A monthly dietitian administered weight‐reduction programme; a daily chewable multivitamin containing cyanocobalamin 6 mg was also prescribed

26.4% had paediatric metabolic syndrome. 64% showed a presence of acanthosis nigricans; all participants had fasting hyperinsulinaemia.

C: placebo + dietitian‐administered weight‐reduction programme

64

10.4 (1.4)

‐

34.6 (6.2)

80.1 (20.5)

31.9% had paediatric metabolic syndrome. 68% showed a presence of acanthosis nigricans; all participants had fasting hyperinsulinaemia

"‐" denotes not reported.

ALT: alanine transaminase; AST: aspartate transaminase; BMI: body mass index; C: comparator; HbA1c: glycosylated haemoglobin A1c; HDL: high‐density lipoprotein; HsCRP: high sensitivity C‐reactive protein; I: intervention; LDL: low‐density lipoprotein; SD: standard deviation.

Trial

Endpoints quoted in trial document(s)
(ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a

Endpoints quoted in publication(s)^b

Time of measurement

Atabek 2008

N/T

Primary outcome measures: ‐

6 months

Secondary outcome measures : ‐

Other outcome measures: % change in BMI, DBP, SBP, pulse rate, lipids, triglycerides, serum insulin, serum glucose, HOMA, HDL, BMI z score, LDL, total cholesterol, weight change, adverse events

Berkowitz 2003

Source:NCT00212173 (added 13 September 2005)

Primary outcome measure(s): BMI, weight

No trial results posted. No link to Berkowitz 2003 publication but links to 2 additional publications. A second protocol for an adolescent lifestyle intervention also included

Primary outcome measure: % change in BMI

3, 6, 9, 12 months

Secondary outcome measure(s): BP, lipids, glucose, insulin

Secondary outcome measures: BP, pulse, hunger

Other outcome measure(s): ‐

Other outcome measures: lipids, triglycerides, serum insulin, serum glucose, HOMA, HDL, BMI z score, LDL, total cholesterol, weight change, waist circumference, adverse events

Berkowitz 2006

Source:NCT00261911

Primary outcome measure(s): absolute change in BMI from baseline to endpoint (12 months)

No trial results posted, publications specified

Primary outcome measures:

absolute change from baseline in BMI

0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months

Secondary outcome measure(s): % change from baseline in BMI, proportions of participants achieving ≥ 5% and ≥ 10% BMI and bodyweight reduction, absolute and % change from baseline in waist circumference, body composition (DEXA), lipid and glycaemic variables (all: 12 months)

Secondary outcome measures: % change in BMI, proportion of participants achieving reductions in BMI of ≥ 5% or ≥ 10%, absolute and % changes in bodyweight and lipid and glycaemic variables, absolute change in waist circumference

Other outcome measure(s): ‐

Other outcome measures: DBP, SBP, pulse rate, QTc interval, maturation (Tanner staging), adverse events

Chanoine 2005

N/T

Primary outcome measures: change in BMI from baseline to trial end (or trial exit)

‐0.5, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12 months

Secondary outcome measures: change in bodyweight, levels of total, HDL and LDL cholesterol, LDL‐to‐HDL cholesterol ratio, triglyceride levels, SBP and DBP,
waist and hip circumference, glucose and insulin responses to an oral glucose challenge, and changes in body composition

Other outcome measures: beta carotene, vitamin A, 25‐hydroxyvitamin D, vitamin E, Tanner staging, adverse events

Clarson 2009

N/T

Primary outcome measures: change in BMI and modification of metabolic risk factors, including insulin resistance, plasma lipids and adipocytokines, assessment of metformin on the attainment of a target metabolic profile

6 months

Secondary outcome measures: ‐

Other outcome measures: BMI z score, BP, adverse events, waist circumference

Franco 2014

N/T

Primary outcome measures: ‐

On average every 40 days for 13 months

Secondary outcome measures: ‐

Other outcome measures:

% of participants loosing 10% of their initial weight, weight, BMI, SBP, DBP, cholesterol, LDL, HDL, triglycerides, leptin, CRP, transaminases, blood glucose, insulin, adverse events, waist circumference

Freemark 2001

N/T

Primary outcome measures: ‐

6 months

Secondary outcome measures: ‐

Other outcome measures:

BMI SDS, insulin, glucose tolerance, leptin, serum lipids, HbA1c, IGF‐1, lactate, cholesterol, LDL, HDL, LDL/HDL, triglycerides, adverse events, ALT, AST

Garcia‐Morales 2006

N/T

Primary outcome measures:

baseline versus endpoint absolute values for bodyweight, BMI, and % of the initial BMI (%BMI)

‐15, 30, 60, 90, 120, 150, 180 days

Secondary outcome measures:

waist circumference and % of the initial waist circumference (%waist)

Other outcome measures: health‐related quality of life, white blood cells, monocytes, eosinophils, glucose, uric acid, creatinine, albumin, chloride, total cholesterol, LDL, AST, alkaline phosphatase, SBP, DBP, heart rate, ST segment, adverse events

Godoy‐Matos 2005

N/T

Primary outcome measures: change in weight and BMI

‐4, 4, 8, 12, 16, 20, 24 weeks

Secondary outcome measures: change in waist, hip, and waist‐to‐hip ratio

Other outcome measures: SBP, DBP, heart rate, glucose, total cholesterol, triglycerides, HDL, LDL, VLDL, insulin, total cholesterol/HDL cholesterol, left atrium diameter, left ventricular mass, adverse events, satiety score

Kendall 2013

Source:ISRCTN19517475

Primary outcome measure: reduction in BMI SDS

Prior to 16 December 2008:

80 participants aged 9 to 18 years

As of 16 December 2008:

• pubertal and postpubertal children: fasting insulin > 26 mIU/L

• prepubertal children: fasting insulin > 15 mIU/L

• 120‐minute insulin > 89 mIU/L or impaired glucose tolerance (OGTT 2‐hour plasma glucose value ≥ 7.8 to < 11.1 (± impaired fasting glucose ≥ 6.1 to < 7), or both

Primary outcome measure: reduction of BMI SDS

3, 6 months

Secondary outcome measures: Added 16 December 2008: fasting and 2‐hour insulin and glucose levels on OGTT, measures of insulin resistance, fasting lipids, CRP, adiponectin, leptin, resistin, BP

Secondary outcome measures: BMI and waist‐to‐hip ratio, fasting and postprandial insulin and glucose levels, metabolic risk factors, adipokines

Other outcome measure(s): ‐

Other outcome measures: weight, height, SBP, DBP, cholesterol, HDL, LDL, triglycerides, bilirubin, CRP, lactate, resistin, adverse events

Maahs 2006

N/T

Primary outcome measures: change in BMI from baseline to 6 months

1, 2, 3, 4, 5, 6 months

Secondary outcome measures: changes in weight, lean body mass, results of blood chemistry studies

Other outcome measures: health‐related quality of life, all‐cause mortality, vitamin A, vitamin D, vitamin E, adverse events

Mauras 2012

Source:NCT00139477

Primary outcome measures: change from baseline in hsCRP at 6 months, change from baseline in fibrinogen at 6 months, change from baseline in IL‐6 at 6 months, change from baseline in PAI‐1 at 6 months

Trial results posted, publications specified

Primary outcome measures: hsCRP and fibrinogen concentrations at 6 months

3, 6 months

Secondary outcome measure(s): ‐

Secondary outcome measures: ‐

Other outcome measure(s): ‐

Other outcome measures: weight, BMI percentile, systolic BP, diastolic BP, IL‐6, PAI‐1, adiponectin, IGF‐1, insulin, total cholesterol, LDL‐cholesterol, HDL‐cholesterol, triglycerides, free fatty acids, glucose tolerance, resting energy expenditure rates, adverse events, waist circumference

NCT00001723

Source:NCT00001723

Primary outcome measure: change in BMI SDS (time frame: baseline to 6 months)

Trial results posted, linked to pilot trial but no link to publication

No publication available

6 months

Secondary outcome measures: change in bodyweight (time frame: baseline to 6 months), weight, change in BMI (time frame: baseline to 6 months), change in body fat (time frame: baseline to 6 months), body fat distribution measures obtained DEXA, effect of race on change in weight (time frame: baseline to 6 months), difference in change of weight according to race (non‐Hispanic white versus non‐Hispanic black)

Other outcome measure(s): ‐

Ozkan 2004

N/T

Primary outcome measures: ‐

1 to 15 months

Secondary outcome measures: ‐

Other outcome measures: weight change, % weight change, BMI, adverse events

Prado 2012

N/T

Primary outcome measures: weight

1, 2, 3, 4, 5, 6 months

Secondary outcome measures: ‐

Other outcome measures: BMI, motivational survey results, glycaemia, afterload glucose, HDL, adverse events, waist circumference

Rezvanian 2010

N/T

Primary outcome measures: ‐

12, 24 weeks

Secondary outcome measures: ‐

Other outcome measures: BMI, BMI SDS, waist circumference, waist‐to‐height ratio, adverse events

Srinivasan 2006

Source:ISRCTN43267711

Primary outcome measures: ‐

No results posted or links to publication

Retrospectively registered

Primary outcome measures: ‐

6, 12 months

Secondary outcome measures: ‐

Secondary outcome measures: ‐

Other outcome measures: ‐

Other outcome measures: BMI, waist circumference z score, fasting insulin, fasting glucose, glucose effectiveness, acute insulin response, disposition index, glucose disposal, acanthosis nigricans neck score, Tanner staging, weight loss, weight z score, BMI z score, adverse events

Van Mil 2007

N/T

Primary outcome measure: change in BMI between the 2 periods (12 weeks' randomised treatment period and 12 weeks' follow‐up)

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24 weeks

Secondary outcome measures: ‐

Other outcome measures: height, weight, sleeping metabolic rate, basal metabolic rate, total energy expenditure, physical activity level, basal metabolic rate adjusted, total energy expenditure residuals, adverse events

Wiegand 2010

Found in the references of included trials section: EudraCT Nr. 2004‐003816‐47 (but currently not available at EU CTR. We contacted EMA and received the following answer "Note that this trial is not in the public domain due to missing information from Ethics Committee therefore we recommend you to contact the National Competent Authority concerned by this application."; in the dissertation by Hübel it is specified "Vor Beginn der Studie wurde die Zustimmung der jeweils zuständigen Ethikkommissionen eingeholt (Charité Berlin, Deutschland; St. Gallen, Schweiz)" ‐ "before start of the study approval of the appropriate ethics committees was obtained (Charité Berlin, Germany; St. Gallen, Switzerland))

Primary outcome measures: HOMA‐IR

‐6, 3, 6 months

Secondary outcome measures: anthropometric measurements (BMI and waist‐to‐hip ratio), cardiovascular risk parameters (SBP and DBP), lipid profile (total, LDL, HDL cholesterol and triglycerides), and other metabolic parameters (glucose tolerance and fasting insulin)

Other outcome measures: adverse events

Wilson 2010

Source:NCT00209482 and NCT00120146

Primary outcome measures: NCT00209482: mean change from baseline in individual BMIs between the 2 groups (compared at 2 time points: at week 52 and week 100)
NCT00120146: change in BMI, BMI

No trial results posted, publications specified

Primary outcome measures: BMI change, BMI z score

‐4, 12, 24, 36, 48, 60, 72, 84, 96 weeks

Secondary outcome measures: NCT00209482: ‐
NCT00120146: change in insulin sensitivity; fasting insulin concentrations; characterisation of insulin dynamics and insulin sensitivity; characterisation of fat distribution and fatty infiltration of the liver; use of CT to characterise abdominal fat distribution; use of CT and ALT levels to assess fatty infiltration of the liver; characterisation of body composition; characterisation of dietary amino acids; characterisation of the insulin‐to‐glucagon ratio; characterisation of the impact of sex on response to metformin XR; characterisation of the impact of race/ethnicity on response to metformin XR; characterisation of health‐related quality of life

Secondary outcome measures: fat mass, lean mass, fat area, HOMA‐IR, area under insulin curve, area under glucose curve, corrected insulin release at glucose peak, LDL cholesterol, HDL cholesterol, triglycerides, triglyceride‐to‐HDL cholesterol ratio, adverse events

Other outcome measures: NCT00209482: ‐
NCT00120146: ‐

Other outcome measures: waist circumference

Yanovski 2011

Source:NCT00005669

Primary outcome measures: changes in bodyweight as determined by BMI SDS (6 months)

Trial results posted, publications specified

Primary outcome measures: change in BMI SD score (BMI z score), as determined at the end of the 6‐month randomised treatment phase

1, 2, 3, 4, 5, 6 months

Secondary outcome measures: change in bodyweight as determined by BMI (6 months), change in bodyweight (6 months), change in body fat by DEXA (6 months), change in body fat by Bod Pod (6 months)

Secondary outcome measures: changes in BMI, bodyweight and fat mass at the conclusion of the randomised phase

Other outcome measures: ‐

Other outcome measures: changes in skinfold thickness, body circumferences, visceral adipose tissue, insulin resistance and laboratory components of the metabolic syndrome ‐ SBP, DBP, serum insulin, plasma glucose, total cholesterol, HDL cholesterol, LDL cholesterol, LDL‐to‐HDL cholesterol ratio, triglycerides, ALT, AST, hsCRP, vitamin B12, adverse events

‐ denotes not reported.

^aTrial document(s) refers to all available information from published design papers and sources other than regular publications (e.g. FDA/EMA documents, manufacturer's websites, trial registers).
^bPublication(s) refers to trial information published in scientific journals (primary reference, duplicate publications, companion documents or multiple reports of a primary trial).

ALT: alanine transaminase; AST: aspartate transaminase; BMI: body mass index; BMI SDS: body mass index standardised deviation score; BP: blood pressure; CDC: Centers for Disease Control and Prevention; CRP: C‐reactive protein; CT: computed tomography; DBP: diastolic blood pressure; DEXA: dual‐energy X‐ray absorptiometry; EMA: European Medicines Agency; EU CTR: European Clinical Trials Register; FDA: Food and Drug Administration (US); HbA1c: glycosylated haemoglobin A1c; HDL: high‐density lipoprotein; HOMA(‐IR): homeostasis model assessment (insulin resistance); hsCRP: high sensitivity C‐reactive protein; IGF‐1: insulin‐like growth factor 1; IL‐6: interleukin‐6; LDL: low‐density lipoprotein; N/T: no trial document available; OGTT: oral glucose tolerance test; PAI‐1: plasminogen activator inhibitor‐1; QTc: heart‐rate corrected QT interval; SBP: systolic blood pressure; VLDL: very low density lipoprotein; XR: extended release.

Trial

Outcome

Clear that outcome was measured and analysed^a (trial report states that outcome was analysed but only reports that result was not significant)

Clear that outcome was measured and analysed^b (trial report states that outcome was analysed but no results reported)

Clear that outcome was measured^c (clear that outcome was measured but not necessarily analysed (judgement says likely to have been analysed but not reported because of nonsignificant results))

Unclear whether the outcome was measured^d (not mentioned but clinical judgement says likely to have been measured and analysed but not reported on the basis of nonsignificant results)

Atabek 2008

Behaviour change

‐

‐

Yes

‐

Berkowitz 2003

N/A

Berkowitz 2006

N/A

Chanoine 2005

N/A

Clarson 2009

Body fat distribution

Yes

‐

‐

‐

Franco 2014

Body fat distribution

‐

‐

Yes

‐

Freemark 2001

N/A

Garcia‐Morales 2006

Behaviour change

‐

‐

Yes

‐

Godoy‐Matos 2005

N/A

Kendall 2013

Behaviour change

‐

‐

Yes

‐

Maahs 2006

Behaviour change

‐

‐

Yes

‐

Health‐related quality of life and self esteem

Yes

‐

‐

‐

Mauras 2012

N/A

NCT00001723

N/A

Ozkan 2004

N/A

Prado 2012

Measured BMI

Yes

‐

‐

‐

Body fat distribution

Yes

‐

‐

‐

Rezvanian 2010

N/A

Srinivasan 2006

Measured BMI

‐

Yes

‐

‐

Body fat distribution

‐

Yes

‐

‐

Van Mil 2007

N/A

Wiegand 2010

Body fat distribution

Yes

‐

‐

‐

Wilson 2010

Body fat distribution

‐

Yes

‐

‐

Yanovski 2011

N/A

BMI: body mass index; N/A: not applicable.

Trial

Measured BMI

Adverse events

Health‐related quality of life and self‐esteem

All‐cause mortality

Morbidity

Atabek 2008

Expressed as BMI (kg/m²). Obesity defined as ≥ the 95th percentile for age and sex based on the standards of the CDC (IO)

Participants were asked to report any adverse effects every month. Serious adverse events defined as vomiting or lactic acidosis (SO)

N/I

N/I

Hyperinsulinaemia was defined from norms for pubertal stages 2 to 4: mid‐puberty > 30 mU/L, and postpubertal hyperinsulinism was defined by adult WHO criteria (> 20 mU/L). Insulin sensitivity was estimated using FGIR, HOMA‐IR and QUICKI (IO)

Berkowitz 2003

The change in raw BMI is not given. Instead it is expressed as % reduction in BMI (kg/m²).

BMI also used to calculate BMI z score (calculated using CDC standards)

Obesity defined as BMI 32 to 44 kg/m² (IO)

Adverse events were recorded at each medical visit. In addition, blood pressure and heart rate were monitored closely, and any abnormalities were considered as adverse events. A serious adverse event was not defined (AO, IO, SO)

N/I

N/I

N/I

Berkowitz 2006

Expressed as BMI (kg/m²) in graphical format and % change in BMI in text and tabular format. Used Rosner 1998 to define obesity (IO)

The investigator recorded all adverse events, both observed and volunteered. The only serious event defined as excessive nausea and vomiting. Unclear whether suicide attempt and depression were defined as serious (AO, IO, SO)

N/I

2 suicide attempts ‐ did not result in mortality (AO, IO)

N/I

Chanoine 2005

Expressed as BMI (kg/m²). Used Barlow 1998 to define obesity (IO)

Gastrointestinal tract adverse effects assessed at each visit by a specially designed dictionary of standard terms for defecation patterns for reproducibility and consistency of reporting. Other adverse events were noted and followed by questioning. Serious adverse events included acute demyelinating encephalomyelitis, facial palsy, pneumonia, worsening of asthma, pain in the right side, pilonidal abscess, depression, asthma attack, seizure, admission for repair of deviated nasal septum, appendicitis, cholelithiasis, gallbladder disorder followed by cholecystectomy, adenoidal hypertrophy and aseptic meningitis. The trial also used electrocardiograms to detect abnormalities and measured gallbladder ultrasounds to detect gallstones (AO, IO, SO)

N/I

N/I

Gallstones and fatty liver infiltration or hepatomegaly identified by gallbladder ultrasound (IO)

Clarson 2009

Expressed as BMI (kg/m²). Obesity defined as BMI > 95th percentile for age and sex (no reference). BMI z scores calculated using the CDC reference data (IO)

No adverse events reported, trial highlights that metformin was well tolerated by all participants ‐ unclear how this was assessed

N/I

N/I

Insulin resistance was defined using HOMA > 3 (IO)

Franco 2014

Weight and height used to calculate BMI. Obesity defined by WHO classification (IO)

Adverse effects were investigated on a preset questionnaire and described voluntarily by the participant at each consultation (on average every 40 days). A serious adverse event was not defined (AO, SO)

N/I

N/I

N/I

Freemark 2001

Expressed change in BMI. Also expressed as BMI SDS. Used Rosner 1998 to adjusting for age, sex and race (IO)

Unclear how and when adverse events were assessed

N/I

N/I

Hyperinsulinaemia defined as fasting insulin concentration exceeding 15 μU/mL. Insulin sensitivity assessed by fasting insulin‐to‐glucose concentration ratio, QUICKI and HOMA‐IR (IO)

Garcia‐Morales 2006

Expressed as BMI (kg/m²). Used CDC growth charts (Kuczmarski 2000) (IO)

Adverse events were reported as they were detected by the participant or investigator. They were also assessed during visits. Severe adverse events defined as life‐threatening or those resulting in hospitalisation or producing long‐term disabilities (AO, IO, SO)

Health‐related quality of life assessed by a 36‐item Short‐Form Health Survey (SF‐36) questionnaire (Alonso 1995) (SO)

N/I

Comorbidities were accessed at baseline and follow‐up. These included high blood pressure, high glucose, high triglycerides, high cholesterol, high LDL and high HDL (IO)

Godoy‐Matos 2005

Expressed as BMI (kg/m²). Obesity defined as BMI between 30 and 45 (no reference) (IO)

Adverse events were assessed and recorded at each visit. A significant event was defined as a serious or rare event ‐ serious event not defined (AO, IO, SO)

N/I

N/I

N/I

Kendall 2013

Expressed as BMI (kg/m²). Obesity defined by UK BMI centile charts. No reference for how BMI SDS was calculated (IO)

How and when trial authors assessed adverse events was not described. No explanation to how they defined a severe/series event

N/I

N/I

Participants had hyperinsulinaemia, impaired fasting glucose or impaired glucose tolerance

Insulin resistance/sensitivity was assessed using:

HOMA‐IR, QUICKI, whole‐body insulin sensitivity index, adiponectin‐to‐leptin ratio (IO)

Maahs 2006

Expressed as BMI (kg/m²). Obesity defined as BMI that exceeded the 85th percentile for age and sex (assume this from the CDC standards) (IO)

Adverse events assessed at each monthly visit. Serious/severe adverse events not defined (AO, IO, SO)

Health‐related quality of life assessed by 4 questionnaires: Brief Symptom Inventory (Derogatis 1983), Parents and Children's KINDL (Ravens‐Sieberer 2001), IWQOL‐Kids (Kolotkin 1997; Kolotkin 2001), and a global ratings scale (SO)

Defined as suicide ‐ 1 participant in the orlistat group (AO, IO)

N/I

Mauras 2012

Expressed as BMI (kg/m²). BMI % determined using CDC standards (Kuczmarski 2000) (IO)

Trial authors did not describe how and when adverse events were assessed. Did not report number or type of adverse events

N/I

N/I

Elevated hsCRP and fibrogen concentrations were measured by immuno‐nephelometry (IO)

NCT00001723

BMI SDS calculated for age and sex according to CDC standards (IO)

Events were collected by systematic assessment. Trial authors did not define what a serious adverse event was (IO, SO)

N/I

N/I

N/I

Ozkan 2004

Expressed as BMI (kg/m²). Severe obesity defined as weight for height index > 140% (no reference) (IO)

Unclear how and when adverse events were assessed. All with mild gastrointestinal complaints apart from 2 (mild diffuse hair loss and another with muscle cramps). A serious/severe event was not defined

N/I

N/I

N/I

Prado 2012

Expressed as BMI (kg/m²). Obesity defined as BMI > 95th percentile for age and sex (no reference) (IO)

Adverse events monitored by ALT, AST and haemoglobin levels (IO)

N/I

N/I

Risk factors for diabetes mellitus type 2: high glycaemia fasting, high postload glucose or high insulin sensitivity. Insulin sensitivity accessed by HOMA

Rezvanian 2010

Expressed as BMI (kg/m²). Gave baseline BMI SDS (calculated using revised CDC growth charts: Kuczmarski 2000 but did not give follow‐up measurements (IO)

Participants and parents educated on possible signs of symptoms of hypoglycaemia. They were also given a 24‐hour mobile phone number to call if any adverse events occurred. No definition of severe/serious adverse events (SO)

N/I

N/I

N/I

Srinivasan 2006

Raw BMI (kg/m²) data not provided BMI z score (presented only on a graph) was calculated from the CDC reference data 2000. Obesity defined by the International Obesity Task Force (Cole 2000) (IO)

Unclear how and when adverse events were assessed. No definition for serious/severe events

N/I

N/I

Clinical suspicion of insulin resistance defined by fasting insulin‐to‐glucose ratio or presence of acanthosis nigricans (assessed by severity at the neck by a validated scale)

Insulin sensitivity was accessed by SI clamp (minimal model), fasting insulin and fasting glucose (IO)

Van Mil 2007

Expressed as BMI (kg/m²). BMI SDS was determined using the Dutch age‐ and sex‐adjusted BMI curves (Hansen 1998). Obesity defined as ≥ 97th percentile (no reference) (IO)

Adverse events were determined at each visit. Heart rate, DBP, SBP were monitored throughout the trial. No definition of a serious/severe event (AO, IO, SO)

N/I

N/I

N/I

Wiegand 2010

Expressed as BMI (kg/m²) ‐ reference: Park 2009. Also provided BMI SDS, no reference (IO)

Adverse events determined at the 3‐month and 6‐month visit by a clinical and biochemical assessment. No definition of a serious/severe event (AO, IO, SO)

N/I

N/I

Risk factors for type 2 diabetes: acanthosis nigricans, signs of metabolic syndrome and impaired fasting glucose

Insulin sensitivity was assessed by HOMA‐IR and insulin sensitivity index (IO)

Wilson 2010

Expressed as BMI (kg/m²). Used CDC charts to convert BMI to BMI z score (Kuczmarski 2000) (IO)

Adverse events assessed at each visit. An appendectomy was defined as a serious/severe event (AO, IO, SO)

N/I

N/I

N/I

Yanovski 2011

Expressed as BMI (kg/m²). Also expressed as BMI SDS (no reference) (IO)

Adverse events accessed at each visit and by laboratory analysis. A serious/severe event was not defined (AO, IO, SO)

N/I

N/I

Insulin sensitivity was calculated (from a SI clamp) using the metabolic rate‐to‐steady‐state insulin ratio. Insulin resistance estimated using HOMA‐IR (IO)

^aIn addition to definition of endpoint measurement, description who measured the outcome (AO: adjudicated outcome measurement; IO: investigator‐assessed outcome measurement; SO: self‐reported outcome measurement).

ALT: alanine transaminase; AST: aspartate transaminase; BMI: body mass index; BMI SDS: body mass index standard deviation score; CDC: Centers for Disease Control and Prevention; DBP: diastolic blood pressure; FGIR: fasting insulin concentration/fasting glucose concentration; HbA1c: glycosylated haemoglobin A1c; HDL: high‐density lipoprotein; HOMA(‐IR): homeostasis model assessment (insulin resistance); hsCRP: high sensitivity C‐reactive protein; IWQOL: Impact of Weight on Quality of Life questionnaire; LDL: low‐density lipoprotein; N/I: not investigated; OGTT: oral glucose tolerance test; QUICKI: quantitative insulin check index; SBP: systolic blood pressure; SI clamp: insulin sensitivity clamp; WHO: World Health Organization.

Trial

Body fat distribution

Behaviour change

Participants views of the intervention

Socioeconomic effects

Atabek 2008

N/I

Food consumption was assessed by the completion of a detailed questionnaire at the beginning and end of the trial (no reference or results given) (SO)

N/I

N/I

Berkowitz 2003

Waist circumference measured using reference: Calloway 1988 (IO)

Hunger was evaluated by the Eating Inventory (range 0 to 14) (Stunkard 1985) (SO)

N/I

N/I

Berkowitz 2006

Waist circumference ‐ no description (IO)

N/I

N/I

N/I

Chanoine 2005

Waist circumference ‐ no description on how it was measured. Body composition measured by whole body DEXA (IO)

N/I

N/I

N/I

Clarson 2009

Waist circumference was measured in the standing position at the level of the umbilicus to the nearest 0.1 cm using a constant tension tape (no reference) (IO)

N/I

N/I

N/I

Franco 2014

Waist circumference and hip circumference measured at the smallest and largest diameter. Arm circumference at the middle third of the left arm (no reference) (IO)

N/I

N/I

N/I

Freemark 2001

N/I

N/I

N/I

N/I

Garcia‐Morales 2006

Waist circumference ‐ measured with a flexible tape between the highest point of the iliac crest and the lowest part of the costal margin at the midaxillary line (no reference) (IO)

A detailed questionnaire on food consumption was completed at the beginning and end of the trial (no reference) (SO)

N/I

N/I

Godoy‐Matos 2005

Waist circumference ‐ measured at the minimal circumference between iliac crest and last rib edge. Hip circumference assessed at the greatest circumference through the major trochanters (no reference) (IO)

N/I

N/I

N/I

Kendall 2013

Waist‐to‐hip ratio (no reference) (IO)

3 previously validated questionnaires (food frequency, diet and eating behaviour, and physical activity) were completed by each child at the start and end of the trial. No results presented (SO)

N/I

N/I

Maahs 2006

BIA

Diet records recorded before enrolment and at 3 and 6 months. No reference or results provided (SO)

N/I

N/I

Mauras 2012

Waist circumference measured at umbilicus (no reference). Intrahepatic fat content measured using fast MRI. References: Fishbein 2001; Fishbein 2003. Body composition was measured DEXA. Also measured waist‐to‐height ratio (no reference) (IO)

N/I

N/I

N/I

NCT00001723

N/I

N/I

N/I

N/I

Ozkan 2004

N/I

N/I

N/I

N/I

Prado 2012

Waist circumference ‐ measured with a central flexible tape, corresponding to the perimeter less between the iliac crest and the bottom edge last rib, then exhale with arms relaxed on both sides (no reference) (IO)

N/I

N/I

N/I

Rezvanian 2010

Waist circumference ‐ measured at a point midway between the lower border of the rib cage and the iliac crest at the end of normal expiration (no reference) (IO)

N/I

N/I

N/I

Srinivasan 2006

Raw waist circumference data not reported. Waist circumference was calculated from the mean of 3 measures at the level of the umbilicus (no reference). Waist circumference z scores calculated from recent multiracial American reference data (Fernandez 2004). Raw body composition data were not reported. DEXA scans also used. MRI whole‐body scans (IO)

N/I

N/I

N/I

Van Mil 2007

Body composition was assessed using a 4‐component reference model: total bodyweight = fat mass + total body water + total bone mineral content and remaining fat‐free mass (references: Fuller 1992; Van Marken Lichtenbelt 1999). To calculate this they used densitometry, deuterium dilution (Maastricht protocol) with labelled water test and DEXA (IO)

Physical activity level was estimated using an activity questionnaire. A 7‐day dietary record was given to each participant. Only the food quotient used in the assessment (respiratory exchange ratio to calculate TEE). Rest of the data not presented (IO, SO)

N/I

N/I

Wiegand 2010

Waist‐to‐hip ratio and body composition (BIA) were measured but no explanation to how and no results given (apart from saying they were not significant) (IO)

N/I

N/I

N/I

Wilson 2010

Abdominal CT scans evaluated abdominal fat content and distribution (Borkan 1982). Whole body DEXA used to measure % body fat and lean body mass (von Scheven 2006). Waist circumference measured at the smallest circumference below the rib cage and above the umbilicus (Wang 2003) (IO)

N/I

N/I

N/I

Yanovski 2011

Abdominal and hip circumferences (assessed in triplicate) and triceps skinfold thickness. Whole‐body fat mass by DEXA and by air displacement plethysmography; and intra‐abdominal and subcutaneous abdominal adipose tissue by MRI at L2 to L3 and L4 to L5 (IO)

N/I

N/I

N/I

^aIn addition to definition of endpoint measurement, description who measured the outcome (AO: adjudicated outcome measurement; IO: investigator‐assessed outcome measurement; SO: self‐reported outcome measurement).

BIA: bioelectrical impedance analysis; CT: computed tomography; DEXA: dual‐energy X‐ray absorptiometry; MRI: magnetic resonance imaging; n: number of participants; N/I: not investigated; TEE: total energy expenditure.

Trial

Intervention(s) and comparator(s)

Participants included in analysis
(N)

Deaths
(N)

Deaths
(% of participants)

Participants with at least one adverse event
(N)

Participants with at least one adverse event
(%)

Participants with at least one severe/serious adverse event
(N)

Participants with at least one severe/serious adverse event
(%)

Atabek 2008

I: metformin + diet and physical activity advice

90

0

0

2

2.2

0

0

C: placebo + diet and physical activity advice

30

0

0

0

0.0

0

0

Berkowitz 2003

I: behavioural programme + sibutramine

43

0

0

6

14.0

‐

‐

C: behavioural programme + placebo

39

0

0

3

7.7

‐

‐

Berkowitz 2006

I: behavioural therapy programme + sibutramine

368

0

0

327

88.9

10

2.7

C: behavioural therapy programme + placebo

130

0

0

111

85.4

1

0.8

Chanoine 2005

I: orlistat + diet + exercise + behavioural therapy

352

0

0

341

97

11

3

C: placebo + diet + exercise + behavioural therapy

181

0

0

170

94

5

3

Clarson 2009

I: metformin + lifestyle intervention

14

0

0

0

0

0

0

C: lifestyle intervention only

17

0

0

0

0

0

0

Franco 2014

I: sibutramine + dietary guidance

63

‐

‐

8

13.4

0

0

C: placebo + dietary guidance

63

‐

‐

3

4.9

0

0

Freemark 2001

I: metformin

15

0

0

4

26.7

0

0

C: placebo

17

0

0

1

5.9

0

0

Garcia‐Morales 2006

I: sibutramine + diet + exercise

23

0

0

10

43.5

0

0

C: placebo + diet + exercise

23

0

0

10

43.5‐

0

0

Godoy‐Matos 2005

I: sibutramine + hypocaloric diet + exercise

30

0

0

‐^a

‐

0

0

C: placebo + hypocaloric diet + exercise

30

0

0

‐^a

‐

0

0

Kendall 2013

I: metformin + healthy lifestyle advice

74

0

0

20

27.0

0

0

C: control + healthy lifestyle advice

77

0

0

8

10.4

0

0

Maahs 2006

I: orlistat + diet and exercise therapy

20

1

5.0

‐

‐

1

5.0

C: placebo + diet and exercise therapy

20

0

0

‐

‐

0

0

Mauras 2012

I: metformin + diet/exercise intervention

35

0

0

‐

‐

0

0

C: diet/exercise intervention

31

0

0

‐

‐

0

0

NCT00001723

I: orlistat + behavioural weight loss programme

100

0

0

95

95

0

0

C: placebo + behavioural weight loss programme

100

0

0

94

94

2

2

Ozkan 2004

I: conventional treatment + orlistat

22

0

0

22

100

‐

‐

C: conventional treatment

20

0

0

0

0

‐

‐

Prado 2012

I: metformin + nutritional guide and exercise programme

10

0

0

‐

‐

0

0

C: placebo + nutritional guide and exercise programme

9

0

0

‐

‐

0

0

Rezvanian 2010

I1: metformin + healthy eating and physical activity advice

45

0

0

7

15.6

0

0

I2: fluoxetine + healthy eating and physical activity advice

45

0

0

‐

‐

0

0

I3: metformin and fluoxetine + healthy eating and physical activity advice

45

0

0

‐

‐

0

0

C: placebo + healthy eating and physical activity advice

45

0

0

‐

‐

0

0

Srinivasan 2006

I: metformin first then placebo + "standardised information on healthy eating and exercise"

13

0

0

‐^b

‐

0

0

C: placebo first then metformin + "standardised information on healthy eating and exercise"

15

0

0

‐^b

‐

0

0

Van Mil 2007

I: sibutramine + energy‐restricted diet and exercise plan

12

0

0

12

100

‐

‐

C: placebo + energy‐restricted diet and exercise plan

12

0

0

9

75

‐

‐

Wiegand 2010

I: metformin + multiprofessional lifestyle intervention

36

0

0

8

22.2

‐

‐

C: placebo + multiprofessional lifestyle intervention

34

0

0

13

38.2

‐

‐

Wilson 2010

I: metformin + lifestyle intervention

38

0

0

‐^c

‐

2

5.3

C: placebo + lifestyle intervention

38

0

0

‐^c

‐

0

0

Yanovski 2011

I: metformin + dietitian‐administered weight‐reduction programme

53

0

0

‐^d

‐

0

0

C: placebo + dietitian‐administered weight‐reduction programme

47

0

0

‐^d

‐

0

0

"‐" denotes not reported.

^aNumber of participants with one or multiple adverse events: sibutramine group 47 events in 30 participants; placebo group 45 events in 30 participants.
^bTwo participants were unable to tolerate metformin 1000 mg twice daily because of nausea and were switched to metformin 750 mg twice daily with slower dose increments.
^cNumber of participants with one or multiple adverse events: metformin group: 52 events in 38 participants; placebo group: 43 events in 38 participants.
^dA total of 9/53 (17%) metformin‐treated children were unable to take the highest dose of 2000 mg/d and were prescribed doses ranging from 500 mg/d to 1500 mg/d; number of participants with one or multiple adverse events: metformin group: 64 events in 53 participants; placebo group: 25 events in 47 participants.

C: comparator; I: intervention; n: number pf participants.

Trial

Intervention(s) and comparator(s)

Participants included in analysis
(N)

Participants discontinuing trial due to an adverse event
(N)

Participants discontinuing trial due to an adverse event
(%)

Participants with at least one hospitalisation
(N)

Participants with at least one hospitalisation
(%)

Participants with at least one outpatient treatment
(N)

Participants with at least one outpatient treatment
(%)

Atabek 2008

I: metformin + diet and physical activity advice

90

0

0

0

0

0

0

C: placebo + diet and physical activity advice

30

0

0

0

0

0

0

Berkowitz 2003

I: behavioural programme + sibutramine

42

0

0

‐

‐

‐

‐

C: behavioural programme + placebo

39

1

2.5

‐

‐

‐

‐

Berkowitz 2006

I: behavioural therapy programme + sibutramine

368

23

6

‐

‐

‐

‐

C: behavioural therapy programme + placebo

130

7

5

‐

‐

‐

‐

Chanoine 2005

I: orlistat + diet + exercise + behavioural therapy

352

12

3

10

2.8

0

0

C: placebo + diet + exercise + behavioural therapy

181

3

2

5

2.8

0

0

Clarson 2009

I: metformin + lifestyle intervention

14

0

0

0

0

0

0

C: lifestyle intervention only

17

0

0

0

0

0

0

Franco 2014

I: sibutramine + dietary guidance

63

0

0

0

0

0

0

C: placebo + dietary guidance

63

0

0

0

0

0

0

Freemark 2001

I: metformin

15

0

0

0

0

0

0

C: placebo

17

0

0

0

0

0

0

Garcia‐Morales 2006

I: sibutramine + diet + exercise

23

0

0

‐

‐

‐

‐

C: placebo + diet + exercise

23

0

0

‐

‐

‐

‐

Godoy‐Matos 2005

I: sibutramine + hypocaloric diet + exercise

30

0

0

0

0

0

0

C: placebo + hypocaloric diet + exercise

30

0

0

0

0

0

0

Kendall 2013

I: metformin + healthy lifestyle advice

74

0

0

‐

‐

‐

‐

C: control + healthy lifestyle advice

77

0

0

‐

‐

‐

‐

Maahs 2006

I: orlistat + diet and exercise therapy

20

3

15

‐

‐

‐

‐

C: placebo + diet and exercise therapy

20

0

0

‐

‐

‐

‐

Mauras 2012

I: metformin + diet/exercise intervention

35

0

0

0

0

0

0

C: diet/exercise intervention

31

0

0

0

0

0

0

NCT00001723

I: orlistat + behavioural weight loss programme

100

1

1

‐

‐

‐

‐

C: placebo + behavioural weight loss programme

100

2

2

‐

‐

‐

‐

Ozkan 2004

I: conventional treatment + orlistat

22

7

32

‐

‐

‐

‐

C: conventional treatment

20

0

0

‐

‐

‐

‐

Prado 2012

I: metformin + nutritional guide and exercise programme

10

0

0

0

0

0

0

C: placebo + nutritional guide and exercise programme

9

0

0

0

0

0

0

Rezvanian 2010

I1: metformin + healthy eating and physical activity advice

45

0

0

0

0

0

0

I2: fluoxetine + healthy eating and physical activity advice

45

0

0

0

0

0

0

I3: metformin and fluoxetine + healthy eating and physical activity advice

45

0

0

0

0

0

0

C: placebo + healthy eating and physical activity advice

45

0

0

0

0

0

0

Srinivasan 2006

I: metformin first then placebo + "standardised information on healthy eating and exercise"

13

0

0

0

0

0

0

C: placebo first then metformin + "standardised information on healthy eating and exercise"

15

0

0

0

0

0

0

Van Mil 2007

I: sibutramine + energy‐restricted diet and exercise plan

12

1

8

0

0

0

0

C: placebo + energy‐restricted diet and exercise plan

12

0

0

0

0

0

0

Wiegand 2010

I: metformin + multiprofessional lifestyle intervention

36

3

8.3

‐

‐

‐

‐

C: placebo + multiprofessional lifestyle intervention

34

1

2.9

‐

‐

‐

‐

Wilson 2010

I: metformin + lifestyle intervention

38

3

7.9

‐

‐

‐

‐

C: placebo + lifestyle intervention

38

1

2.6

‐

‐

‐

‐

Yanovski 2011

I: metformin + dietitian‐administered weight‐reduction programme

53

1

1.9

‐

‐

‐

‐

C: placebo + dietitian‐administered weight‐reduction programme

47

0

0

‐

‐

‐

‐

"‐" denotes not reported.

C: comparator; I: intervention; n: number of participants.

Trial

Intervention(s) and comparator(s)

Participants included in analysis
(N)

Participants with a specific adverse event
(description)

Participants with at least one specific adverse events
(N)

Participants with at least one specific adverse event
(%)

Atabek 2008

I: metformin + diet and physical activity advice

90

1. Diarrhoea and mild abdominal pain

2. Mild discomfort from the abdomen

1. 1

2. 1

1. 1.1

2. 1.1

C: placebo + diet and physical activity advice

30

‐

‐

‐

Berkowitz 2003

I: behavioural programme + sibutramine

42

1. High blood pressure and pulse rate

2. High blood pressure only

3. High pulse rate only

4. Knee surgery

5. Ventricular premature beats

6. Cholelithiasis/cholecystectomy

7. Rash, viral

1. 3

2. 1

3. 1

4. 1

5. 1

6. 1

7. 1

1. 7.1

2. 2.4

3. 2.4

4. 2.4

5. 2.4

6. 2.4

7. 2.4

C: behavioural programme + placebo

39

1. Elevated blood pressure and pulse rate*

2. Elevated pulse rate only*

3. Atrial premature beats

4. Tonsillectomy

5. Ventricular premature beats*

6. Ecchymoses*

1. 1

2. 1

3. 1

4. 2

5. 1

6. 2

1. 2.6

2. 2.6

3. 2.6

4. 5.1

5. 2.6

6. 5.1

Berkowitz 2006

I: behavioural therapy programme + sibutramine

368

1. Infection

2. Headache

3. Pharyngitis

4. Tachycardia

5. Accidental injury

6. Dry mouth

7. Pain

8. Hypertension

9. Rhinitis

10. Abdominal pain

11. Dysmenorrhoea

12. Vomiting

13. Cough increased

14. Nausea

15. Dizziness

16. Rash

17. Sinusitis

18. Constipation

19. Flu syndrome

20. Insomnia

21. Viral infection

22. Allergic reaction

23. Suicide attempt

24. Depression

25. Syncope

26. Chest pain

27. Arrhythmia

28. Extra systoles

1. 167

2. 113

3. 49

4. 46

5. 41

6. 41

7. 42

8. 39

9. 41

10. 37

11. 21

12. 32

13. 28

14. 31

15. 28

16. 25

17. 24

18. 24

19. 23

20. 23

21. 20

22. 18

23. 1

24. 5

25. ‐

26. ‐

27. ‐

28. ‐

1. 45.3

2. 30.7

3. 13.3

4. 12.5

5.11.1

6.11.1

7. 11.4

8. 10.6

9. 11.1

10. 10.1

11. 5.7

12. 8.7

13. 7.6

14. 8.4

15. 7.6

16. 6.8

17. 6.5

18. 6.5

19. 6.3

20. 6.3

21. 5.4

22. 4.9

23. 0.3

24. 1.4

25. ≤ 1.5

26. ≤ 1.5

27. ≤ 1.5

28. ≤ 1.5

C: behavioural therapy programme + placebo

130

1. Infection

2. Headache

3. Pharyngitis

4. Tachycardia

5. Accidental injury

6. Dry mouth

7. Pain

8. Hypertension

9. Rhinitis

10. Abdominal pain

11. Dysmenorrhoea

12. Vomiting

13. Cough increased

14. Nausea

15. Dizziness

16. Rash

17. Sinusitis

18. Constipation

19. Flu syndrome

20. Insomnia

21. Viral infection

22. Allergic reaction

23. Suicide attempt

24. Depression

25. Syncope

26. Chest pain

27. Arrhythmia

28. Extra systoles

1. 53

2. 39

3. 23

4. 8

5. 8

6. 8

7. 12

8. 11

9. 17

10. 12

11. 13

12. 7

13. 12

14. 12

15. 5

16. 7

17. 6

18. 3

19. 7

20. 4

21. 2

22. 7

23. 1

24. 1

25. ‐

26. ‐

27. ‐

28. ‐

1. 41

2. 30

3. 18

4. 6.2

5. 6.2

6. 6.2

7. 9.2

8. 8.5

9. 13.1

10. 9.2

11. 10

12. 5.4

13. 9.2

14. 9.2

15. 3.8

16. 5.4

17. 4.6

18. 2.3

19. 5.4

20. 3.1

21. 1.5

22. 5.4

23. 0.8

24. 0.8

25. ≤ 1.5

26. ≤ 1.5

27. ≤ 1.5

28. ≤ 1.5

Chanoine 2005

I: orlistat + diet + exercise + behavioural therapy

352

1. Fatty/oily stool

2. Oily spotting

3. Oily evacuation

4. Abdominal pain

5. Fecal urgency

6. Flatus with discharge

7. Soft stool

8. Nausea

9. Increased defecation

10. Flatulence

11. Fecal incontinence

12. Headache

13. Upper respiratory tract infection

14. Nasopharyngitis

15. Sore throat

16. Sinusitis

17. Joint sprain

18. Nasal congestion

19. Back pain

20. Gastroenteritis

21. Seasonal rhinitis

22. Limb injury

23. Asymptomatic gallstones

24. Pilonidal abscess

25. Depression

26. Asthma attack

27. Seizure

28. Admission for repair of deviated nasal septum

29. Appendicitis

30. Cholelithiasis

31. Gallbladder disorder followed by cholecystectomy

32. Adenoidal hypertrophy

33. Aseptic meningitis

34. Electrocardiogram abnormalities

1. 177

2. 102

3. 82

4. 77

5. 73

6. 70

7. 53

8. 52

9. 48

10. 32

11. 31

12. 134

13. 114

14. 99

15. 59

16. 40

17. 35

18. 31

19. 28

20. 23

21. 21

22. 18

23. 6

24. 1

25. 2

26. 1

27. 1

28. 1

29. 1

30. 1

31. 1

32. 1

33. 1

34. 10

1. 50.3

2. 29.0

3. 23.3

4. 21.9

5. 20.7

6. 19.9

7. 15.1

8. 14.8

9. 13.6

10. 9.1

11. 8.8

12. 38.1

13. 32.4

14. 28.1

15. 16.8

16. 11.4

17. 9.9

18. 8.8

19. 8.0

20. 6.5

21. 6.0

22. 5.1

23. 1.7

24. 0.3

25. 0.6

26. 0.3

27. 0.3

28. 0.3

29. 0.3

30. 0.3

31. 0.3

32. 0.3

33. 0.3

34. 2.8

C: placebo + diet + exercise + behavioural therapy

181

1. Fatty/oily stool

2. Oily spotting

3. Oily evacuation

4. Abdominal pain

5. Fecal urgency

6. Flatus with discharge

7. Soft stool

8. Nausea

9. Increased defecation

10. Flatulence

11. Fecal incontinence

12. Headache

13. Upper respiratory tract infection

14. Nasopharyngitis

15. Sore throat

16. Sinusitis

17. Joint sprain

18. Nasal congestion

19. Back pain

20. Gastroenteritis

21. Seasonal rhinitis

22. Limb injury

23. Acute demyelinating encephalomyelitis

24. Facial palsy

25. Pneumonia

26. Worsening of asthma

27. Pain in the right side

28. Electrocardiogram abnormalities

1.15

2. 7

3. 3

4. 20

5. 20

6. 5

7. 19

8. 23

9. 16

10. 8

11. 1

12. 56

13. 48

14. 46

15. 29

16. 19

17. 17

18. 11

19. 11

20. 8

21. 9

22. 5

23. 1

24. 1

25. 1

26. 1

27. 1

28. 1

1. 8.3

2. 3.9

3. 1.7

4. 11.0

5. 11.0

6. 2.8

7. 10.5

8. 12.7

9. 8.8

10. 4.4

11. 0.6

12. 30.9

13. 26.5

14. 25.4

15. 16.0

16. 10.5

17. 9.4

18. 6.1

19. 6.1

20. 4.4

21. 5.0

22. 2.8

23. 0.6

24. 0.6

25. 0.6

26. 0.6

27. 0.6

28. 0.6

Clarson 2009

I: metformin + lifestyle intervention

14

‐

‐

‐

C: lifestyle intervention only

17

‐

‐

‐

Franco 2014

I: sibutramine + dietary guidance

63

1. Anorexia

2. Dry mouth

3. Headache

4. Constipation

5. Changing the mood

6. Dyspnoea

7. Epigastralgia

8. Hypertension

9. Insomnia

10. Nausea

11. Tachycardia

12. Dizziness

13. Tremors

14. Vomiting

‐

1. 0.9

2. 1.7

3. 6.8

4. 3.8

5. 1.3

6. 0.4

7. 0.9

8. 0.9

9. 1.3

10. 2.1

11. 1.3

12. 3.4

13. 0.4

14. 0.4

C: placebo + dietary guidance

63

1. Change in taste

2. Headache

3. Diarrhoea

4. Hypertension

5. Irritability

6. Tachycardia

7. Dizziness

‐

1. 0.9

2. 3.3

3. 2.8

4. 0.5

5. 1.4

6. 0.5

7. 0.9

Freemark 2001

I: metformin

15

1. Transient abdominal discomfort or diarrhoea

2. Intermittent nausea

1. 3

2. 1

1. 20

2. 6.7

C: placebo

17

1. Transient abdominal discomfort or diarrhoea

1. 1

1. 5.9

Garcia‐Morales 2006

I: sibutramine + diet + exercise

23

1. Headache

2. Dry mouth

3. Headache with nausea

4. Headache with weakness

5. High DBP

6. High heart rate

7. High blood pressure (baseline)

8. High blood pressure (end of trial)

1. 1

2. 1

3. 1

4. 1

5. 1

6. 3

7. 2

8. 2

1. 4.3

2. 4.3

3. 4.3

4. 4.3

5. 4.3

6. 13.0

7. 8.7

8. 8.7

C: placebo + diet + exercise

23

1. Headache

2. Headache with somnolence

3. Headache with dry mouth

4. High DBP

5. High heart rate

6. High blood pressure (baseline)

7. High blood pressure (end of trial)

1. 2

2. 1

3. 1

4. 2

5. 2

6. 7

7. 2

1. 8.7

2. 4.3

3. 4.3

4. 8.7

5. 8.7

6. 30.4

7. 8.7

Godoy‐Matos 2005

I: sibutramine + hypocaloric diet + exercise

30

1. Dry mouth

2. Headache

3. Constipation

4. Abdominal pain

5. Cold

6. Dizzy

7. Tonsillitis

8. Menstrual cramp

9. Nausea

10. Toothache

11. Otitis

12. Hair loss

13. Rhinitis

14. Sinusitis

15. Sleepiness

16. Dry cough

17. Myalgia

18. Viral infection

19. Lumbago

1. 7

2. 13

3. 12

4. 3

5. 9

6. 3

7. 2

8. 8

9. 3

10. 3

11. 3

12. 2

13. 1

14. 1

15. 1

16. 1

17. 1

18. 2

19. 2

1. 23.3

2. 43.3

3. 40.0

4. 10.0

5. 30.0

6. 10.0

7. 6.7

8. 26.7

9. 10.0

10. 10.0

11. 10.0

12. 6.7

13. 3.3

14. 3.3

15. 3.3

16. 3.3

17. 3.3

18. 6.7

19. 6.7

C: placebo + hypocaloric diet + exercise

30

1. Dry mouth

2. Headache

3. Constipation

4. Abdominal pain

5. Cold

6. Dizzy

7. Tonsillitis

8. Menstrual cramp

9. Nausea

10. Toothache

11. Otitis

12. Hair loss

13. Rhinitis

14. Sinusitis

15. Sleepiness

16. Dry cough

17. Myalgia

18. Bronchitis

19. Inguinal dermatitis

20. Fever

1. 3

2. 21

3. 4

4. 4

5. 11

6. 2

7. 2

8. 6

9. 1

10. 1

11. 1

12. 1

13. 2

14. 2

15. 2

16. 2

17. 2

18. 2

19. 2

20. 2

1. 10.0

2. 70.0

3. 13.3

4. 13.3

5. 36.7

6. 6.7

7. 6.7

8. 20.0

9. 3.3

10. 3.3

11. 3.3

12. 3.3

13. 6.7

14. 6.7

15. 6.7

16. 6.7

17. 6.7

18. 6.7

19. 6.7

20. 6.7

Kendall 2013

I: metformin + healthy lifestyle advice

74

‐

‐

‐

C: control + healthy lifestyle advice

77

‐

‐

‐

Maahs 2006

I: orlistat + diet and exercise therapy

20

‐

‐

‐

C: placebo + diet and exercise therapy

20

‐

‐

‐

All:

40

1. Soft stools

2. Oily spotting

3. Fatty or oily stools

4. Oily evacuation

5. Liquid stools

6. Cramping

7. Flatus with discharge

8. Fecal incontinence

‐

‐

Mauras 2012

I: metformin + diet/exercise intervention

35

‐

‐

‐

C: diet/exercise intervention

31

‐

‐

‐

NCT00001723

I: orlistat + behavioural weight loss programme

100

1. Hypoglycaemia

2. Left lower quadrant pain and vomiting

3. Ear disorders (otitis, earache, ear pain)

4. Eye disorders (change in vision, conjunctivitis, styes)

5. Abdominal pain or cramping

6. Bloating or gas

7. Borborygmi

8. Constipation

9. Controlled discharge of oil without stool

10. Decreased frequency of bowel movements

11. Diarrhoea

12. Fatty‐appearing stools

13. Flatulence (passage of gas)

14. Flatus with discharge

15. Frequent urge for bowel movement

16. Hiccups

17. Increased frequency of bowel movements

18. Nausea

19. Oily spotting

20. Rectal bleeding ‐ haemorrhoids

21. Soft or deliquescent stools

22. Stomach pain or cramps

23. Stools almost all liquid with very few solid parts

24. Stools hard and in the shape of small pellets

25. Stools mixed with fat or with a separate oily layer

26. Uncontrolled passage of stool or oil

27. Urgent, but controlled, need to produce stools

28. Vomiting

29. Dizziness

30. Epistaxis

31. Feeling cold

32. Headache

33. Increased sweating

34. Increased thirst

35. Sinusitis, postnasal drip or nasal stuffiness

36. Unusual tiredness or weakness (fatigue)

37. Pharyngitis

38. Sinusitis, postnasal drip or nasal stuffiness

39. Decrease in appetite

40. Muscle pain, stiffness, cramps or ache

41. Migraine headaches

42. Mental depression

43. Dysuria or UTI

44. Nocturia

45. Asthma symptoms

46. Cough

47. Upper respiratory infection

48. Skin rash

1. 0

2. 0

3. 7

4. 8

5.16

6. 18

7. 6

8. 1

9. 56

10. 25

11. 21

12. 61

13. 60

14. 43

15. 19

16. 1

17. 68

18. 10

19. 6

20. 4

21. 68

22. 8

23. 64

24. 11

25. 83

26. 60

27. 44

28. 7

29. 4

30. 5

31. 5

32. 14

33. 3

34. 5

35. 2

36. 1

37. 6

38. 1

39. 11

40. 16

41. 3

42. 1

43. 1

44. 0

45. 5

46. 0

47. 14

48. 5

1. 0

2. 0

3. 7

4. 8

5.16

6. 18

7. 6

8. 1

9. 56

10. 25

11. 21

12. 61

13. 60

14. 43

15. 19

16. 1

17. 68

18. 10

19. 6

20. 4

21. 68

22. 8

23. 64

24. 11

25. 83

26. 60

27. 44

28. 7

29. 4

30. 5

31. 5

32. 14

33. 3

34. 5

35. 2

36. 1

37. 6

38. 1

39. 11

40. 16

41. 3

42. 1

43. 1

44. 0

45. 5

46. 0

47. 14

48. 5

C: placebo + behavioural weight loss programme

100

1. Hypoglycaemia

2. Left lower quadrant pain and vomiting

3. Ear disorders (otitis, earache, ear pain)

4. Eye disorders (change in vision, conjunctivitis, styes)

5. Abdominal pain or cramping

6. Bloating or gas

7. Borborygmi

8. Constipation

9. Controlled discharge of oil without stool

10. Decreased frequency of bowel movements

11. Diarrhoea

12. Fatty‐appearing stools

13. Flatulence (passage of gas)

14. Flatus with discharge

15. Frequent urge for bowel movement

16. Hiccups

17. Increased frequency of bowel movements

18. Nausea

19. Oily spotting

20. Rectal bleeding ‐ haemorrhoids

21. Soft or deliquescent stools

22. Stomach pain or cramps

23. Stools almost all liquid with very few solid parts

24. Stools hard and in the shape of small pellets

25. Stools mixed with fat or with a separate oily layer

26. Uncontrolled passage of stool or oil

27. Urgent, but controlled, need to produce stools

28. Vomiting

29. Dizziness

30. Epistaxis

31. Feeling cold

32. Headache

33. Increased sweating

34. Increased thirst

35. Sinusitis, postnasal drip or nasal stuffiness

36. Unusual tiredness or weakness (fatigue)

37. Pharyngitis

38. Sinusitis, postnasal drip or nasal stuffiness

39. Decrease in appetite

40. Muscle pain, stiffness, cramps, or ache

41. Migraine headaches

42. Mental depression

43. Dysuria or UTI

44. Nocturia

45. Asthma symptoms

46. Cough

47. Upper respiratory infection

48. Skin rash

1. 1

2. 1

3. 7

4. 9

5. 21

6. 5

7. 2

8. 7

9. 11

10. 22

11. 8

12. 6

13. 47

14. 11

15. 3

16. 3

17. 45

18. 9

19. 0

20. 2

21. 42

22. 9

23. 34

24. 10

25. 18

26. 11

27. 18

28. 7

29. 4

30. 2

31.2

32. 17

33. 4

34. 4

35. 5

36. 5

37. 12

38. 3

39. 9

40. 12

41. 0

42. 3

43. 5

44. 3

45. 3

46. 7

47. 17

48. 2

1. 1

2. 1

3. 7

4. 9

5. 21

6. 5

7. 2

8. 7

9. 11

10. 22

11. 8

12. 6

13. 47

14. 11

15. 3

16. 3

17. 45

18. 9

19. 0

20. 2

21. 42

22. 9

23. 34

24. 10

25. 18

26. 11

27. 18

28. 7

29. 4

30. 2

31.2

32. 17

33. 4

34. 4

35. 5

36. 5

37. 12

38. 3

39. 9

40. 12

41. 0

42. 3

43. 5

44. 3

45. 3

46. 7

47. 17

48. 2

Ozkan 2004

I: conventional treatment + orlistat

22

1. Frequent stools

2. Soiling, frequent defecation

3. Mild hair loss

4. Reported muscle cramps

1. 22

2. 5

3. 1

4. 1

1. 100

2. 22.7

3. 4.5

4. 4.5

C: conventional treatment

20

‐

‐

‐

Prado 2012

I: metformin + nutritional guide and exercise programme

10

1. Increase levels of ALT

2. Increase levels of AST

3. Reduction in haemoglobin

‐

‐

C: placebo + nutritional guide and exercise programme

9

1. Increase levels of ALT

2. Increase levels of AST

3. Reduction in haemoglobin

‐

‐

Rezvanian 2010

I1: metformin + healthy eating and physical activity advice

45

1. Headache

2. Abdominal pain

3. Loose stool

1. 2

2. 2

3. 3

1. 4.4

2. 4.4

3. 6.6

I2: fluoxetine + healthy eating and physical activity advice

45

1. Dry mouth

2. Loose stool

1. 3

2. 2

1. 6.6

2. 4.4

I3: metformin and fluoxetine + healthy eating and physical activity advice

45

‐

‐

‐

C: placebo + healthy eating and physical activity advice

45

‐

‐

‐

Srinivasan 2006

I: metformin first then placebo + "standardised information on healthy eating and exercise"

13

‐

‐

‐

C: placebo first then metformin + "standardised information on healthy eating and exercise"

15

‐

‐

‐

Van Mil 2007

I: sibutramine + energy‐restricted diet and exercise plan

12

1. Clinical depression

2. Flu syndrome

3. Headache

4. Abdominal complaints

5. Agitation

6. Increased appetite

7. Rash

8. Dizziness

9. Dysmenorrhoea

10. Joint problem

11. Heart rate > 100 bpm on 2 occasions

12. DBP > 85 mmHg on 2 occasions

1. 1

2. 6

3. 2

4. 7

5. 3

6. 4

7. 2

8. 3

9. 3

10. 2

11. 4

12. 1

1. 8.3

2. 50

3. 16.6

4. 58.3

5. 25

6. 33.3

7. 16.6

8. 25

9. 25

10. 16.6

11. 33.3

12. 8.3

C: placebo + energy‐restricted diet and exercise plan

12

1. Flu syndrome

2. Headache

3. Agitation

4. Increased appetite

5. Dizziness

6. Joint problem

7. DBP > 85 mmHg on 2 occasions

1. 6

2. 3

3. 1

4. 2

5. 1

6. 2

7. 1

1. 50

2. 25

3. 8.3

4. 16.6

5. 8.3

6. 16.6

7. 8.3

Wiegand 2010

I: metformin + multiprofessional lifestyle intervention

36

1. Gastrointestinal symptoms

2. Unspecific (e.g. weakness or fatigue)

1. 5

2. 3

1. 13.9

2. 8.3

C: placebo + multiprofessional lifestyle intervention

34

1. Gastrointestinal symptoms

2. Unspecific (e.g. weakness or fatigue)

1. 9

2. 4

1. 26.5

2. 11.8

Wilson 2010

I: metformin + lifestyle intervention

38

1. Headache

2. Nausea

3. Vomiting

4. Upper respiratory tract infection

5. Musculoskeletal complaints

6. Elevated ALT levels

7. Appendectomy

8. Leg vein thrombosis

1. 18

2. 9

3. 6

4. 18

5. 5

6. 2

7. 1

8. 1

1. 47

2. 24

3. 16

4. 47

5. 13

6. 5

7. 3

8. 3

C: placebo + lifestyle intervention

38

1. Headache

2. Nausea

3. Vomiting

4. Upper respiratory tract infection

5. Musculoskeletal complaints

6. Elevated ALT levels

1. 13

2. 3

3. 1

4. 23

5. 7

6. 1

1. 34

2. 8

3. 3

4. 61

5. 18

6. 3

Yanovski 2011

I: metformin + dietitian‐administered weight‐reduction programme

53

1. Liquid or loose stools

2. Vomiting

3. Fatigue

4. Lost interest in usual pleasurable activities

1. 22

2. 22

3. 20

4. 1

1. 41.5

2. 41.5

3. 37.7

4. 1.9

C: placebo + dietitian‐administered weight‐reduction programme

47

1. Liquid or loose stools

2. Vomiting

3. Fatigue

1. 8

2. 10

3. 7

1. 17

2. 21.3

3. 14.9

*Berkowitz 2003: these adverse events occurred during the open‐label phase where all participants received sibutramine

ALT: alanine transaminase; AST: aspartate transaminase; bpm: beats per minute; DBP: diastolic blood pressure; n: number of participants; UTI: urinary tract infection

Trial

Date trial author contacted

Date trial author replied

Date trial author was asked for additional information
(short summary)

Date trial author provided data
(short summary)

Atabek 2008

24 January 2014

15 May 2014

No

24 January 2014 ‐ asked for additional unpublished data and other ongoing trials

15 May 2014 ‐ asked for further details about the trial including funding, allocation concealment, randomisation method, dropout rates and adverse events

N/A

Berkowitz 2003

20 January 2014

15 May 2014

No

20 January 2014 ‐ asked for additional unpublished data and other ongoing trials

15 May 2014 ‐ asked for further details about the trial including randomisation method, allocation concealment and adverse events

N/A

Berkowitz 2006

20 January 2014

15 May 2014

No

20 January 2014 ‐ asked for additional unpublished data and other ongoing trials

15 May 2014 ‐ asked for further details on the trial's adverse events

N/A

Chanoine 2005