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ARTICLE

Randomized Placebo-Controlled Trial of Metforminfor Adolescents With Polycystic Ovary Syndrome

Tracey Bridger, MD, FRCPC; Suzanne MacDonald, MD, FRCPC;Franziska Baltzer, MD, FRCPC; Celia Rodd, MD, FRCPC

Objective: To determine whether metformin or pla-cebo could, in conjunction with healthy lifestyle coun-seling, decrease serum testosterone levels and related ab-errations in adolescents with hyperandrogenism,hyperinsulinemia, and polycystic ovarian syndrome.

Design: Randomized, placebo-controlled, double-blind trial.

Setting: Pediatric university teaching hospital.

Participants: Twenty-two adolescents aged 13 to 18years with hyperinsulinemia and polycystic ovariansyndrome.

Intervention: Participants were randomly assigned totake a 12-week course of either metformin or placebo.

Main Outcome Measures: Pretreatment and post-treatment oral glucose tolerance tests, fasting lipid pro-files, and clinical measurements.

Results: There was a significant decline in mean serum

testosterone concentration with metformin (38.3 ng/

dL) compared with placebo (0.86 ng/dL) (95% confi-dence interval, to 0.29 for the mean difference be-tween groups). At completion, the relative riskof menseswas 2.50 times higher in the metformin group com-pared with the placebo (95% confidence interval, 1.12to 5.58). Measures of insulin sensitivity, including insu-lin area under the curve and HOMA (homeostasis modelassessment), demonstrated improvement only with met-formin, but these did not reach statistical significance.High-density lipoprotein cholesterol levels increased by6.98 mg/dL with metformin vs a decrease of 2.33 mg/dLwith placebo (95% confidence interval, 0.78 to 18.23 forthe mean difference between groups). There were no sig-nificant changes in body mass index, hirsutism, triglyc-eride levels, or total and low-density lipoprotein choles-terol levels.

Conclusion: Metformin significantly lowered total tes-tosterone concentrations,increased the likelihood of men-ses, and improved high-density lipoprotein cholesterollevels without affecting measures of insulin sensitivityor body weight.

Arch Pediatr Adolesc Med. 2006;160:241-246

POLYCYSTIC OVARY SYNDROME

(PCOS) is a common disor-der in women, characterizedby menstrual dysfunction andevidence of hyperandrogen-

ism (clinical or biochemical).1,2 It is diag-nosed in at least 5% to 10% of women be-tween adolescence and menopause, makingit one of the most prevalent hormonal dis-orders in this population.3-6 Once thoughtto be purely a cosmetic and fertility prob-

lem, it is now known that women withPCOS have increased risk factors for car-diovascular disease and are at risk of de-veloping diabetes.7-9

Although the pathogenesis is not fullyunderstood, evidence suggests insulinresistance and hyperinsulinemia play akey pathophysiologic role by promotingexcess androgen production from boththe ovaries and adrenal glands.10,11 Manystudies have demonstrated improvement

of hyperinsulinemia, hyperandrogen-emia, and clinical status in women byweight loss or treatment with insulin-sensitizing agents (such as metformin ortroglitazone).12,13

Polycystic ovary syndrome is increas-ingly recognized in adolescent girls and isone of the most frequent causes of andro-gen excess in this age group.14 The meta-bolic features seen in adult women withPCOS have also been reported in adoles-

cents with the disorder, including hyper-insulinemia.15-17 From these data, we in-fer that the pathogenesis is likely similarto that in adult women, which suggests atherapeutic role for reducing insulin lev-els or increasing insulin sensitivity in ado-lescents with PCOS.

There are currently very few studies ofmetformin in adolescent girls, and its usein this population remains controversial.Moreover, there are no randomized, pla-

Author Affiliations:Department of Pediatrics,Memorial University ofNewfoundland, St Johns(Dr Bridger); Department ofPediatrics, McGill University,Montreal, Quebec(Drs MacDonald, Baltzer,and Rodd).

(REPRINTED) ARCH PEDIATR ADOLESC MED/VOL 160, MAR 2006 WWW.ARCHPEDIATRICS.COM241

2006 American Medical Association. All rights reserved.

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cebo-controlled studies of metformin in adolescents withPCOS.1,14,18

The primary objective of this study was to determinewhether metformin or placebo, in conjunction withhealthy lifestyle counseling, could reduce serum testos-terone levels in adolescents with hyperandrogenism, hy-perinsulinemia, and PCOS. Secondary objectives cen-tered on the efficacy of metformin in restoring menses,attenuating insulin resistance, and/or improving lipid pro-

files in adolescents with this disorder.

METHODS

STUDY PARTICIPANTS

We enrolled 22 adolescents with PCOS and concomitant hy-perinsulinemia from the Endocrinology and Adolescent Medi-cine clinics of the Montreal Childrens Hospital (Montreal, Que-bec) between 1999 and 2002. Participants were at least 12 yearsold and had a history of menarche at least 2 years prior to en-rollment. Diagnosis of PCOS was based on previously re-ported criteria.7 All subjects had chronic oligomenorrhea (6menses in the preceding year) and clinical or biochemical evi-dence of hyperandrogenism. We excluded subjects with other

causes of hyperandrogenism, such as hyperprolactinemia, an-drogen-secreting tumors, or late-onset congenital adrenal hy-perplasia. Congenital adrenal hyperplasia was specifically ruledout by measuring 17 hydroxyprogesterone levels using an ad-renocorticotropin (ACTH) stimulation test.

Sample size was based on power calculations and the pub-lished effects of metformin treatment in adult women. We ap-proached eligible candidates sequentially until this goal wasachieved, and baseline demographic features did not differ be-tween participants and nonparticipants (not shown). Exclu-sion criteria included diabetes mellitus, renal or hepatic dis-ease,pregnancy, allergiesto metformin,taking oralcontraceptivesin the 6 months prior to enrollment, or taking medications thatcould influence the effects of insulin or androgens.

The study was approved by the research ethics board of the

Montreal Childrens Hospital. Each young woman gave in-formed consent and/or assent, and informed consent was ob-tained from their parents.

STUDY PROTOCOL

After a 12-hour overnightfast, theadolescentscame to thestudycenterand underwent a standard 75-g oral glucose tolerancetest(OGTT). At baseline, serum was collected to measure total tes-tosterone level, progesterone level, and lipid profile. At 0-, 30-,60-,90-,and120-minuteintervalsafter theglucose load,glucoseandinsulin levels weredrawn. Glucose tolerancewas assessedbycriteria from the American Diabetes Association (Alexandria,Va).19 Progesterone was measured to determine the phase of themenstrual cycle for accurate assessment of the serum lipids.

We performed a complete physical examination forall par-ticipants, including measuring height and weight, determin-ing blood pressure, and assessing hirsutism using the Ferri-man and Gallwey scoring system.20 This scoring system rangesfrom 0 to 36, with valuesgreateror equal to 8 consideredmod-erately hirsute.

All participantswereprovidedwith healthy eating and physi-cal activity counseling according to the Health Canada and Fit-ness Vitality healthy lifestyle program. A copy of this informa-tion was provided with a 3-month calendar to documentmedication adverse events, menses, and lifestyle changes. Pa-tients werethen randomized by drawsequentialsampling, with-

out replacement, to receive either metformin at the final doseof 750mg or identically appearing placebo tablets twice per day.They were advised to increase the medications over a 4-weekperiod to minimizeadverse effects. Telephonecontact was madeafter 4 to 6 weeks to discuss their progress.

After 12 weeks, theadolescents returned fora secondOGTT,baseline blood samples, andan interviewas duringthe first visit.Unused pills were returned to estimate compliance.

ASSAYS

Blood samples were centrifuged immediately, and serum forhormones and high-density lipoprotein (HDL) cholesterol wasstored at 20 C until assayed. Glucose, triglyceride, and totalcholesterol levels were immediately analyzed on the Vitros (Or-tho-Clinical, Johnson and Johnson, New Brunswick, NJ). High-density lipoprotein cholesterol was analyzedon the Cobas Mirosplatform(RocheDiagnostics, HoffmanLa Roche Ltd,Basel, Swit-zerland). Progesterone was assayed by Centaur chemilumines-cence platform (Chiron Corp, Emeryville, Calif). Insulin, de-hydroepiandrosterone sulfate, and prolactin were analyzed bythe chemiluminescent Immulite platform (Diagnostic Sys-tems, Webster, Tex). Serum was analyzed by radio immuno-assay kits for total testosterone (Pantax, Santa Monica, Calif ),17 beta estradiol, 17 hydroxyprogesterone (Diagnostic Sys-tems) and luteinizing hormone and follicle-stimulating hor-mone (Diagnostic Products Corp, Los Angeles, Calif).

Insulin sensitivity was estimated by calculating the insulinarea under the curve (AUC), a measure that has been vali-dated in women with PCOS against the hyperglycemic-euglycemic clamp.21We also calculated the homeostasis modelassessment(HOMA=[fasting insulin resultfasting glucose re-sult]/22.5) and quantitative insulin sensitivity check index(QUICKI= 1/[logarithm of fasting insulin resultlogarithm offasting glucose result]), both previously validated using the hy-perglycemic-euglycemic clamp.22-24

DATA ANALYSIS

Statistical analysis wasperformed with R, version 2.1.1.For con-tinuousvariables, thedifference between posttreatmentandbase-line values were calculated foreach subject andthe groups com-pared for equality of variance by F test. When variances wereequal, the mean difference in each group and 95% confidenceinterval (CI) for the difference between the 2 means were testedfor equality by a standard Welch t test procedure. The Satter-thwaite method was invoked for unequal variances (null hy-pothesis, HO; mean difference, 0). Categorical data (eg, returnof menses) were compared by Fisher exact test and expressedas a relative risk with associated 95% confidence interval (HOrelative risk, 1). In both cases, failure of the 95% confidenceinterval to cross the HO value reflects P.05.

RESULTS

Of 22 subjects recruited (n=11 in each group), only 1subject did not complete the study. One adolescent inthe placebo arm was able to provide information abouther compliance and clinical well-being at the end of thestudy period but was unable to present for the OGTT andphysical examination.

PREINTERVENTION CHARACTERISTICS

The clinical characteristics of the 2 groups of adolescentgirls at baseline are depicted in Table 1. They ranged



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in age from 13 to 18 years with an average age of 16.0years at the start of the study period. All were over-weight or obese with body mass index (BMI), calculatedas weight in kilograms divided by the square of heightin meters, ranging from 26.0 to 44.7. By definition, allwere hyperandrogenemic with significantly elevatedlevels of total testosterone. Subjects in both groups camefrom similar ethnic backgrounds. All participantshad had fewer than 6 menses in the year preceding thestudy with no significant difference in the 2 proportionsat baseline.

POSTINTERVENTION CHARACTERISTICS

At completion, the weights and BMI had not signifi-cantly changed. Total testosterone levels dropped sig-nificantly in the cohort treated with metformin (meandifference, 38.3 ng/dL) compared with placebo (meandifference, 0.86 ng/dL) (95% CI, to 0.29 for the dif-ference between group means). In neither group wastherea change in the Ferriman and Gallwey scores or acan-thosis nigricans (Table 2). Ten of 11 adolescents in themetformin group experienced menses, compared withonly 4 of 11 adolescents in the placebo group. The rela-tiveriskof menses wasstatistically significantat 2.50 (95%CI, 1.12 to 5.58).

GLUCOSE AND INSULIN PROFILES

Fasting blood glucose levels were all normal at baselineand remained this way at the end of the study regardlessof the treatment prescribed. None of the study recruitswere diabetic based on the American Diabetes Associa-tion interpretation of the OGTT, a requirement for par-ticipation. The baseline OGTTs revealed that 1 adoles-centin the metformin arm hadimpaired glucosetolerance.At the end of the study, her results demonstrated per-

sistent impaired glucose tolerance. None of the girls inthe placebo arm had any glucose intolerance at base-line, but 1 developed this at the end of the 12-week in-terval.

The areas under the insulin response curve were el-evated and were not significantly different in the 2 armsat baseline. With metformin, there was a suggestive trendtoward lower insulin AUC with treatment, but this wasnot statistically significant (with metformin, insulin AUCdeclinedby 3662 U/mL minute,compared with2093U/mL minute for placebo; 95% CI, 17 531 to 6024 forthe mean difference between groups). Homeostasismodel

assessment calculations also showed a trend toward im-proved insulin sensitivity with metformin treatment, butagain these were not statistically significant (HOMA:met-formin therapy [mean difference, 1.06] compared withplacebo [mean difference, 0.86] [95% CI, 9.26 to 5.42for the difference between group means]; QUICKI: met-formin therapy [mean difference, 0.00] compared withplacebo [mean difference, 0.01] [95% CI, 0.03 to 0.05for the difference between group means]).

LIPID PROFILE

On average, the baseline levels of total, low-density li-poprotein and HDL cholesterol were normal for all par-

ticipants (Table 1). At the end of the trial, metformin hadsignificantly improved HDL cholesterol concentrationscompared with placebo. The increase with treatment was6.98 mg/dL vs 2.33 mg/dL for placebo (95% CI, 0.78to 18.23 for the mean difference between groups). Othercholesterol parameters were not significantly different(Table 2). Triglycerides were elevated in both baselinecohorts and fell with metformin treatment, but this didnot reach statistical significance. No decline was notedwith placebo. All young women were in the follicularphase of their menstrual cycle at baseline; 1 participant

Table 1. Clinical Characteristics and Serum Hormone Concentrations in Adolescents With PCOS at Baseline

Characteristic Metformin Group Placebo Group

Age, mean SD, y 16.07 0.97 16.08 1.39

Body mass index, mean SD* 33.6 5.6 30.81 3.0

Ferriman and Gallwey score, mean SD 5.3 5.0 7.2 7.6

Total testosterone, mean SD, ng/dL (nmol/L) 174.3 54.0 (6.03 1.88) 167.3 46.0 (5.80 1.58)

Insulin AUC, mean SD, U/mL min (pmol/L min) 15 246 10 097 (109 374 72 433) 15 460 12 377 (110 905 88 788)

Fasting glucose, mean SD, mg/dL (mmol/L) 77.9 7.2 (4.33 0.4) 80.6 8.3 (4.48 0.46)

HOMA, mean SD 5.75 10.08 2.79 1.45QUICKI, mean SD 0.34 0.07 0.36 0.05

Total cholesterol, mean SD, mg/dL (mmol/L) 164.9 27.5 (4.25 0.71) 171.1 48.9 (4.41 1.26)

LDL cholesterol, mean SD, mg/dL (mmol/L) 88.5 19.8 (2.28 0.51) 93.5 41.9 (2.41 1.08)

HDL cholesterol, mean SD, mg/dL (mmol/L) 45.8 18.6 (1.18 0.48) 42.3 10.9 (1.09 0.28)

Triglycerides, mean SD, mg/dL (mmol/L) 133.9 55.1 (1.53 0.63) 168 77.9 (1.92 0.89)

Ethnicity, No.

White, non-Hispanic 7 10

Black, non-Hispanic 2 0

Hispanic 1 0

Asian 1 1

Menses in 6 months before enrollment, No. 2 3

Girls with menses during 6 months before enrollment, No. 2 3

Abbreviations: AUC, area under the curve; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; LDL, l ow-density lipoprotein;PCOS, polycystic ovarian syndrome; QUICKI, quantitative insulin sensitivity check index.*Body mass index is calculated as weight in kilograms divided by the square of height in meters.



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in the placebo group was excluded from the compari-sons because she was in the luteal phase at completion

of the study.

COMPLIANCE

Pill counts were performed at the end of the trial. Twoadolescents in the placebo arm admitted to not takingall the required tablets. One ofthem stated that they causedgastrointestinal adverseeffects and discontinued the pillsafter taking about 45% of them. The second participantdid not return for the second OGTT and stated that sheonly took about 50% of the pills. In the metformin treat-ment arm, 5 of 11 admitted to poor compliance (de-fined as70% of pills taken), citing gastrointestinal dis-turbances. Based on pill counts, 8% to 60% of the

metformin tablets were not consumed. Of note, in themetformin group, all of the noncompliant subjectsand 6 of 7 compliant subjects had least 1 menses duringthe study period; therefore, metformin treatment wasassociated with restoration of menses in 10 of 11 treatedsubjects.

COMMENT

To our knowledge, this is the first study to evaluate theeffect of metformin and lifestyle counseling on insulinlevels, testosterone levels, and menstrual patterns in ado-lescent girls with hyperinsulinemia and PCOS in a ran-

domized, double-blind, placebo-controlled study. Wefound that metformin resulted in a clinically significantimpact on menses, significantly reduced serum testos-terone levels, and significantly increased HDL choles-terol levels.

All of our study subjects were overweight or obese atbaseline and did not achieve a significant reduction inBMI with lifestyle intervention and metformin or pla-cebo. In the 2 published pediatric, unrandomized, anduncontrolled studies using metformin for PCOS, a mod-erate reduction in weight was noted. Both studies by

Glueck et al25 and Arslanian et al26 were small in samplesize, and in the latter, the BMI was significantly lowered

because of a significant increase in height. Two small,randomized, double-blind, placebo-controlled trials byKayet al27 and Freemark and Bursey28 evaluated metfor-min in obese adolescents (not with PCOS) and showedthat those treated with metformin had a significantlygreater weight loss compared with the placebo groups,although the differences were modest. Of note, the sub-jects in the Kay et al27 and Freemark and Bursey28 stud-ieswere also prescribed weight-reduction diets. The adultliterature is equally inconclusive with regard to weightreduction, which suggests that metformin may not con-tribute to weight loss directly.

Metformin did, however, result in a significant reduc-tion in total testosterone levels compared with placebo.Our study design could not determine whether reducedandrogen levelswere a consequence ofthedownwardtrendin insulin levels or some other biologic effects of metfor-min. Given the duration of the study, it comes as little sur-prise that this did not necessarily translate into a changein degree of hirsutism. Two earlier studies in overweightadolescents with PCOS demonstrated conflicting results;Arslanian et al26 described significant reductions in bothfree and total testosterone levels with metformin, andGlueck et al25 noted a nonsignificant downward trend intestosterone levels. In both studies, moderate weight losswas noted and only in the former study were insulin lev-els measured, which were decreasedwith metformin. The

small (n=10) study by Ibanez et al29

in nonobese adoles-cent girls with PCOS observed a decrease in both andro-gen levels and hirsutism with metformin, associated witha concomitant decrease in insulin concentrations andwith-out any weight loss.

We found a significant rise in HDL cholesterol levelsin the metformin group compared with the placebo groupby the end of the study period. We did not find signifi-cant changes in other lipid parameters. The mean tri-glyceride concentrations were elevated in both studygroups at the start of the study, with a nonsignificant re-

Table 2. Change From Baseline in Clinical Characteristics and Blood TestsAfter Administration of Metformin or Placebo for 12 Weeks

Characteristic

Mean Difference95% Confidence Interval for the

Mean Difference Between GroupsMetformin Group Placebo Group

Body mass index* 0.16 0.19 1.01 to 0.32

Ferriman and Gallwey score 0 0 NA

Total testosterone, ng/dL 38.3 0.86 to 0.29

Insulin AUC, U/mL

min 3662 2093 17 531 to 6024

Fasting glucose, mg/dL 0.31 0.36 3.42 to 5.22

HOMA 1.06 0.86 9.26 to 5.42

QUICKI 0.00 0.01 0.03 to 0.05

Total cholesterol, mg/dL 0.78 8.15 17.07 to 31.82

LDL cholesterol, mg/dL 3.10 7.76 12.80 to 20.56

HDL cholesterol, mg/dL 6.98 2.33 0.78 to 18.23

Triglycerides, mg/dL 13.13 7.00 70.00 to 29.75

Girls with restored menses, No. 10/11 4/11 1.12 to 5.58 (relative risk, 2.50)

Abbreviations: AUC, area under the curve; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; LDL, l ow-density lipoprotein; NA, notapplicable; QUICKI, quantitative insulin sensitivity check index.*Body mass index is calculated as weight in kilograms divided by the square of height in meters.



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duction in triglyceride levels observed in the metformin-treated group alone. Again, the impact of metformin inadolescents has been inconsistent. Glueck et al25 ob-served a significant reduction in total cholesterol levelsin a nonrandomized study while Arslanian et al26 saw nosignificant change in cholesterol or triglyceride levels. Inthe randomized double-blind placebo-controlled trial byKay et al27 of obese adolescents (not with PCOS), a sig-nificant improvement in the lipid profile was seen with

metformin treatment (decreased total cholesterol and tri-glyceridelevels). In all 3 of these studies, metformin treat-ment was associated with weight loss. In 2 of these stud-ies, insulin levels were assessed and found to be reducedwith metformin.

Most importantly, menses was 2.5 times more likelyto occur in the metformin group compared with the pla-cebo group. Metformin has been deemed to be benefi-cial in the restoration of menses in other studies, from40% to 100% (40%, Glueck et al25; 91%, Arslanian et al26;and 100%, Ibanez et al29). Indeed, Ibanez et al con-firmed that menses returned, and the majority of thesecycles were ovulatory.30,31

Wenoted an improvement in measures of insulin sen-

sitivity, includingthe insulin AUCand HOMA,in theado-lescents treated with metformin, but not in the controlgroup. However, this trend failedto achieve statistical sig-nificance, possibly reflecting samplesize andinherent vari-ability of the measure. Because some clinical benefits werenoted, we postulate that this reduction may have had bio-logic effects. Earlier studies by Arslanian et al26 andIbanez et al30,31 in adolescents with PCOS have demon-strated a significant decline in insulin levels assessed byboth fasting insulin-glucose ratios and formal pharma-cokineticAUC. However, most studies in femaleand maleadolescents have also demonstrated a decrease in BMI orbody weight with metformin treatment, which could con-ceivably alter insulin sensitivity.25-28

Poor compliance in nearly half (5/11) of the adoles-cents randomized to metformin and/or our small samplesize may have limited the ability to detect statistically sig-nificant differences in insulin concentrations despite theclinical impact on menses and testosterone levels. Com-paring our results with the other trials carried out in ado-lescents suggests that important biologic effects can oc-cur without weight loss andwithout statistically significantimprovements in measures of insulin sensitivity. Thisraises the question as to whether metformin has addi-tional biologic actions besides that of an insulin sensi-tizer or whether the impact of metformin is noted withvery small decreases in insulin concentrations.

The use of insulin-sensitizing agents, especially met-

formin, has generally been accepted in adult women withPCOS although not all studies have demonstrated con-sistent benefits.13 In adolescents with PCOS, there havebeen fewer studies of metformin, and controversy re-mains with regards to its benefits and mechanisms of ac-tion. It is difficult to directly compareour study with thosepreviously published because of the inherent differ-ences in study design, although most appear to demon-strate that metformin treatment leads to clinical improve-ment. The goal of this therapy in the adolescent is morelikely to focus on the reduction of hirsutism and acne

with return of menses as a less important outcome. Fer-tility and long-term cardiovascular health appear moreremote concerns for these young adults.

Our randomized placebo-controlled study, albeit smallin sample size, demonstrated a significant decrease in tes-tosterone levels and an increase in the frequency of men-ses in adolescents with oligomenorrhea or amenorrhea.Measures of insulin sensitivity improved, although notsignificantly. Poor compliance with metformin and/or

sample size were major limitations as was the short du-ration of the study.Despite other adolescent preoccupations, the in-

creased frequency of menses observed with a combina-tion of metformin and lifestyle therapy may benefit uter-ine health. In addition, the significant increase in HDLcholesterol levels may benefit overall health in the fu-ture, as might the trend toward improvement in insulinAUC, although longer term follow-up studies will beneeded to explore these questions.

Accepted for Publication: September 13, 2005.Corresponding Author: Tracey Bridger, MD, FRCPC, Pae-diatric Endocrinology, Janeway Child Health and Reha-

bilitation Centre, 300 Prince Philip Dr, St Johns, New-foundland and Labrador, Canada A1B 3V6 ([email protected]).Funding/Support: Montreal Childrens Hospital Re-search Institute, Montreal, Quebec, and Aventis Phar-maceutical, Laval, Quebec, supplied metformin and anidentical appearing placebo.

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ovulationin eumenorrheic, nonobese adolescentgirls bornsmall for gestational

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