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Trial · Interventional

CompletedPhase 2/3Results postedRegistry data

Liver and Fat Regulation in Overweight Adolescent Girls

Short name APPLE

NCTNCT02157974 (opens ClinicalTrials.gov in a new tab)Other id14-0542Other idUL1TR001082Other idK23DK107871
Open at ClinicalTrials.govAsk about this trial

Overview

Status
Completed
Phase
Phase 2/3
Enrollment
92 participants (actual)
Sponsor
University of Colorado, Denver · Other
Design
Not randomized · Open label (no masking)
Countries
1 country

United States

Start
Aug 2014
Primary completion
Dec 2022
Completion
Dec 2022
First posted
6 Jun 2014 (estimated)
Last update posted
4 Jun 2024
Conditions
Hepatic Steatosis · Polycystic Ovarian Syndrome · Obesity

Timeline

1 trial · 1 completed · 1 with posted results

  • Completed
  • Ongoing
  • Not yet recruiting
  • Stopped
  • Estimated dates (est.)
  • Results posted
20142016201820202022
  1. Ph 2/3

    APPLE

    NCT02157974

    Aug 2014 to Dec 2022

Registry summary

Text and fields below are the sponsor's entries at ClinicalTrials.gov, shown as posted.

Women with polycystic ovarian syndrome (PCOS) have increased rates of hepatic steatosis compared to weight similar women with regular menses. It is unclear if this is related to high testosterone or insulin resistance. The investigators will assess hepatic glucose release, rates of lipolysis and hepatic de novo lipogenesis in the fasted and postprandial state to determine if alterations in the processes contribute to hepatic steatosis. Participants will be overweight, sedentary girls with or without PCOS. Those with PCOS will either be medication naive, or must be taking metformin or combined oral contraceptives (COCPs) for a period of at least 6 months prior to study procedures.

Interventions

  • Byetta 5Mcg Pen InjectionDrug

Arms5

  • Experimental

    PCOS, medication naive + Byetta

    PCOS, medication naive; 10 girls with PCOS will receive 2 doses of Byetta.

  • No intervention

    Control

    Up to 25 girls without PCOS

  • No intervention

    PCOS medication naive

    Up to 45 girls with PCOS with no exposure to hormone therapy or metformin in the preceding 6 months.

  • No intervention

    PCOS on COCPs

    Up to 10 girls with PCOS and 6 months of therapy with combined oral contraceptives (COCPs) prior to study procedures.

  • No intervention

    PCOS on metformin

    Up to 10 girls with PCOS and 6 months of therapy with metformin prior to study procedures

Primary outcomes1

Outcomes the sponsor listed as primary.

  1. Hepatic Glucose Release

    Time frame · Measured up to 4 months from enrollment

    Registry description

    Hepatic glucose release will be measured by the rate of appearance of a glucose tracer. Glucose rate of appearance reflects the amount of glucose being release by primarily the liver during fasting. A higher glucose rate of appearance is often seen with dysglycemia

Secondary outcomes(4)

  1. Hepatic Phosphate Concentrations

    Time frame · Measured up to 4 months from enrollment

    Registry description

    Hepatic phosphate relative concentrations will be measured with 31 phosphorus magnetic resonance spectroscopy. The ratio of the following will be reported over total phosphate concentration: Phosphodiesterase (PDE), phosphomonoester (PME), Adenosine triphosphate (ATP), Inorganic Phosphate (Pi),Nicotinamide adenine dinucleotide phosphate (NADPH), Uridine diphosphate glucose (UDPG)

  2. Rates of Lipolysis

    Time frame · Measured up to 4 months from enrollment

    Registry description

    Rate of lipolysis will be measured by the rate of appearance of a glycerol tracer. Glycerol rate of appearance reflects the amount of glycerol being released into the blood stream as a results of lipolysis. Higher rates of lipolysis are thought to be associated with insulin resistance.

  3. Hepatic Fat Fraction

    Time frame · Measured up to 4 months from enrollment

    Registry description

    Amount of fat in the liver measured by MRI and calculated via the Dixon method as the proton density hepatic fat fraction, which ranges from 0-75%. Greater than 5% is considered extra fat in the liver.

  4. Hepatic de Novo Lipogenesis

    Time frame · Measured up to 4 months from enrollment

    Registry description

    Hepatic de novo lipogenesis will be measured by with an acetate tracer by mass spectroscopy. De novo lipogenesis can contribute to non-alcoholic fatty liver disease, so having a lower value is better.

Posted results

Values are shown as posted at ClinicalTrials.gov, with their units. PepBank has not converted, pooled or compared them.

Primary outcome results

Primary outcomeMean· Measured up to 4 months from enrollment

Hepatic Glucose Release

GroupValue (mg/kg/min)Spread
Control1.851.24
PCOS Medication Naive1.460.21
PCOS, Medication Naive + Byetta1.540.38
PCOS on COCPs1.880.49
PCOS on Metformin1.570.07
Secondary and other outcome results(7)
Secondary outcomeMean· Measured up to 4 months from enrollment

Hepatic Phosphate Concentrations

GroupValue (ratio over total phosphate)Spread
Control0.1676847280.056413082
PCOS Medication Naivenot posted–
PCOS, Medication Naive + Byetta0.1986402550.040933351
PCOS on COCPs0.1987874760.045832565
PCOS on Metformin0.1869234690.039481266
Secondary outcomeMean· Measured up to 4 months from enrollment

Rates of Lipolysis

GroupValue (mg/kg/min)Spread
Control0.540.17
PCOS Medication Naive0.490.22
PCOS, Medication Naive + Byetta0.490.24
PCOS on COCPs0.780.18
PCOS on Metformin0.650.19
Secondary outcomeMean· Measured up to 4 months from enrollment

Hepatic Fat Fraction

GroupValue (percent fat)Spread
Control4.13.1
PCOS Medication Naive7.66.3
PCOS, Medication Naive + Byetta6.95.3
PCOS on COCPs6.89.4
PCOS on Metformin13.312.1
Secondary outcomeMean· Measured up to 4 months from enrollment

Hepatic de Novo Lipogenesis

GroupValue (mg/dL)Spread
Control9.35.3
PCOS Medication Naive6.64.2
PCOS, Medication Naive + Byetta7.97.2
PCOS on COCPs18.214.9
PCOS on Metformin19.417.4
Other pre specified outcomeMean· Measured up to 4 months from enrollment

Whole Body Insulin Sensitivity

GroupValue (dL/kg/min/μU/mL)Spread
Control0.0003193830.00021025
PCOS Medication Naive0.000210770.000275814
PCOS, Medication Naive + Byetta0.000335160.000366279
PCOS on COCPs0.000217910.000255919
PCOS on Metformin0.00009598333330.0000414436685
Other pre specified outcomeMean· Measured up to 4 months from enrollment

Sleep Quality

GroupValue (Apnea Hypopnea Index)Spread
Control9.154.71
PCOS Medication Naivenot posted–
PCOS, Medication Naive + Byetta31.2512.09
PCOS on COCPs19.3211.85
PCOS on Metformin190.57
Other pre specified outcomeMean· Measured up to 4 months from enrollment

Sleep Duration

GroupValue (minutes)Spread
Control430.8548.38
PCOS Medication Naive437.8849.32
PCOS, Medication Naive + Byetta410.358
PCOS on COCPs438.2949.76
PCOS on Metformin414.8762.29

Adverse events, as posted

Adverse events as posted: participants affected out of participants at risk, by group
GroupDeathsSerious eventsOther events
ControlUp to 25 girls without PCOS0 / 240 / 240 / 24
PCOS Medication NaiveUp to 45 girls with PCOS with no exposure to hormone therapy or metformin in the preceding 6 months.0 / 420 / 420 / 42
PCOS, Medication Naive + ByettaPCOS, medication naive; 10 girls with PCOS will receive 2 doses of Byetta. Byetta 5Mcg Pen Injection: 10 participants will receive 2 doses of Byetta, one at 7 PM the night prior to metabolic study and the second 30 min before ingestion of glucola0 / 100 / 100 / 10
PCOS on COCPsUp to 10 girls with PCOS and 6 months of therapy with combined oral contraceptives (COCPs) prior to study procedures.0 / 100 / 100 / 10
PCOS on MetforminUp to 10 girls with PCOS and 6 months of therapy with metformin prior to study procedures0 / 60 / 60 / 6

Each cell reads participants affected / participants at risk, as the registry posted them.

Registry data comes from ClinicalTrials.gov. Study results come from studies, not from the registry. How PepBank works

Studies0

Studies that cite this trial.

No study cites this trial.

Other registry references

References listed at the registry that are not in PepBank. They link to PubMed.

  • DerivedBoster JM, Cree MG, Kelsey MM, Nadeau KJ, Chaidez A, Pan Z, Sundaram SS. Relative Skeletal Muscle Mass Is Associated With Hepatic Steatosis in Adolescents With Overweight and Obesity. Pediatr Obes. 2026 Apr;21(4):e70108. doi: 10.1111/ijpo.70108. PMID 42014131
  • DerivedCarreau AM, Pyle L, Garcia-Reyes Y, Rahat H, Vigers T, Jensen T, Scherzinger A, Nadeau KJ, Cree-Green M. Clinical prediction score of nonalcoholic fatty liver disease in adolescent girls with polycystic ovary syndrome (PCOS-HS index). Clin Endocrinol (Oxf). 2019 Oct;91(4):544-552. doi: 10.1111/cen.14062. Epub 2019 Aug 16. PMID 31301251
  • DerivedSimon SL, McWhirter L, Diniz Behn C, Bubar KM, Kaar JL, Pyle L, Rahat H, Garcia-Reyes Y, Carreau AM, Wright KP, Nadeau KJ, Cree-Green M. Morning Circadian Misalignment Is Associated With Insulin Resistance in Girls With Obesity and Polycystic Ovarian Syndrome. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3525-3534. doi: 10.1210/jc.2018-02385. PMID 30888398

Eligibility

Who could join, as posted.

Sex
Female
Age
from 12 Years up to 21 Years
Healthy volunteers
Accepted
Inclusion and exclusion criteria, as posted
Inclusion Criteria: * Females * 2 years post-menarche * BMI percentile \>90% Exclusion Criteria: * Type 2 diabetes * Anemia * Liver disease * Medications known to effect insulin sensitivity * Cause of oligomenorrhea or hirsutism other than PCOS, * \>3 hours a week of moderate exercise.

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