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Free Fatty Acids, Body Weight, and Growth Hormones Secretion in Children

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ClinicalTrials.gov Identifier: NCT01237041
Recruitment Status : Terminated (Study Medication unavailable)
First Posted : November 9, 2010
Results First Posted : December 17, 2018
Last Update Posted : December 17, 2018
Sponsor:
Information provided by (Responsible Party):
Jack Yanovski, M.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Tracking Information
First Submitted Date  ICMJE November 6, 2010
First Posted Date  ICMJE November 9, 2010
Results First Submitted Date  ICMJE November 14, 2018
Results First Posted Date  ICMJE December 17, 2018
Last Update Posted Date December 17, 2018
Actual Study Start Date  ICMJE July 1, 2011
Actual Primary Completion Date October 17, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 7, 2018)
Growth Hormone Secretion Area Under the Curve in Response to Niacin and Placebo Over Time [ Time Frame: 4 hours ]
Growth hormone Area Under the Curve in response to niacin versus placebo over 4 hours. For growth hormone, samples collected at 0, 30, 60, 90, 120, 150, 180, 210, and 240 minutes.
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT01237041 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 7, 2018)
  • Free Fatty Acids (FFA) Area Under the Curve in Response to Niacin and Placebo Over 4 Hours [ Time Frame: 4 hours ]
    Effect of niacin vs placebo on Free Fatty Acids (FFA) Area Under the Curve in response to Niacin and Placebo over 4 hours. For FFA, samples collected at 0, 30, 60, 90, 120, 150, 180, 210, and 240 minutes
  • Growth Hormone-releasing Hormone (GHRH) Area Under the Curve in Response to Niacin and Placebo Over 4 Hours [ Time Frame: 4 hours ]
    Growth hormone-releasing hormone (GHRH) Area Under the Curve in response to Niacin and Placebo over 4 hours. For GHRH, samples collected at 0, 60, 120, 180, and 240 minutes.
  • Somatostatin (SST) Area Under the Curve in Response to Niacin and Placebo Over 4 Hours [ Time Frame: 4 hours ]
    Effect of niacin vs placebo on Somatostatin (SST) Area Under the Curve in response to Niacin and Placebo over 4 hours. For somatostatin, samples collected at 0, 60, 120, 180, and 240 minutes.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Free Fatty Acids, Body Weight, and Growth Hormones Secretion in Children
Official Title  ICMJE Free Fatty Acids, Body Weight, and Growth Hormone Secretion in Children
Brief Summary

Background:

- Overweight and obese children and adults often have lower levels of growth hormone in the blood. Regulation of growth hormone may be tied to weight and free fatty acids in the blood. Current tests of growth hormone (such as those used when evaluating the heights of children who are markedly shorter than other children of comparable age) may be affected by other factors, including obesity. Researchers are interested in evaluating the levels of growth hormone and free fatty acids in the blood of children between 7 and 14 years of age who weigh more than children of a comparable age, or who are shorter than other children of a comparable age and have been recommended for growth hormone testing as part of an evaluation for their height.

Objectives:

- To determine the effect of changes in free fatty acids in the blood on changes in growth hormone secretion in overweight or shorter children and young adolescents.

Eligibility:

- Children and adolescents between 7 and 14 years of age who weigh more than or are shorter than other children of a comparable age and do not have any medical illnesses.

Design:

  • Participants will have two study visits, one of which will be a half day screening visit in the outpatient clinic and one of which will require 2 nights as an inpatient at the National Institutes of Health Clinical Center.
  • Participants should not eat or drink anything except water after 10 PM the night before or on the morning of the screening visit.
  • At the screening visit, participants will have a physical examination and medical history, provide blood and urine samples, have an oral glucose tolerance test (to check blood sugar levels), and have an x-ray of the left hand to check bone age.
  • The inpatient study visit will involve a physical examination and medical history, a full x-ray scan to study body fat and muscle, frequent blood tests throughout the visit, and various medications to stimulate growth hormone production and lower levels of free fatty acids in the blood.
Detailed Description

Obese children and adults display lower spontaneous and stimulated growth hormone (GH) secretion. It is presumed that dysregulation of some of the factors normally involved in controlling GH secretion underlies the hyposomatotropinemia of obesity, given that GH production usually normalizes after weight loss. Free fatty acids (FFA) are one factor thought to be involved in regulation of GH secretion. Niacin is a nicotinic acid derivative that inhibits lipolysis and lowers circulating FFA concentrations. Nicotinic acid derivatives have been used in several adult studies examining GH secretion. Specifically in obese adults, inhibition of lipolysis has been found to increase spontaneous and stimulated GH production, presumably due to direct effects of FFA on hypothalamic GH-regulating neurons. Thus far no pediatric studies have examined the effects of niacin on GH secretion, and there is only one small pediatric study of normal weight prepubertal children growing at the 5th-10th percentile in height has tested the effects of lipolytic inhibition by acipimox (a related medication also derived from nicotinic acid) on GH secretion. There are no data in obese children demonstrating the effects of inhibition of lipolysis on GH secretion.

We propose to investigate one of the mechanisms through which high adiposity alters GH secretion in children by testing the effects of inhibiting lipolysis. First we will conduct dose establishing studies to determine the appropriate dose of niacin needed to suppress FFA concentrations in children. We will then conduct the main study, designed as a pilot randomized, double-blind placebo controlled trial of niacin administration, to assess its effects on stimulated GH secretion. We hypothesize that in overweight children niacin will lead to a fall in free fatty acid concentrations and consequently a rise in stimulated GH secretion. We further hypothesize that the overweight subjects will demonstrate stimulated GH secretion profiles with niacin similar to those of control subjects who receive placebo. We expect this pilot study may help improve how diagnostic testing is carried out for growth hormone deficiency in children.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
First, we conducted dose-establishing studies using 250mg every 2 hours x 3 doses (2 subjects), 500mg every two hours x 3 doses (5 subjects), and 500mg hourly x 4 doses (5 subjects). This dose-establishing study was followed by the randomized crossover trial using 500mg hourly x 4 doses in conjunction with growth hormone stimulation testing. The RCT was terminated early because of inability to obtain necessary study medications.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Masking only during the two arms of the randomized trial portion of the study, not during the dose-finding arms.
Primary Purpose: Diagnostic
Condition  ICMJE
  • Obesity
  • Short Stature
  • Growth Hormone Deficiency
Intervention  ICMJE
  • Drug: Niacin First
    Niacin 500 mg po four times on one of the inpatient days, then placebo on another inpatient day
    Other Name: RCT Niacin First
  • Drug: Placebo First
    Placebo po four times on one of the inpatient days, then Niacin 500 mg po four times on another inpatient day
    Other Name: RCT Placebo First
  • Drug: Dose-Establishing Study 1 Niacin 250mg
    Niacin 250 mg po three times at 2 hour intervals on an inpatient day
    Other Name: Open-Label Niacin 250mg x 3 doses
  • Drug: Dose-Establishing Study 1 Niacin 500mg
    Niacin 500 mg po three times at 2 hour intervals on an inpatient day
    Other Name: Open-Label Niacin 500mg x 3 doses
  • Drug: Dose-Establishing Study 2 Niacin 500mg
    Open-Label Niacin 500mg four times at 1 hour intervals on an inpatient day
    Other Name: Open-Label Niacin 500mg x four doses
Study Arms  ICMJE
  • Experimental: Niacin First
    Subjects receive niacin 500mg hourly for 4 hours on day 1 (at 7:30am, 8:30am, 9:30am, and 10:30am) then cross over to receive placebo hourly for 4 hours on day 2 at (7:30am, 8:30am, 9:30am, and 10:30am).
    Interventions:
    • Drug: Niacin First
    • Drug: Placebo First
  • Experimental: Placebo First
    Subjects receive placebo hourly for 4 hours on day 1 (at 7:30am, 8:30am, 9:30am, and 10:30am) then cross over to receive niacin hourly for 4 hours on day 2 (at 7:30am, 8:30am, 9:30am, and 10:30am).
    Interventions:
    • Drug: Niacin First
    • Drug: Placebo First
  • Experimental: Dose-Establishing Study 1 Niacin 250mg
    Subjects received Niacin 250 mg every 2 hours for 3 doses (at 6am, 8am, and 10am).
    Intervention: Drug: Dose-Establishing Study 1 Niacin 250mg
  • Experimental: Dose-Establishing Study 1 Niacin 500mg
    Subjects received Niacin 500 mg every 2 hours for 3 doses (at 6am, 8am, and 10am).
    Intervention: Drug: Dose-Establishing Study 1 Niacin 500mg
  • Experimental: Dose-Establishing Study 2 Niacin 500mg
    Subjects received Niacin 500 mg hourly for 4 doses (administered at 7:30am, 8:30am, 9:30am, and 10:30am).
    Intervention: Drug: Dose-Establishing Study 2 Niacin 500mg
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: December 14, 2017)
37
Original Estimated Enrollment  ICMJE
 (submitted: November 6, 2010)
66
Actual Study Completion Date  ICMJE December 13, 2017
Actual Primary Completion Date October 17, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

Subjects will qualify for the overweight group for the dose-establishing studies 1 and 2 and main study) if they meet the following criteria:

  1. Good general health.
  2. Age greater than or equal to 7 and less than 15 years.
  3. Tanner stage I, II or III for the breast among girls and testes less than10 mL for boys based upon an examination by a trained physician or nurse practitioner.
  4. Weight > 30 kg.
  5. Fasting plasma glucose < 100 mg/dL, 2 hour post-dextrose glucose < 140 mg/dL, and HgbA1C less than or equal to 6.4%.
  6. Females who are age 10 or greater must have a negative pregnancy test.
  7. Body mass index greater than or eqaul to 95th percentile determined by Centers for Disease Control age and sex specific data (given that most pathology of obesity does not usually emerge until children cross the 95th percentile).
  8. No evidence of growth failure as defined as height > 5th percentile.

Subjects will qualify for the non-overweight control group (for the main study only) if they meet the following criteria:

  1. Recommended by a pediatric endocrinologist to undergo GH stimulation testing to establish the diagnosis of GH-deficiency.
  2. Good general health.
  3. Age greater than or equal to 7 and less than15 years.
  4. Tanner stage I, II or III for the breast among girls and testes less than 10 mL for boys based upon an examination by a trained physician or nurse practitioner.
  5. Weight > 30 kg.
  6. Fasting plasma glucose < 100 mg/dL, 2 hour post-dextrose glucose < 140 mg/dL, and HgbA1C less than or equal to 6.4%.
  7. Females who are age 10 or greater must have a negative pregnancy test.
  8. Height < 5th percentile.
  9. BMI between the 5th and 85th percentiles determined by Centers for Disease Control age and sex specific data.
  10. Birth weight and length not consistent with small for gestational age (SGA) criteria or a history of intrauterine growth restriction (IUGR) based on recall history.

EXCLUSION CRITERIA (for the dose-establishing sutides 1 and 2, and the main study):

Subjects will be excluded if they have any of the following:

  1. Baseline creatinine greater than or equal to 1.0 mg/dl.
  2. Significant cardiac or pulmonary disease likely to or resulting in hypoxia or decreased perfusion.
  3. Hepatic disease with elevated liver function tests (ALT or AST)greater than or equal to 1.5 the upper limits of normal.
  4. Pregnancy.
  5. Evidence for impaired glucose tolerance or Type 2 diabetes, including fasting plasma glucose greater than or equal to 100 mg/dL, 2 hour post-dextrose glucose greater than or equal to 140 mg/dL, or HgbA1C > 6.4%.
  6. Presence of other endocrinologic disorders leading to obesity (e.g. Cushing Syndrome).
  7. Any disorder that is known to affect GH secretion (e.g. untreated hypothyroidism) or use of any medication known to affect GH levels (including glucocorticoids and GH itself).
  8. Any other disorder that is known to affect stature including skeletal dysplasias.
  9. Recent use (within two years) of anorexiant medications, stimulant medications, or other medications felt to impact growth.
  10. Individuals who have, or whose parent or guardians have, current substance abuse or a psychiatric disorder or other condition that, in the opinion of the investigators, would impede competence or compliance or possibly hinder completion of the study.
  11. Individuals receiving medical treatment other than diet for hypertension or dyslipidemia.
  12. Individuals with evidence of precocious puberty as defined as palpable breast tissue noted in females before the age of 7, testicular size greater than or equal to 4cc in males before the age of 9, or bone age advancement more than 2 SD for chronologic age.
  13. Individuals receiving androgen or estrogen hormone therapy.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 7 Years to 14 Years   (Child)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01237041
Other Study ID Numbers  ICMJE 110004
11-CH-0004 ( Other Identifier: NIH Clinical Center Protocol Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jack Yanovski, M.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study Sponsor  ICMJE Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jack A Yanovski, M.D. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP