Conditions: Obesity Short Stature Growth Hormone Deficiency
Keywords: Child Body Fat Niacin Growth Hormone Obesity Overweight Growth Hormones Short Stature Children
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 37
Healthy volunteers: yes

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.

Arms:
arm 1: 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). arm 2: 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). arm 3: Subjects received Niacin 250 mg every 2 hours for 3 doses (at 6am, 8am, and 10am). arm 4: Subjects received Niacin 500 mg every 2 hours for 3 doses (at 6am, 8am, and 10am). arm 5: Subjects received Niacin 500 mg hourly for 4 doses (administered at 7:30am, 8:30am, 9:30am, and 10:30am).

Interventions: intervention 1: Niacin First intervention 2: Placebo First intervention 3: Dose-Establishing Study 1 Niacin 250mg intervention 4: Dose-Establishing Study 1 Niacin 500mg intervention 5: Dose-Establishing Study 2 Niacin 500mg
Intervention descriptions: intervention 1: Niacin 500 mg po four times on one of the inpatient days, then placebo on another inpatient day intervention 2: Placebo po four times on one of the inpatient days, then Niacin 500 mg po four times on another inpatient day intervention 3: Niacin 250 mg po three times at 2 hour intervals on an inpatient day intervention 4: Niacin 500 mg po three times at 2 hour intervals on an inpatient day intervention 5: Open-Label Niacin 500mg four times at 1 hour intervals on an inpatient day

Protocol document:
Prot_SAP_000.pdf: 
 
 
Project Number   
11-CH-0004 
 
 
IND/IDE Number 
111,512 (Niacin) 
Date of this version: October 6, 2017 
IND/IDE Holder  
Jack Yanovski 
To: 
Karim A. Calis, PharmD, Chair, IRB, NICHD 
 
Recommended by:  
 
, Branch Chief, PDEGEN, NICHD 
 
 
, Clinical Director, NICHD 
 
 
, Chief, DRD, CC 
 
 
, Clinical Director, CC 
 
 
, Clinical Director, NIDDK 
 
Subject: 
Protocol 11-CH-0004: 
 
Free fatty acids, body weight, and growth hormone secretion in children 
 
Identifying Words: 
Child, Body Fat, Free Fatty Acids, Adipose, Growth Hormone 
 
Principal Investigator: 
*Jack A. Yanovski, MD, PhD 
SGO/PDEGEN, NICHD 
 
Accountable Investigator: 
Jack A. Yanovski, MD, PhD 
SGO/PDEGEN, NICHD 
 
*May obtain consent and assent from participants 
 
Estimated Duration of Study: 3 years 
 
Subjects of Study: 
 
 
 
 
 
 
Number 
Gender 
Age Range 
 Obese children (dose-establishing study 1) 
10 
M, F 
7-14.99 y at study entry 
Obese children (dose-establishing study 2) 
5 
M, F 
7-14.99 y at study entry 
 Obese children (main study) 
33 
M, F 
7-14.99 y at study entry 
 Short, healthy children (main study) 
33 
M, F 
7-14.99 y at study entry 
 Screened but not enrolled in pilot studies 
10 
M, F 
7-14.99 y at study entry 
 
Project uses ionizing radiation 
Yes (for main study only) 
 
Radiation use is  
       medically indicated 
 
   X    indicated for research 
Project involves use of Durable Power of Attorney:  
 
No 
Off-Site Project: 
 
 
 
 
 
 
No 
Multi-Institutional Project 
 
 
 
 
 
Yes 


 
 
2
Précis: 
 
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. 
 
 


 
 
3
Table of Contents: 
Page 
 
I. 
Précis 
2 
II. 
Table of Contents 
3 
III. 
Introduction 
5 
IV. 
Objectives 
18 
V. 
Specific Hypotheses 
19 
VI. 
Study Design and Methods 
19 
a. Subject Enrollment 
19 
i. Inclusion Criteria 
19 
ii. Exclusion Criteria 
20 
b. Procedures 
22 
i. Initial Screening Evaluation 
22 
ii. Dose-Establishing Study 1 
23 
iii. Dose-Establishing study 2 
24 
iv. Main Study: Randomization 
25 
v. Main Study: Inpatient evaluation 
26 
vi. Monitoring subjects and criteria for withdrawal 
27 
vii. Reporting of Adverse Events 
28 
viii. Waiver of Reporting to the IRB of anticipated minor protocol  
deviations and adverse events 
29 
ix. Data safety monitoring board 
31 
VII. 
Analysis of the Study 
32 
a. Primary and secondary outcomes  
32 
b. Determination of Sample Size and Analytic Plan 
32 
VIII. Pharmaceutical information 
33 
a. Packaging and Labeling of Niacin 
33 
b. Randomization of Niacin 
34 
c. Arginine 
34 
d. L-dopa 
34 
e. Unblinding Procedure 
35 
IX. 
Study Administration and Data Collection, Management, and Storage 
36 
X. 
Protection of Participants’ Privacy and Confidentiality 
37 
XI. 
Limitations to the Study Design 
38 
XII. 
Human Participant Protections 
39 
a. Rationale for Subject Selection 
39 
b. Recruitment Strategies 
39 
c. Justifications for exclusions 
39 
d. Risks/Benefits Analysis 
40 
i. Risks  
40 
ii. Benefits 
43 
iii. Assessment of Risk/Benefit Ratio 
43 
iv. Alternatives to Participation 
44 
e. Compensation 
44 
f. Participation of Children and Other Vulnerable Populations 
44 
i. Approval under 45-CFR-46, Subpart D 46.406 
44 
ii. Requirement for both parents to provide permission 
48 
iii. Consent/Assent Process 
49 
iv. Non-English–Speaking Participants 
50 


 
 
4
g. Conflicts of Interest 
51 
h. Monitoring Plan  
51 
XIII. References 
54 
 


 
 
5
Introduction: 
Assessment of GH secretion is an important component of the evaluation of the short child.1 
The tests designed for this purpose, however, have been found to have relatively low specificity 
such that more than 40% of all children treated for isolated GH deficiency during childhood may be 
found to produce normal quantities of GH when retested as adults.2,3 Among the many confounding 
factors that may impact the assessment of GH secretory capacity is obesity. A recent retrospective 
study of patients presenting for short stature evaluation at an endocrine clinic and undergoing GH 
stimulation testing with arginine, clonidine, L-dopa (L-3,4-dihydroxyphenylalanine), and/or 
propranolol revealed a negative association between body mass index (BMI) standard deviation 
score (SDS) and peak GH, particularly in prepubertal children.4 This study highlights the difficulty 
of interpreting GH deficiency testing in overweight and obese children. Given the decline in GH 
secretion with increasing weight, the standard cutoffs for GH deficiency may not apply to patients 
with higher BMIs. In particular, patients with predisposition to both GH deficiency and obesity, 
such as children with Prader Wili Syndrome, or children with a history of brain tumor and resulting 
hypothalamic obesity, may be difficult to diagnose accurately. More appropriate normative data for 
GH concentrations in these patients have not been established, nor have high specificity diagnostic 
tests for overweight subjects been found. This study aims to further elucidate one mechanism 
behind diminished GH production and to pilot test a modified protocol for assessing GH deficiency 
in obesity. 
Growth hormone production 
GH secretion is a complex process regulated by multiple feedback mechanisms. Growth 
hormone-releasing hormone (GHRH) and somatostatin, both of which are secreted from the 
hypothalamus, are the main regulators of pituitary production of GH. Several other factors are 
believed to influence secretion of these hypothalamic hormones as well as directly affect the 


 
 
6
somatotrophs including, but not limited to, GH itself, insulin-like growth factor 1 (IGF-1), ghrelin, 
leptin, glucose, and FFA.5  
Growth hormone stimulation testing 
 
GH is secreted in short pulsatile bursts, mostly during nighttime sleep. The concentrations of 
GH in the serum are highly variable without predictable times of nadirs or peaks; thus, a random 
GH measurement is not helpful for assessing GH deficiency. Instead GH secretion is typically 
assessed through stimulation testing in order to measure peak GH production. Appendix A shows 
the most common medications used to induce GH secretion, including data on dosing and 
mechanism of action. Normative data have been established for various types of stimulation testing 
to appropriately diagnose GH deficiency. Because of the low specificity for any one GH stimulation 
test, this testing usually involves administration of two separate stimuli for GH release with 
measurements of GH concentrations every 15 to 30 minutes thereafter for 1-3 hours. For children 
and adolescents, a peak value following administration of a provocative stimulus of 7 
nanograms/milliliter or higher is typically considered diagnostic of sufficient GH production.  
Growth hormone production in obesity 
GH secretion in obese patients was first noted to be different from normal controls by Roth, 
et al in a 1963 publication.6 While studying the effects of exercise, hypoglycemia, and glucose 
loading on GH concentrations, the authors noted lower responses in their obese patients, leading 
them to conclude, “Marked obesity is associated with, and possibly conditioned by, a deficient 
secretory response of pituitary GH to certain physiologic stimuli…” 6 Many subsequent studies 
have shown lower GH concentrations in obese individuals, both during spontaneous 7-13 and 
stimulated 7,13-24 measurements. In particular, GH concentrations show negative correlation with 
BMI, percent overweight, amount of fat mass, and waist circumference.10,20,25-27 Additionally obese 
patients do not demonstrate a substantial decrease in GH secretion in response to a glucose load as 
demonstrated in normal controls.9,14,20,24,28,29 It is presumed that dysregulation of some of the factors 


 
 
7
normally involved in GH secretory regulation underlies the hyposomatotropinemia of obesity, given 
that GH production usually normalizes after weight loss,12,30-39 with peak GH response to 
pharmacologic stimuli correlating with degree of weight loss.27,38,40,41 Similarly, when exercise is 
used as a stimulation for GH secretion, obese patients do not respond as robustly as normal 
controls.42 
Results comparable to those observed in obese adults have also been reported in obese 
children. Peak GH concentration after stimulation testing is lower in obese children compared to 
controls in studies using arginine and L-dopa,43 clonidine,44 and dexamethasone45 as stimuli. As 
with adults, obese children show a blunted degree of GH secretion during exercise,46,47 and do not 
respond to a glucose load.48 A study of 24-hour GH secretion in boys demonstrated an inverse 
correlation between BMI SDS and daily GH production rate, as well as mass and amplitude of each 
burst of GH.49 Similarly a study comparing lean and obese children showed the lean female subjects 
had greater GH secretion during periods of sleep and higher and more frequent GH peaks during the 
day compared to their obese counterparts; the trend was similar in lean versus obese males but 
without achieving statistical significance.50 Similar studies of sleep-associated GH release show 
fewer and smaller peaks of secretion in obese children compared to lean.51,52 Weight loss reverses 
these trends with 24-hour GH secretion among formerly obese prepubertal children whose BMI 
returned to the normal range mirroring that of a control population.53 Even short term calorie 
restriction showed a 60% improvement in average GH secretion.54  
Free fatty acids in obesity 
 
Fatty acids are absorbed from the intestine after the breakdown of dietary lipids. They 
combine with glycerol to form triglycerides, which are stored in adipose tissue. Triglycerides in the 
adipose cells can then be broken down again to liberate free fatty acids into the circulation. Serum 
free fatty acids concentrations correlate positively with body weight.55 The rate of free fatty acid 
turnover is also faster in obese patients, suggesting increased mobilization of these compounds from 


 
 
8
the adipose tissue.56-58 Measurements of free fatty acids in obese children have been less frequently 
performed but overall show elevations compared to normal weight controls.50,59 Some studies have 
found increases in polyunsaturated fatty acids, monounsaturated fatty acids, and total saturated fatty 
acids.60,61 
Effects of lipids on growth hormone secretion in animals 
In animal models, infusion of fatty acids leads to blunting of GH secretion. This effect has 
been demonstrated in vitro with porcine pituitary cells where linoleic acid and oleic acid suppressed 
the GH response to GHRH.62 In vivo, rats given lipid infusions (with demonstrated rises in free 
fatty acids levels) showed diminished GH secretion after GHRH treatment, suggesting that free 
fatty acids lead to inhibition of the GH axis.63,64 The ability of the isolated porcine pituitaries to be 
inhibited by a lipid-rich environment suggests that at least to some degree free fatty acids may exert 
their effect directly on pituitary somatotrophs. This theory is supported by one in vivo animal study 
in which the free fatty acid inhibition was unable to be reversed by the addition of an 
antisomatostatin antibody, suggesting the FFA do not induce somatostatin release.64 Another in vivo 
study with similar methodology did see reversal of the effect with antisomatostatin, which may be 
due to different timing of the antisomatostatin antibody in relation to the GHRH administration.63 
Humans also demonstrate decreased growth hormone response when FFA concentrations are 
elevated. Lipid infusion lowers basal GH levels in anorexic women and lowers the responsiveness 
to GHRH stimulation in normal weight and anorexic women.65 
This evidence (that FFA inhibit GH secretion) suggests a possible explanation for the 
decreased GH levels in obese individuals. As discussed previously, overweight children and adults 
have higher circulating free fatty acid concentrations than do normal weight individuals. Thus, these 
higher free fatty acid levels may inhibit GH secretion and thus be responsible for the observed 
hyposomatotropinemia of obesity. 
Effects of inhibiting lipolysis on growth hormone secretion 


 
 
9
Niacin is a nicotinic acid derivative that inhibits lipolysis and lowers circulating FFA 
concentrations. This medication has been used in several human studies of GH secretion. Most of 
these studies have examined healthy volunteers and demonstrated increased spontaneous,66-69 
stimulated,70 and post-exercise 71-73 GH production, presumably by preventing the suppressive 
effects of free fatty acids on GH secretion. When niacin was administered to obese adults, the 
inhibition of lipolysis led to increased spontaneous GH secretion in one study,74 although no effects 
were seen in a second study.75 A third study did see increased spontaneous GH secretion in diabetic 
subjects.76 Acipimox, a similar medication also derived from nicotinic acid, has shown consistent 
suppression of FFA concentrations leading to increased spontaneous77,78 and stimulated79-85 GH 
production in obese adults. There are no data in obese children demonstrating the effects of 
inhibition of lipolysis on GH secretion. Thus far only one small pediatric study of normal weight 
prepubertal children growing at the 5-10th percentile in height has tested the effects of lipolytic 
inhibition by acipimox on GH stimulation tests and found non-significant differences in peak GH 
concentrations between acipimox and placebo arms after L-dopa infusion.86 We propose to examine 
the effects of inhibition of lipolysis on GH secretion in overweight children. Physiology in children 
is often different from that in adults, and no nicotinic acid-derived medications have been tested in 
overweight or obese children as an augmenter of growth hormone release. Thus, we believe the 
question of the effects of niacin on overweight children warrants further investigation and will add 
significantly to scientific knowledge. We have chosen to use niacin to suppress lipolysis in this 
study because we have been unable to obtain acipimox, and niacin is FDA approved while acipimox 
is not. We also hope that this study will pilot an alternative and possibly more sensitive test of 
growth hormone deficiency in overweight children, who often fail current growth hormone 
stimulation tests despite probable growth hormone sufficiency. 
Niacin (Nicotinic acid), administered alone, is approved by the FDA for the treatment of 
dyslipidemia in adults. Niacin has been shown in adults to decrease total and LDL-cholesterol by 


 
 
10 
10-20%, decrease triglycerides by 30-70%, and raise HDL-cholesterol by 20-35%. Multiple 
placebo-controlled studies document the ability of niacin or extended-release niacin, when 
administered without a statin and, at least in a few studies, with a statin, to reduce the progression of 
atherosclerosis and lower the incidence of cardiovascular events in patients with established 
vascular disease.87-91 Since statin medications are at least as effective in controlling total and LDL-
cholesterol and do not have the gastrointestinal consequences or the skin flushing of niacin, statins 
have supplanted niacin as first-line treatment. However, since statin medications also generally 
reduce HDL-cholesterol, there has been continued interest in niacin for its potential to increase 
HDL-cholesterol.  Recently, two large coronary outcomes trials (AIM-HIGH92,93 and HPS2-
THRIVE94,95) have demonstrated that extended-release niacin offered no benefits beyond statin 
therapy alone in reducing cardiovascular events in patients with established cardiovascular disease. 
The second study94,95 added an additional medication to niacin, laropiprant, a type 1 prostaglandin 
D2 receptor antagonist, to increase adherence by decreasing the flushing associated with niacin. 
These studies suggest there are no long-term unique benefits to niacin treatment, but do not aid 
understanding of the use of niacin for improving diagnostic growth hormone testing. 
Niacin and growth hormone: Overview of proposed pilot study 
We propose to carry out a randomized, double blind, placebo controlled pilot study to 
evaluate the effect of niacin administration on stimulated GH secretion in children who are 
overweight (BMI > 95th percentile for age). We will compare these results to a control group of 
otherwise healthy children who are growing below the 5th percentile for height and are undergoing a 
short stature evaluation that results in a recommendation for growth hormone stimulation testing. 
We will not accept children who are clearly not growth hormone deficient and therefore do not need 
growth hormone testing. This control group is important to include because there are many children 
who falsely fail growth hormone stimulation testing. For example, Marin et al found that the 
percentage of normal children with normal height and growth velocity who failed to attain a GH 


 
 
11 
level greater than 7 micrograms/L during any of three stimulation tests was 61% at pubertal stage 1, 
44% at pubertal stage 2, and 11% in pubertal stage 3.96 We do not fully understand the reasons for 
such failure, but it is possible that varying levels of free fatty acids, even among normal weight 
children, may be contributing. Thus we feel it is scientifically and ethically justified to evaluate the 
response of normal weight children to growth hormone stimulation testing in the presence and 
absence of niacin. Given the lack of this type of testing in children, we do not know if children are 
susceptible to the effects of elevated free fatty acid concentrations, other factors, or both. Being able 
to compare the responses of obese children and normal weight children would provide better insight 
into this physiology. 
Because there were no data demonstrating niacin’s efficacy to suppress lipolysis, we first 
needed to conduct a small dose-establishing study. For dose-establishing study 1, only overweight 
subjects participated, so we could attempt to determine the dose of niacin needed to suppress FFA 
concentrations sufficiently in the sample of greatest interest. After an overnight fast, we 
administered three doses of niacin and measure FFA concentrations. We began with obese children 
studied using 250 mg niacin per dose; since failure to suppress FFA consistently below 200 uEq/L 
was seen, we studied 5 more children using 500 mg niacin per dose. We chose to start with 250 mg 
per dose based on a study by Stokes et al that administered adult subjects 1 g of niacin at the 
commencement of the study followed by 500 mg two and four hours later.71 These subjects had an 
average weight of 81 kg, suggesting they received 12.3 mg/kg as the first dose and a total of 24.7 
mg/kg total. Our subjects will have a minimum weight of 30 kg; a dose of 250 mg would amount to 
a maximum of 8.3 mg/kg for a total maximum of 25 mg/kg after three doses. The 500 mg dose, 
would amount to a maximum of 16.6 mg/kg per dose or 50 mg/kg per day. Based on long-term data 
of children receiving niacin for treatment of hyperlipidemia, typical daily doses range from 550-
2250 mg/day (7-98 mg/kg/day).97 Thus, we believed our chosen doses were well within the safe 
administration range and might be effective in suppression of lipolysis.  


 
 
12 
Figure 1: FFA Suppression
by  Niacin
0
60
120
180
240
300
360
0
500
1000
1500
2000
2500
250 mg Niacin (n=2)
500 mg Niacin (n=5)
Niacin
Time (min)
Free  Fatty Acids
(uEq/L)
*
*
*
Figure 2: Growth Hormone Secretion
After Niacin
0
60
120
180
240
300
360
0
2
4
6
250 mg Niacin (n=2)
500 mg Niacin (n=5)
Niacin
Time (min)
Growth Hormone
(ng/mL)
 
Results from dose-establishing study 1 are shown in Figure 1. Seven children, mean age 
10y, all with BMI over the 97th percentile, were studied. There was only temporary suppression of 
lipolysis with 250 mg niacin per dose; therefore as outlined in the experimental plan, only 2 subjects 
were studied with 250 mg niacin per dose. We observed that 500 mg niacin per dose led to greater 
suppression of lipolysis than 250 mg per dose (dose x time interaction p=0.017), but the 2 hour 
intervals between niacin doses were also accompanied by subsequent rises in FFA levels to near 
baseline concentrations. Small but non-significant increases in growth hormone concentrations were 
found with 500 mg niacin per dose (Figure 2). GHRH concentrations showed little change across 
time and no differences according to dose of Niacin (Figure 3). Somatostatin data were available 
only from patients given 500 mg Niacin. A nonsignificant decrease was observed during the first 
hour of Niacin treatment (Figure 4). 


 
 
13 
Figure 4: Somatostatin After Niacin
0
60
120
180
240
300
360
0
10
20
30
40
500 mg Niacin (n=5)
Niacin
Time (min)
Somatostatin (pg/mL)
Figure 3: GHRH After Niacin
0
60
120
180
240
300
360
0
2
4
6
8
10
12
14
250 mg Niacin (n=2)
500 mg Niacin (n=5)
Niacin
Time (min)
GHRH (pg/mL)
 
There were no serious adverse events, either unexpected or expected involving subjects 
participating in this protocol. As expected, flushing and nausea were observed frequently with the 
first dose of niacin, but, as also anticipated based on the extant literature, there was tachyphylaxis 
(sudden development of tolerance) such that side effects abated after the third dose of medication: 
Table 1: Reported Adverse Events During Niacin Dose-Finding Study 1 
 
Expected 
adverse 
reactions 
(%) 
250 mg Niacin (n=2) 
500 mg Niacin (n=5) 
Time (hours) 
Time (hours) 
0 
1 
2 
3 
4 
5 
6 
0 
1 
2 
3 
4 
5 
6 
Headache 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Flushing 
0 
100 
100 
100 
50 
50 
0 
0 
80 
40 
80 
40 
20 
0 
Feeling 
warm 
0 
100 
50 
50 
50 
0 
0 
0 
80 
60 
100 
60 
20 
0 
Nausea 
0 
0 
0 
0 
0 
0 
0 
0 
0 
20 
0 
0 
0 
0 
Vomiting 
0 
0 
0 
0 
0 
0 
0 
0 
0 
20 
0 
0 
0 
0 
Stomach 
Ache 
0 
0 
0 
0 
0 
0 
0 
0 
20 
20 
0 
0 
0 
0 
Diarrhea 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Tingling 
0 
0 
0 
0 
0 
0 
0 
20 
0 
0 
0 
0 
0 
0 
Light-
headedness 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Itchiness 
0 
100 
100 
0 
0 
0 
0 
0 
60 
20 
60 
40 
0 
0 
Rashes 
0 
0 
0 
0 
0 
0 
0 
0 
20 
0 
20 
20 
0 
0 
*Note: niacin doses administered at time 0, 2, and 4. Time 0 data reflect reactions before the first dose was administered. 
 
Based on the preliminary results from Dose-Establishing study 1, we performed a second 
dose-establishing study examining 5 obese children, to determine whether niacin doses 


 
 
14 
administered more frequently will further suppress FFA. We administered niacin hourly, instead of 
every 2 hours, to increase FFA suppression throughout the entirety of the test. We tested only 
500mg doses of niacin administered hourly for 4 hours (2,000 mg total), as we found clear evidence 
of insufficient suppression with 250mg niacin and greater suppression with 500mg niacin (Figure 
1). To limit the niacin daily dose to 2,000 mg/day, a dose previously administered long-term to 
children for the treatment of hyperlipidemia 97, and accommodate nursing preference on the 
inpatient ward, we shortened the test to conduct a 4 hour study from 7:30am-11:30am.  
We specified that, after establishing the necessary dose of niacin, we would report back to 
the IRB before initiating the main study, which will be performed using both overweight and 
control subjects.  
In the Dose-Establishing Study 2, a total of 5 obese children received 500 mg hourly for 4 
hours. We found significant suppression of free fatty acids (Figure 5) to the pre-specified outcome 
(200 UEq/L = 0.2 mEq/L).  
0
6 0
1 2 0
1 8 0
2 4 0
0 .0
0 .5
1 .0
1 .5
2 .0
F ig u re  5 : F F A  S u p p re s s io n
b y   N ia c in
T im e  (m in )
F re e  F a tty  A c id s
(m E q /L )
5 0 0  m g  q 1H
5 0 0  m g  q 2H
2 50  q2H
 
 
Dose p=0.048; Dose x time interaction p=0.018 
 
We also observed stimulation of growth hormone concentrations (Figure 6). 
 


 
 
15 
0
6 0
1 2 0
1 8 0
2 4 0
0
1
2
3
4
5
F ig u re  6 : G ro w th  H o rm o n e  S e c re tio n
A fte r N ia c in
T im e  (m in )
G ro w th  H o rm o n e
(n g /m L )
5 0 0  m g  q 1 H
5 0 0  m g  q 2 H
2 5 0  q 2 H
 
 
Dose p=0.019; Dose x time interaction p=0.61 
 
For the dose-finding studies, the goal is suppression of FA concentrations. All 5 participants 
who received 500 mg qH demonstrated suppression of FFA below 200 µEq/L (0.2 mEq/L) during 
niacin administration. The suppression was much more consistent with the highest frequency of 
niacin administration: 
 
Table 2: Suppression of FFA <2 mEq/L by Niacin 
Group 
Number of 
Subjects 
Percentage of measurements post 
niacin with FFA <0.2 mEq/L 
250 mg q 2H 
2 
11.5% 
500 mg q 2H 
5 
43.1% 
500 mg q 1H 
5 
67.5% 
 
Adverse events during Dose Establishing Study 2 were largely as expected. All participants 
reported flushing or warmth, 60% tingling or rash, and 20-40% abdominal discomfort, nausea, or 
emesis. 
 
Data Table 3: Reported Adverse Events During Niacin Dose-Finding Study 2 


 
 
16 
 
Expected adverse reactions (%) 
500 mg Niacin every hour 
(n=5) 
Time (hours) 
0 
1 
2 
3 
4 
Headache 
0 
20 
0 
0 
0 
Flushing 
0 
100 
40 
40 
0 
Feeling warm 
40 100 
40 
20 
20 
Nausea 
20 
20 
40 
0 
20 
Vomiting 
0 
20 
0 
0 
20 
Stomach Ache 
20 
40 
20 
20 
20 
Diarrhea 
0 
0 
0 
0 
0 
Tingling 
0 
60 
20 
0 
0 
Light-headedness 
0 
0 
0 
0 
0 
Itchiness 
0 
60 
40 
20 
0 
Rashes 
0 
0 
0 
0 
0 
 
Note: niacin doses administered at time 0, 1, 2, and 3. Time 0 data reflect reactions before the first dose was administered. The 
symptoms at hour 4 were of short duration with only moderate severity. The symptoms reported at earlier hours were also of mild or 
moderate intensity and, with the exception of feeling warm or flushing, of short duration.  All symptoms had resolved completely by 
the end of the 4th hour. 
 
 
We therefore will initiate the main study protocol. 
 
During the main study, two sets of GH stimulation tests will be performed on two 
consecutive days. On one day, the testing will be performed in conjunction with four hourly doses 
of niacin 500 mg, and on the other day with four doses of a placebo, with the order (niacin first day 
or second) randomly determined. Subjects will not receive sex hormone “priming” pretreatment 
(which is used by some clinicians to overcome the naturally lower occurring GH concentrations 
found in prepubertal children) due to the design of the study; no protocols have established 
methodology for priming when performing GH stimulation testing on sequential days. We were 
concerned that administration of sex-steroids could differentially affect the first stimulation test 
compared to the second. Additionally it might be difficult to assure compliance with the medication 
as it would be taken at home prior to the admission. Furthermore this protocol will be restricted to 


 
 
17 
prepubertal and early pubertal subjects to limit the degree of sex hormone influence. It should also 
be noted that the vast majority of pediatric growth hormone testing performed in the US is done in 
the absence of such sex steroid priming.  
Stimulation testing will consist of arginine followed one hour later by L-dopa, both of which 
are standard medications used to assess GH secretion. Arginine is thought to inhibit somatostatin 
release, thereby allowing for GH secretion from the pituitary. Studies of the effect of arginine 
infusions on GHRH-stimulated GH release show enhanced GH response compared to GHRH 
alone.98,99 Furthermore, incubation of rat anterior pituitary cells with arginine shows no change in 
GH secretion,100 suggesting arginine is not itself a direct GH secretagogue but likely works by 
decreasing somatostatin tone. Arginine has been reported to produce long term changes in free fatty 
acid concentrations101 but no short term changes were seen after a single infusion.102 In contrast, L-
dopa (L-3,4-dihydroxyphenylalanine) is thought to increase GHRH secretion, thereby promoting 
pituitary GH secretion. Studies of humans given GHRH antagonists showed suppressed GH 
concentrations after L-dopa administration, suggesting L-dopa’s actions were blocked.103 In 
children with a robust GH response to L-dopa, GHRH plasma levels have also been found to rise in 
direct proportion to the GH response.104 Furthermore, studies combining L-dopa infusions with 
GHRH administration do not show enhancement of GH secretion compared to GHRH alone.98 Such 
results are not consistent with an effect of L-dopa on somatostatin release. We have chosen to use 
arginine and l-dopa in order to separately stimulate each hypothalamic hormone (GHRH and 
somatostatin) involved in growth hormone release and thus examine the physiologic effects of free 
fatty acids more carefully. We did not use GHRH as the stimulus because it would act directly on 
the pituitary and prevent us from examining the effects of niacin on the hypothalamus. We also 
chose not to use glucagon because it likely acts by two mechanisms, stimulating GHRH and 
inhibiting somatostatin via hypoglycemia.105  


 
 
18 
 
We hypothesize that niacin will lead to a fall in free fatty acid concentrations in both groups 
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.  
 
In the first dose-establishing study, 7 children (two given 250 mg niacin x 3 doses every 2 
hours, 5 given 500 mg niacin x 3 doses every 2 hours) were screened and enrolled. In the second 
dose-establishing study, 5 children to be given 500 mg niacin x 4 doses every hour will be screened 
and enrolled. In the main study, up to 66 children will be screened for study entry and enrolled until 
the goal of 40 completed subjects, 20 for each group, is met. Children will be recruited from two 
sites, the Hatfield Clinical Center at the NIH in Maryland and Children’s National Medical Center 
in Washington, DC; however, testing will be performed exclusively at the NIH. 
We have chosen to pilot a randomized, double blind, placebo controlled trial in order to 
minimize the opportunity for bias in our study and maximize the interpretation of our results. We 
used a cross-over design to help eliminate potential of temporal factors related to giving niacin or 
placebo first. We consider this study a pilot to examine new methodology for growth hormone 
testing in obese children, and thus we did not choose to start with an unblinded smaller study first. 
We also did not want to expose subjects to the risks, however minimal, of a medication not 
approved for children under age 16y that requires IND filing without powering the study for the 
possibility of finding significant results.  
 
Objectives: 
 
We propose to determine the effects of lipolytic inhibition on GH secretion in obese children 
as compared to the effects of such inhibition on GH secretion in short healthy children who are 
undergoing growth hormone stimulation testing. We plan to use our findings to better elucidate the 


 
 
19 
pathophysiology underlying diminished GH secretion in obesity as well as to pilot an improved 
testing of GH deficiency in overweight children. 
Specific Hypotheses: 
 
In the course of this study we will test the following hypotheses: 
• Inhibition of lipolysis by niacin will lead to a decrease in plasma FFA in obese and control 
children without inducing significant adverse effects. 
• In the control group of short children (that are not found to be growth hormone deficient) 
peak stimulated GH concentration will be significantly greater than that observed in obese 
children. GH secretion of non-obese short children will be significantly augmented by niacin 
treatment. 
• In obese children, peak stimulated GH concentration will be blunted after placebo but with 
niacin these measurements will increase significantly to achieve values similar to those seen 
in the non-GH-deficient control subjects after placebo.  
Study Design and Methods: 
 
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 > 7 and < 15 years. 
3. Tanner stage I, II, or III for the breast among girls and testes <10 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 < 6.4%. 


 
 
20 
6. Females who are age 10 or greater must have a negative pregnancy test. 
7. Body mass index > 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 > 7 and < 15 years. 
4. Tanner stage I, II, or III for the breast among girls and testes < 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 < 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 studies 1 and 2 and the main study): 
Subjects will be excluded if they have any of the following: 
1. Baseline creatinine > 1.0 mg/dl. 


 
 
21 
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) > 1.5 the upper limits of 
normal. 
4. Pregnancy. 
5. Evidence for impaired glucose tolerance or Type 2 diabetes, including fasting plasma 
glucose ≥ 100 mg/dL, 2 hour post-dextrose glucose ≥ 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 possible 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 ≥ 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. 
 
 
Each subject will receive a written explanation of the purposes, procedures, and potential 
hazards of the study. Communication of this information and of the subject’s assent as well as the 
consent of the parent or guardian will be documented in the medical record. All subjects will be 


 
 
22 
informed of their right to withdraw from the study. Prior to blood draws subjects will be offered 
application of ELA Max cream to the surface of the skin for a minimum of one-half hour, to 
anesthetize the skin surface. 
Procedures of the study: 
Initial Screening Evaluation for the dose-establishing studies 1 and 2 and the main study: 
Performed in the outpatient clinic. Study subjects will be screened at the Clinical Center in 
Bethesda. 
1.   Protocol review and signing of consent and assent forms. All study procedures will be 
discussed and study risks and benefits explained. 
2.  Complete medical history and physical exam with Tanner pubertal staging, weight (in kg), 
and height (in cm) by stadiometer (3 repeated measures). 
3.  Fasting Blood Work including fasting insulin and glucose concentrations, and fasting lipid 
profile to include total cholesterol, LDL, HDL, and triglycerides. 
4.  Additional blood tests for complete blood count, HgbA1C, electrolytes, renal, mineral, and 
hepatic profiles, thyroid functions, gonadotropins, testosterone and SHBG, IGF-1, IGF binding 
protein 3 (IGFBP-3), sedimentation rate, total IgA, tissue transglutaminase (TTG) IgA, iron, 
vitamin D, urinalysis, and research samples to be saved (10 mL) for future genetic analyses of 
genes important for obesity and/or GH deficiency. Urine pregnancy test for all females age 10 
and over. 
5.  Glucose tolerance test: Following the fasting blood work, an oral dextrose solution (75 g per 
300 mL) will be administered in a dose of 1.75 g of dextrose per kg of body weight up to a 
maximum dose of 75 g. Two hours after this administration blood glucose and insulin levels 
will be drawn. 
6.  Bone age X-ray as part of the evaluation for pubertal development. The bone age is considered 
a more objective measure of pubertal staging, especially in obese children where the ability to 


 
 
23 
determine sexual maturation by physical exam can be compromised. The bone age is also useful 
for secondary analysis, including correlation of bone age, pubertal staging, growth hormone, 
and final height predictions. (This evaluation will not be performed in the dose-establishing 
study.) 
7.  Hyperphagia questionnaire.  A hyperphagia questionnaire106 that was originally designed for 
and validated in children and adults with PWS will be administered to the caregiver of all child 
subjects and any adult subjects who still reside with a caregiver to assess hyperphagic behavior, 
drive, and severity (see Appendix E). 
 
Dose-Establishing Study 1 
Only subjects meeting the inclusion and exclusion criteria during the screening visit will be 
evaluated. For dose-establishing study 1, we tested 2 subjects with the 250 mg niacin dose given 
every 2 hours. Since we did not see appropriate suppression of FFA concentrations (<200 uEq/L), 
we increased the dose to 500 mg every 2 hours and tested five more subjects. Since we did not see 
consistent suppression of FFA below 200 uEq/L with 500 mg every 2 hours, we will conduct 
another dose-establishing study lasting four hours, where niacin will be administered hourly (4 
doses of 500 mg – see below). We will update the IRB on the results of dose-establishing study 2 
before we initiate the main study. 
The dose-establishing study visit 1 occurred within two months of screening visit to ensure 
consistency of physical exam and medical history throughout the study period. Patients were 
admitted the night before the first day of testing. Additionally, literature suggests that several 
vitamins influence growth hormone secretion;107,108 109,110,111,112 thus, if applicable, vitamin 
supplements were discontinued for three days prior to admission. All subjects were admitted to the 
NIH Clinical Center for an evaluation that included: 


 
 
24 
1. 
Medical History and Physical Examination with Tanner pubertal staging and 
anthropometric measurements including weight (in kg) and height (in cm) by stadiometer (3 
repeated measures). 
2. 
Placement of an intravenous line to be used for medication administration and blood 
sampling over a 24 hour time period. 
3. 
Repeat urine pregnancy test in girls age 10 and older. 
4. 
Overnight Fast beginning at 10 pm and ending after completion of testing the following 
day. 
5. 
Administration of niacin: For dose-establishing study 1, niacin was given at 6am, 8am, and 
10am. Each dose was either 250 mg or 500 mg as described above. 
6. 
Frequent blood sampling from an indwelling intravenous line just prior to the first dose of 
niacin and then every 30 minutes for the next six hours. After completion of this sampling, 
the subjects were given an ad lib diet. Blood samples were analyzed for GHRH, 
somatostatin, GH, FFA, glucose (via bedside glucometer), and insulin concentrations. FFA 
assays were performed using the WAKO NEFA C diagnostic kit.  
7. 
Discharge: Subjects were discharged following the completion of the frequent blood 
sampling.  
Dose-Establishing study 2 
The dose-establishing visit for dose-establishing study 2 will occur within two months of 
screening visit to ensure consistency of physical exam and medical history throughout the study 
period. Patients will be admitted the night before the first day of testing. Additionally, literature 
suggests that several vitamins influence growth hormone secretion;107-112 thus, if applicable, vitamin 
supplements will be discontinued for three days prior to admission. All subjects will be admitted to 
the NIH Clinical Center for an evaluation that will include: 


 
 
25 
8. 
Medical History and Physical Examination with Tanner pubertal staging and 
anthropometric measurements including weight (in kg) and height (in cm) by stadiometer (3 
repeated measures). 
9. 
Repeat urine pregnancy test in girls age 10 and older. 
10. 
Overnight Fast beginning at 10 pm and ending after completion of testing the following 
day. 
11. 
Placement of an intravenous line to be used for medication administration and blood 
sampling over a 5 hour time period. 
12. 
Administration of niacin at 7:30am, 8:30am, 9:30am, and 10:30am. Each dose will be 500 
mg. 
13. 
Frequent blood sampling from an indwelling intravenous line just prior to the first dose of 
niacin and then every 30 minutes for the next four hours. After completion of this sampling, 
the subject will be given an ad lib diet. Blood samples will be analyzed for GHRH, 
Somatostatin, GH, FFA, glucose (via bedside glucometer), and insulin concentrations. 
GHRH and Somatostatin will be sampled once per hour. Based on our first dose-establishing 
study, we believe that hourly samples for these two hormones will be sufficient to measure 
the changes that these hormones undergo during testing. 
14. 
Discharge: Subjects will be discharged following the completion of the frequent blood 
sampling. 
 
Main Study: Randomization 
Only subjects meeting the inclusion and exclusion criteria during the screening visit will be 
randomized. Subjects will be assigned to receive placebo x 4 doses on the first day of GH 
stimulation testing and niacin  500 mg x 4 doses on the second day or they will be assigned to 
receive niacin 500 mg x 4 doses on the first day and placebo x 4 doses on the second day. Subjects 


 
 
26 
will be stratified by group and sex in blocks of 4 such that roughly equal numbers of subjects in 
each stratum will be assigned to each placebo and active medication administration order. 
Additionally randomization of obese subjects will be stratified by BMI (95-99th percentile or >99th 
percentile). 
Main Study: Inpatient evaluation: 
Only subjects meeting the inclusion and exclusion criteria during the screening visit will be 
evaluated as inpatients. A total of 40 subjects in the two main groups will complete inpatient 
evaluation, although up to 50 may initiate inpatient evaluation in order to achieve full enrollment.  
The inpatient visit will occur within two months of screening visit to ensure consistency of physical 
exam and medical history throughout the study period. Patients will be admitted the night before the 
first day of testing. Additionally, literature suggests that several vitamins influence growth hormone 
secretion;107-112 thus, if applicable, vitamin supplements will be discontinued for three days prior to 
admission. All subjects will be admitted to the NIH Clinical Center for an evaluation that will 
include: 
1. 
Medical History and Physical Examination with Tanner pubertal staging and 
anthropometric measurements including weight (in kg) and height (in cm) by stadiometer (3 
repeated measures). 
2. 
DXA scanning for determination of lean body mass and body fat mass. 
3. 
Placement of an intravenous line to be used for medication administration and blood 
sampling over a 48 hour time period. 
4. 
Repeat urine pregnancy test in girls age 10 and older. 
5. 
Overnight Fast beginning at 10 pm on both nights; ending after completion of testing each 
day. 
6. 
Growth Hormone Stimulation testing consisting of arginine (500 mg/kg IV up to 
maximum of 30 g, infused over 30 min) at 8:30am, followed by L-dopa (500 mg by mouth) 


 
 
27 
at 9:30am. A dose of niacin (dose determine in the dose-establishing study) or placebo will 
be administered by mouth at 7:30am, 8:30am, 9:30am, and 10:30am . The study will be 
repeated the next day in the same fashion. The order of niacin 500 mg or placebo will be 
randomized. Blood will be sampled from an indwelling intravenous line at times -60, -30, 0, 
+30, +45, +60 minutes of arginine infusion for measurements of GH, free fatty acids, 
glucose (via bedside glucometer), and insulin concentrations. Blood will also be sampled at 
times -30, 0, +30, +45, +60, +75, +90, and +120 minutes of L-dopa administration for the 
same serum concentrations. GHRH and Somatostatin will be sampled hourly at 7:30am, 
8:30am, 9:30am, 10:30am, and 11:30am, with two additional measurements at +30 minutes 
(9am) of arginine infusion and +30 minutes (10am) of L-dopa administration. After 
completion of this sampling, the subject will be given an ad lib diet.  
7. 
Discharge: Subjects will be discharged following the growth hormone stimulation test on 
the second day. 
Monitoring subjects and criteria for withdrawal of subjects from study: 
 
The types, frequency, and duration of tests and visits are outlined on the flow diagrams at 
the end of this protocol document (Appendices B and C). Subjects will be examined at each of the 
two visits, which will be completed within a 2 month time period. If unanticipated toxicities are 
uncovered during the study, we will report these promptly to the IRB and FDA. 
 
Subjects will be informed that they may withdraw from the study at any time. 
Noncompliance with study procedures may lead to withdrawal of study subjects. Other events that 
will result in discontinuation of treatment include:  
1.  Inability to tolerate drug secondary to perceived or observed side effects. 
2.  Pregnancy. 
3.  Any verified abnormalities in laboratory values or physical status that cannot be 
explained by an intercurrent unrelated illness (or by obesity and insulin resistance itself) 


 
 
28 
that are considered WHO grade 2 or greater for gastrointestinal, hematologic, clinical 
hemorrhage, kidney/bladder, alopecia, pulmonary, cardiac, neurocerebellar, allergy, 
flu-like symptoms, metabolic, or eye toxicities; and grade 3 or greater for infection, 
anorexia, circulatory, neurologic, dermatologic, coagulation, endocrine, or performance 
status toxicities.113 
Adverse event reporting: 
 
Adverse events, protocol deviations, unanticipated problems (UP), Unanticipated Adverse Device 
Effects (UADEs), serious adverse events, sponsor and serious, are defined as described in NIH 
HRPP SOP 16 (“Reporting Requirements for Unanticipated Problems, Adverse Events and Protocol 
Deviations.”). All adverse events occurring during the study, including those observed by or 
reported to the research team, will be recorded. Serious unanticipated problems, and serious 
protocol deviations, will be reported to the IRB and CD as soon as possible but not more than 7 
days after the PI first learns of the event. Not serious unanticipated problems will be reported to the 
IRB and CD as soon as possible but not more than 14 days after the PI first learns of the event. Not 
serious protocol deviations will be reported to the IRB as soon as possible but not more than 14 
days after the PI first learns of the event. 
Deaths will be reported to the Clinical Director within 7 days after the PI first learns of the event. 
 
The PI will immediately report SAEs to the Sponsor according to the requirements of 21 CFR 
312.64(b) and as agreed upon with the sponsor. The PI will record nonserious AEs and report them 
to the Sponsor according to the timetable for reporting specified in the protocol (21 CFR 312.64(b)). 
 
A post test questionnaire will be administered after the inpatient admission in the main study, and 
the questionnaire will also be administered every hour from 6am to Noon during the inpatient 


 
 
29 
admission in the dose-establishing study. A sample questionnaire is attached to the end of this 
document as Appendix D. 
 
Waiver of Reporting to the IRB of anticipated minor protocol deviations, adverse events and 
deaths due to underlying disease or population under study unless determined to be an 
Unanticipated Problem 
 
• 
For waiver of Reporting to the IRB of anticipated minor protocol deviations  
The following anticipated minor deviations in the conduct of the protocol will not be reported to the 
IRB unless they occur at a rate greater than that which is anticipated to occur: 
 
 
Problem 
Expected Frequency 
Rescheduled appointment for protocol visit 
50% 
Inability to obtain intravenous access after 2 attempts 
25% 
Venous sample at a time point not obtained 
25% 
Hemolysis or other issue preventing analysis of a blood or urine 
sample 
25% 
A research subject was enrolled but did not meet eligibility 
criteria 
5% 
A research subject met withdrawal criteria but was not 
withdrawn 
5% 
Subject had to make an additional visit for lab work (e.g. arrived 
too late for bloodwork, specimen result hemolyzed/equivocal, 
etc.) 
30% 
Inadvertent loss of samples or data 
10% 
Inadvertent collection of additional noninvasive data (e.g. extra 
survey) 
5% 
Appointment conducted >2 weeks beyond anticipated date 
10% 


 
 
30 
Participant did not take all medication doses as prescribed 
10% 
Lost medication 
5% 
 
If the rate of these events exceeds the rate specified by the protocol, the events will be classified and 
reported as though they are Unanticipated Problems. 
 
• 
For waiver of Reporting to the IRB of anticipated adverse events: 
The following anticipated non-UP adverse events will not be reported to the IRB unless they occur 
at a rate greater than that known to occur in this population:  
 
Problem 
Expected Frequency 
Pain during intravenous catheter insertion 
60% 
Bruising, fainting or lightheadedness after a blood draw 
20% 
Red or white skin reaction to ELA Max numbing cream 
100% 
Phlebitis after intravenous catheter 
20% (1 subject) 
Occurrence of adverse response to niacin administration 
See Table 2 for time point 
based frequencies 
 
• 
For waiver of Reporting to the IRB of anticipated adverse events on an FDA-regulated 
trial: 
The following anticipated adverse events will not be reported to the IRB unless they occur at a rate 
or severity greater than that known to be associated with Niacin. Examples of expected adverse 
events include but are not limited to those events detailed in the FDA-approved package insert for 
niacin and in the protocol’s risk section. The waivers that apply here are:  
 
Table 2: Time Point Based Expected Adverse Reactions During Niacin Administration 
 
Time (hours after Niacin administration) 


 
 
31 
Expected adverse 
reactions (%) 
1 
2 
3 
4 
5 
6 
Headache 
20 
0 
0 
0 
0 
0 
Flushing 
100 
100 
100 
50 
50 
0 
Feeling warm 
100 
100 
100 
60 
20 
0 
Nausea 
20 
20 
0 
0 
0 
0 
Vomiting 
20 
20 
0 
0 
0 
0 
Stomach Ache 
20 
20 
0 
0 
0 
0 
Diarrhea 
20 
0 
0 
0 
0 
0 
Tingling 
20 
20 
0 
0 
0 
0 
Light-headedness 
20 
0 
0 
0 
0 
0 
Itchiness 
100 
100 
60 
40 
0 
0 
Rashes 
20 
20 
20 
20 
0 
0 
 
If the rate or severity of these events exceeds the rate or severity anticipated in the protocol or FDA-
approved package insert, the events will be classified and reported as though they are Unanticipated 
Problems. 
Because we anticipate that other mild symptoms may occur in the course of participation in the 
protocol that are unrelated to study drug or participation, we will not submit Unanticipated 
Problems for mild signs/symptoms (CTCAE Grade ≤ 2), such as rhinorrhea, nasal congestion, 
watery eyes, cough, lightheadedness, fever blister, etc., that occur infrequently (≤ 10%). Such 
events will be reported at the time of the IRB Annual Review. 
Data safety monitoring board (DSMB): A DSMB will be assembled for oversight of this protocol 
by the Clinical Director, NICHD, with membership and scope determined by applicable 
institutional guidelines. The DSMB will meet to evaluate all serious adverse events and will at a 
minimum convene yearly. The DSMB will examine whether there is evidence of safety for niacin 
administration. The DSMB will review adverse event questionnaire data, and reports of side effects 
from all visits. These reports will also be supplemented by a manual review by the investigators, 
who will add any other events not captured by these systems. Results will be presented as an A vs. 
B analysis prepared by the data manager. The DSMB will be asked to prepare a detailed report to 


 
 
32 
supply to the IRB that describes any adverse events discussed, and that explains the DSMB's vote to 
allow the study to continue or recommendation to end the study.  
Data Analysis 
 
Primary research outcome will be niacin-induced changes in arginine and L-dopa stimulated 
GH concentrations, measured as both area under the curve and peak values, in the overweight group 
compared with the control group. Secondary research outcomes will include changes in free fatty 
acid, glucose, and insulin concentrations during the GH stimulation tests. Since non-completion of 
the study is expected to be due to technical failures (e.g., nonfunctioning IVs) rather than subject 
factors, all analyses will be limited to subjects who complete both placebo and niacin studies. We 
do expect that some members of the control group will not reach a peak GH concentration of 7 
ng/mL during the stimulation testing. We will report all control subjects in the final analyses. 
Analyses will be performed with age, Tanner stage, and initial BMI-SDS as covariates. 
Furthermore, tertiary analyses will also be performed to compare subjects in the Tanner I, Tanner II, 
and Tanner III groups to determine if any differences exist among these pubertal development 
stages. This analysis will be for exploratory purposes only; the study is not powered for this 
subgroup analysis. Additionally if any members of the control group have abnormally elevated lipid 
levels, we will specifically examine these subjects and their growth hormone concentrations. The 
primary outcome analysis will therefore be a repeated measures ANCOVA with subject group 
(obese and control) as the between factor, treatment (niacin or placebo) as the repeated measure, 
GH concentration (peak and AUC) as the outcome variables, and age, sex, and Tanner pubertal 
stage as covariates. We will also model the subject group by treatment interaction but no other 
interaction terms will be entered into the primary analysis. 
Determination of Sample Size 
 
Using data from the available studies that used acipimox, we performed power calculations 
based on the difference in effect on peak GH secretion found with and without use of acipimox in 


 
 
33 
obese adults. Following acipimox, this cohort showed an increase of 10.3 micrograms per liter in 
peak GH concentrations with a standard deviation of 6.1. Thus, at a power of .80 and an alpha of 
.05, the sample size necessary to detect a 10 microgram per liter difference in GH secretion is 14 in 
each group (e.g. obese versus control), and at a power of .95 and an alpha of .05, the sample size 
necessary to detect a 10 microgram per liter difference in GH secretion is 22 in each group. Given 
these calculations, we will aim for 20 subjects per group who complete all aspects of the study. 
 
Allowing for 20% of subjects to fail to complete the main study for various reasons, the total 
number of subjects needed to be studied is 50 (25 in each group). We expect that we will need to 
screen no more than 66 children to find the 50 who meet the inclusion and exclusion criteria. 
Subjects will be randomized with the assistance of the NIH Investigational Drug Management and 
Research Section (IDMS); we anticipate sex and race/ethnicity to be similar in each study arm. For 
the pilot dose-finding studies, we will study no more than 5 per group (15 total) and screen at most 
an additional 10 subjects who do not qualify for these studies. 
 
Pharmaceutical information  
Packaging and Labeling: 
 
Niacin will be purchased from Upsher-Smith Laboratories, Inc, as 500 mg tablets, USP, that 
have been manufactured according to GMP. Each table contains 500 mg of nicotinic acid. In 
addition, each tablet contains the following inactive ingredients: croscarmellose sodium, 
hydrogenated vegetable oil, magnesium stearate and microcrystalline cellulose. From 2011-2016, 
niacin, and the niacin placebo were packaged, supplied, and distributed to the inpatient staff by the 
NIH pharmaceutical development section. The study was placed on hold when use of all PDS-
prepared compounds was quarantined in December 2016. Afterwards, starting in mid- 2017, all 
study compounds will be prepared following the same procedures by Pine Pharmaceuticals. The 
niacin study medication will be packaged as 250 mg capsules using a Swedish orange/caramel 


 
 
34 
opaque #1 capsule. The same capsule components used for the niacin will used for the placebo.  
From 2011-2016 PDS, and subsequently, Pine Pharmaceuticals, supplies inert placebo capsules that 
match the weight of the unlabeled niacin capsules. Pine Pharmaceuticals will perform bioburden 
testing per the United States Pharmacopeia (USP) <61> and <62> standards. Purity and stability 
testing will be performed by the NIH Investigational Drug Management and Research Section. 
Labels for medication will be computer generated by the NIH CRIS system.   
Randomization 
For randomizing order of administration of niacin and placebo, investigators will assign 
consecutive code numbers to participants from prespecified lists stratified by group, sex, and BMI 
(95-99th percentile or >99th percentile).  The NIH Clinical Center Investigational Drug 
Management and Research Section will use permuted blocks with stratification to generate the 
allocations that translate code numbers into study group assignments by using a pseudo-random 
number program. Pharmacy personnel not otherwise involved with the conduct of the study will 
dispense study capsules in containers that appear identical and differ only by participant code 
number. No participant, investigator, or other medical or nursing staff interacting with participants 
will be aware of study group assignments during the trial.   
Arginine hydrochloride 10% solution is approved by the FDA for growth hormone testing. 
This agent is available through the NIH pharmacy and is on the formulary. It will be used at a dose 
of 500 mg/kg IV up to maximum of 30g infused over 30 min on two consecutive days. This dosing 
corresponds to 5 mL/kg, with a maximum dose of 300 mL on two consecutive days.  
L-dopa is not approved by the FDA for growth hormone testing, but is approved for other 
uses. L-dopa has been used clinically for many years for the purpose of growth hormone testing. L-
dopa powder will be obtained from Spectrum Chemicals, which has supplied us with a Certificate 
of GMP.  From 2011-2016, L-dopa was packaged, supplied, and distributed to the inpatient staff by 
the NIH pharmaceutical development section as 250 mg capsules. The analytical group of 


 
 
35 
Pharmaceutical Development Service conducted testing according to USP standards for medications 
used in this protocol prior to release for human consumption. Starting in mid-2017, Pine 
Pharmaceuticals will compound the 250 mg capsules and perform bioburden testing per the United 
States Pharmacopeia (USP) <61> and <62> standards. Purity and stability testing will be performed 
by the NIH Investigational Drug Management and Research Section, which will track and dispense 
all medications to the inpatient staff. 
Unblinding Procedure 
In this trial, all participants, Study Site staff, and pathology and laboratory personnel are 
blinded to the individual assignment of the order in which niacin and placebo are administered. 
Participants will learn their individual assignments (i.e., be unblinded) when the trial is complete. In 
rare instances, it may be necessary to unblind a participant's order of assignment before completion 
of the trial, to a physician, to the Study Site, or to the participant.  
In general, however, participants should not be unblinded. Anytime a staff member learns 
the treatment assignment of a participant, the staff member is at risk of being influenced by that 
information. For example, if the unblinded participant was known to have taken the active agent and 
reported a toxicity, the staff member might make inferences about the effects of niacin on that 
participant, and possibly on other participants as well. The management of future participants may 
be influenced by this information. Maintaining the double-blind design offers the best protection 
against this potential bias. 
In the unlikely event that a Serious and Unexpected Suspected Adverse Reaction (SUSAR) 
occurs and a physician must be unblinded to the treatment group to which an affected trial subject 
belongs, the Investigational Drug Management and Research Section (IDMS) will be contacted by a 
study investigator (usually by the Principal Investigator). The study investigator will request that 
IDMS release the needed information and specify the individual to receive the information. IDMS 
will normally supply unblinding information only to a physician who is not a co-investigator on the 


 
 
36 
study and make clear that group assignment must not be given to study investigators. This 
procedure is intended to ensure that the identity of the investigational medicinal product is revealed 
only insofar as is necessary. As much as possible, the blinding should be maintained for the 
investigators and for anyone responsible for data analysis or interpretation. A subject’s treatment 
group should not be revealed to a study investigator except in a medical emergency, i.e. when this 
appears necessary to ensure the subject’s safety and would be instrumental in further treatment 
decisions. If a subject’s treatment is unblinded, this must be documented by IDMS in their written 
records. In all cases, the reasons and rationale for unblinding will be also documented in writing and 
maintained in the study file. 
Unblinded data are also available to the Data Safety Monitoring Committee (DSMC). In the 
case of a SUSAR, the DSMC is informed and will thus have the opportunity to review subject-level 
data and make any changes to the experimental plan that are required. In the case of a SUSAR, the 
DSMC may elect to reveal the treatment group to which a subject belongs, request additional 
safeguards, or stop the study. The DSMC will assist investigators in deciding if a SUSAR requires 
any of the study investigators to become unblinded so that the FDA can be informed of subject 
assignment because of a SUSAR. 
Study Administration and Data Collection, Management, and Storage 
The study will be conducted by the research team as listed above.  Human biospecimens will be collected 
using procedures appropriate for the type of biospecimen being collected and will be handled in accordance 
with the U.S. Occupational Safety and Health Administration’s Bloodborne Pathogens Standard for Samples. 
The principal investigator and the co-investigators will have access to identifiable participant records. Data 
will be coded by subject number, but will be readily associated with identifiable participant records. Records 
containing personal identifiers will be maintained consistent with the security measures required by the NIH. 
Data will either be transferred directly from the electronic medical record into the NICHD Clinical Trials 
Data Base (CTDB), or for data where direct transfer is unavailable, will be double-entered by hand into 


 
 
37 
CTDB.  All data will be kept on secure computers in the SGO office, whose doors will be locked when staff 
is not present.  All paper data will also be kept in locked areas in the SGO office. Serum and Plasma samples 
not analyzed immediately (as described above) will be stored in locked freezers by the NICHD sample 
management team supervised by the NICHD Clinical Director and tracked/managed through CTDB. Human 
biospecimens in storage will have a unique identifier, will be labeled with a printed label and will contain a 
barcode. Samples will be tracked using a computer‐based inventory system that records the location and 
detailed information of every specimen in the repository.  
 
Sample freezers will be operated using facility environments that include ambient temperature controls, good 
air circulation, lighting, and security. Systems are in place to allow for local and remote temperature 
monitoring of freezers. The NIH has an emergency preparedness plan that covers equipment failures and 
power interruption, including back‐up storage capacity and back‐up power generators.  
 
Parents of participants give explicit permission regarding sample use in the consent form of the study, 
indicating if samples may be used for future experimental testing related to growth hormone response, body 
weight and metabolism without additional consent.  
 
At the conclusion of the study, samples will be retained for future experimental testing related to growth 
hormone response, body weight and metabolism. 
The PI will inform the IRB if samples are lost or destroyed before they are assayed for free fatty acids and 
growth hormone. Loss or destruction of samples saved only for future unspecified research will not be 
routinely reported, unless such loss also entails a breach of the Privacy Act. 
 
Protection of Participants’ Privacy and Confidentiality 
We will follow all relevant NIH policies and HRPP SOPs. Samples and data will be coded.  Only 
individuals involved in consenting and patient care will have access to identifiers.  Records 


 
 
38 
containing personal identifiers will be maintained consistent with the security measures required by 
the NIH. Access to the code will be limited to the study investigators.  Electronic data will be 
password protected and accessible only by authorized study personnel. Electronic data will be 
backed up daily and stored at a secure server. All hardcopy data will be locked in Dr. Yanovski’s 
storage cabinets in research offices at the NIH Clinical Research Center and will be accessible only 
by authorized study personnel. All data will be collected specifically for the purpose of the current 
proposed research project. Any email communications that involve PII will be sent using encryption 
or the secure email system of the NIH. Since even when precautions are taken to ensure participant 
confidentiality, data collection in any study is accompanied by threat to privacy and confidentiality, 
in the unlikely event of a potential breach of confidentiality, the PI will immediately inform the 
IRB.  
 
Limitations to the Study Design 
We have identified several possible limitations to our study, including: 
1) Given that the GH stimulation tests are being performed on consecutive days, it is possible 
that effects of the first day’s testing could carry-over to the second day and affect the results. 
However, many studies in the adult literature have used similar study designs. Furthermore, 
Cavallo et al114 showed no difference in response to GH stimulation testing on two 
consecutive days. Additionally, by randomizing the order of placebo or niacin given during 
the stimulation tests, we believe any effects of order will be detected. 
2) Niacin is known to cause flushing shortly after administration. We anticipate that this side 
effect may conceivably lead the subjects and investigators to become aware of which day 
the niacin and placebo capsules were administered. We do not believe the blinding is critical 
to the success of the study given that we are only measuring objective hormonal data. 
 


 
 
39 
Human Subject Protections: 
a) Rationale for research subject selection: 
 
This is a study to examine the effect of niacin on GH secretion in pediatric obesity and in 
short stature. School-age children are chosen as the study group because of the importance of GH 
on normal growth and development of childhood. Children of various racial/ethnic groups will be 
recruited to ensure that its possible beneficial effect is applicable across racial and ethnic subgroups. 
The mechanism by which obesity changes GH secretion is important as a guide to appropriately 
diagnosing and treating GH deficiency in children. The impact of niacin on GH secretion in both 
groups will aide in development of improved GH provocative tests among children. 
b) Strategies/procedures for recruitment: 
Participants will be recruited by sending letters to appropriate-aged children in the 
Montgomery County, Fairfax County, and Washington, DC school systems, by advertisements in 
local papers, and by referral from physicians who see obese children and short children. 
c) Justifications for exclusions: 
 
All exclusions are either based on identification of problems in the subject’s physical or 
mental health, or based on the ability of the subject to complete protocol studies or are required for 
the goals of the study. We have chosen to study only prepubertal and early pubertal children for 
several reasons. First, we are aware of only one study of prepubertal children, which did not include 
obese children, and did not show any increased response to l-dopa stimulation in the presence of 
acipimox.86 Thus, we feel that the prepubertal population has not been sufficiently studied. 
Secondly, most growth evaluation is performed when children are prepubertal or in early puberty, 
creating a need to understand this physiology carefully. We aim to pilot niacin as a supplemental 
part of growth hormone testing in obese children in order to improve the sensitivity of the growth 
hormone stimulation test in this population. Developing a test for the prepubertal or early pubertal 
population is particularly useful. We included early pubertal subjects (Tanner stage II and Tanner 


 
 
40 
stage III) because the growth hormone concentrations in response to secretagogues do not vary 
significantly from prepubertal levels96 and are not different between males and females in 
prepuberty or early puberty.115 
d) Risks/Benefits Analysis 
i.  Risks and Discomforts: 
1. Physical Examination by a health care provider will be performed with the child unclothed. 
Although appropriate measures will be taken to protect privacy, some children may find this 
embarrassing.  
2. Total blood withdrawal will remain within the NIH guideline of 5mL/kg/day and up to 
9.5mL/kg every 6 weeks. Blood collection by venipuncture is associated with mild 
discomfort, which will be attenuated by offering administration of ELA Max cream before 
venipunctures, and the possibility of local bruising and extravasation. The risk of infection 
or fainting is extremely small. 
3. Dextrose solution administration is without known risks but may cause mild feelings of 
nausea. 
4. Bone age X-ray is without known risks. The total radiation exposure to the left hand and 
wrist for a volunteer undergoing bone age X-ray is 20 millirem. Maximum total radiation 
exposure is estimated to be 0.007 millirem per year, which is well below the recommended 
radiation exposure for child volunteers (no more than 500 millirem in one year). This 
protocol has been approved by the NIH Radiation Safety Committee. 
5. DXA scanning involves passing a collimated X-ray beam of 45 and 105 keV through the 
subject and collecting the X-rays that pass through the patient with a standard X-ray 
detector. Because the delivery and attenuation of the X-rays are measured separately for the 
two principal energies, the procedure allows the differentiation of substances in their path if 
the attenuation coefficients of these substances are known. The procedure requires that the 


 
 
41 
child lie still for 15-20 minutes on a padded table that is part of the instrument. According to 
the manufacturer’s specifications, DXA scanning for body composition delivers no more 
than 1 millirem total body radiation. Volunteers undergo DXA scanning in the Nuclear 
Medicine Department using the Hologic QDR4500A machine. To perform the DXA scan, 
the subject will be placed between the collimated X-ray source and the detector. This is 
achieved by having the subject lie down on a cushioned table. The X-ray source and detector 
are contained in a C-arm construction that is moved to cover the patient. At all times the 
child can see, and be seen by, a person standing nearby. A parent may safely be in the room 
and be in visual and auditory contact with the child. The subject is also in constant voice 
contact with the operating personnel. Fat, bone, and muscle in many body regions will be 
determined during a total body scan. Maximum total radiation exposure is estimated to be 
0.02 millirem per year, which is well below the recommended radiation exposure for child 
volunteers (no more than 500 millirem in one year). This protocol has been approved by the 
NIH Radiation Safety Committee. 
6. Niacin: We successfully applied for FDA approval for the use of niacin in children under an 
investigational new drug application (IND) with Jack Yanovski, MD, PhD as sponsor. 
Niacin is currently FDA-approved in the United States, but only for adults. Niacin has been 
used off-label to treat hyperlipidemia in children.97 A retrospective chart review of 21 
children, age 4 to 14, found one subject who developed a febrile illness with elevation in 
serum aminotransferase who was discontinued off niacin after two months. Reversible 
adverse effects of niacin included flushing (71%), itching (19%), abdominal pain (14%), 
nausea (14%), vomiting (14%), headache (14%), and constipation (5%). 29% also 
demonstrated reversible dose-related elevations in AST concentrations. Niacin is known to 
cause transient skin flushing likely due to prostacyclin formation leading to cutaneous blood 
flow.116 In some trials testing GH secretion in adults, flushing has been observed after niacin 


 
 
42 
with rapid resolution.66,67,73,117,118 In the event of intolerable flushing as reported subjectively 
by the patient, we will administer a single dose of 10 mg/kg of ibuprofen to help alleviate 
the reaction. Nausea, vomiting, and temporary tightness of the chest have also been noted in 
some subjects.66,67,117 No other side effects have been noted in these studies; however, in 
uses of niacin to treat hyperlipidemia, the following other side effects have infrequently 
been reported: atrial arrhythmias,119 dental pain,120 liver injury,94,121-123 myalgia,124 
myopathy,94,95 skin rashes,95 peptic ulcers,95 gastrointestinal bleeding as well as bleeding from 
other sites, 95 diarrhea,95 onset of diabetes and worsening of diabetic control,94,95,125-127 
infections,93,95 blurred vision  and macular degeneration.128  Additionally the effects of niacin 
in pregnancy are unknown.  
7. L-dopa: L-dopa is a precursor to dopamine that is normally synthesized in vivo from 
tyrosine in neurons. It has been used for GH stimulation testing for over thirty years, 
although its current use is primarily outside the United States at this time. L-dopa has been 
well-tolerated with side effects reported only as transient nausea, emesis, and headaches.129-
131 L-dopa is also used as chronic treatment for Parkinson disease, and more severe side 
effects are seen with this treatment regimen. 
8. Arginine is a naturally-occurring amino acid used frequently in clinical settings for testing 
of GH secretion. Although generally well tolerated, there have been reports of 
thromobphlebitis,132 flushing and histamine release,133 necrosis of the skin in one patient 
likely due to overly concentrated formulation,134 release of GH, insulin, glucagon, and 
prolactin, nausea and vomiting, thrombocytopenia in one patient with unclear causal 
effect,135 anaphylaxis in one patient,136 numbness and headache,135 and elevations in blood 
urea nitrogen and creatinine concentrations.135 In patients with cirrhosis elevation in body 
temperature occurred.137 Hyperkalemia has been observed in patients with diabetes, liver 
disease, and renal insufficiency, 138,139 and hypophosphatemia has been seen in diabetic 


 
 
43 
patients.140 Arginine is a category B in the FDA’s pregnancy rating, meaning that no 
controlled pregnancy studies have been performed in humans. 
ii. Benefits 
 
There may be some direct benefit for the subjects involved from the medical evaluations 
each subject will undergo. Abnormal results will be communicated to the participants and their 
parents or guardians and will be made available to the primary care physician. Providing GH 
stimulation testing for children with short stature who require evaluation for GH deficiency may be 
a benefit for some participants, but since most will not have GH deficiency, most will not 
experience a direct benefit from this testing. Treatment will not routinely be provided for any 
condition noted during evaluation. We will refer participants to appropriate treatment programs at 
the conclusion of the study. Even if no individual benefit exists, the knowledge obtained will be 
important for understanding childhood growth and development.  
 
iii. Assessment of Risk/Benefit Ratio  
 
Overall, there are a number of potential benefits, not just to study participants but also to the 
larger population of children who are at risk for metabolic dysregulation due to obesity and short 
stature. Study participation will enable the participant to be screened for clinically-significant 
pathology, and in cases where identified, may facilitate treatment. The procedures for participants 
are described above. Taken together, we believe these represent a minor increment above minimal 
risk (detailed below in Approval under 45-CFR-46, Subpart D 46.406). The investigators have 
further taken many steps to minimize potential discomfort, for instance by administration of ELA 
max cream before blood is drawn. Children also routinely undergo venipuncture, which in children 
not infrequently requires multiple sticks to obtain samples. Furthermore, children are routinely 
required to complete questionnaires during school. We believe the studies outlined in this protocol 
are reasonably commensurate with those children may be exposed to in their actual or expected 


 
 
44 
medical, dental, psychological, social, or educational experiences. We therefore believe that the 
benefits to individual participants and to our understanding of short stature and obesity outweigh the 
minor increment above minimal risk. 
 
iv. Alternatives to Participation 
The current proposal is a physiological study that does not treat any known condition; as a 
result, there are no alternatives other than non-participation. Participants and their families will be 
informed that they will not receive treatment as a result of study participation. For participants 
interested in weight management, treatment referrals will be provided. 
 
e) Compensation 
 
Compensation will be offered to study participants in the amounts of $60 for completing the 
screening visit, $100 for completing the dose-establishing study’s inpatient visit, and $200 for 
completing the main study’s inpatient visit. NIH guidelines indicate that compensation for all visits 
is appropriate and potentially unethical to not provide, and our compensation rates are consistent 
with these guidelines. 
f) Participation of Children and Other Vulnerable Populations: 
i. Approval under 45-CFR-46, Subpart D 46.406 
We propose that this research project be approved under the provisions of 45-CFR-46, 
Subpart D 46.406. Research can be carried out under the provisions of 45-CFR-46, Subpart D, 
46.406 when an IRB finds that more than minimal risk to children is presented by an intervention or 
procedure that does not hold out the prospect of direct benefit for the individual subject, or by a 
monitoring procedure which is not likely to contribute to the well-being of the subject only if the 
IRB finds that four conditions are met: (a) The risk represents a minor increase over minimal risk; 
(b) the intervention or procedure presents experiences to subjects that are reasonably commensurate 


 
 
45 
with those inherent in their actual or expected medical, dental, psychological, social, or educational 
experiences; (c) the intervention or procedure is likely to yield generalizable knowledge about the 
subjects' disorder or condition; and (d) adequate provisions are made for soliciting assent of the 
children and permission of their parents or guardians, as set forth in 46.408. 
We believe this protocol clearly meets the criteria of 45-CFR-46, Subpart D46.406: 
(a) The risk represents a minor increase over minimal risk 
The protocol's procedures presently include the following: outpatient and inpatient visits, 
history and physical examination, anthropometric measurements, placement of intravenous 
lines, blood draws, administration of oral niacin and L-dopa and intravenous arginine, urine 
collections, bone age x-ray, and DXA scan. Each of these procedures, including intravenous 
infusions of arginine and oral administration of L-dopa, has been performed safely and 
without significant sequelae in pediatric studies. In the medical literature, there are reports of 
children, many of whom do not have other medical conditions, who have undergone each of 
these tests in IRB-approved studies. 
Individually, many of the procedures proposed as part of this protocol may possibly 
be considered to represent minimal risk. For example, a panel convened in 1993 by the 
Secretary of Health found that placement of two intravenous catheters, administration of 
insulin and dextrose for the purpose of inducing mild hypoglycemia, and monitoring of 
blood glucose measurements every 5 minutes for many hours were of "minimal risk." The 
investigators have further taken many steps to minimize potential discomfort, for instance by 
administration of ELA max cream before blood is drawn. Given the large pediatric 
experience with each of the proposed procedures, we believe there can be little question, that 
the proposed procedures in the aggregate represent, at most, a minor increment over minimal 
risk. 


 
 
46 
(b) The intervention or procedure presents experiences to subjects that are reasonably 
commensurate with those inherent in their actual or expected medical, dental, 
psychological, social, or educational experiences 
Among the procedures that are part of this protocol are: venipuncture, administration of 
ELA Max cream, oral and intravenous medication, removal of samples at frequent intervals 
from an intravenous line, temporary movement restriction for periods up to 20 minutes, and 
x-rays. Children are routinely exposed to vaccination injections that today often require 
multiple injections on a single day. Children also routinely undergo venipunctures, which in 
children not infrequently require multiple sticks to obtain samples. Dental procedures may 
entail: 1) administration of topical and injected medications (some of which can cause pain), 
2) restriction of movement for significant periods of time, 3) discomfort from the 
manipulations, and 4) exposure to x-rays. Many children have orthodontic braces placed on 
their teeth, including night braces, which are worn for many hours and can be uncomfortable 
during the night. Given these facts, we believe the studies outlined in this protocol are 
reasonably commensurate with those children may be exposed to in their actual or expected 
medical, dental, psychological, social, or educational experiences. 
(c) The intervention or procedure is likely to yield generalizable knowledge about the 
subjects' disorder or condition 
There are two groups of children studied in this protocol: children who are obese and 
children with short stature who are being evaluated for GH deficiency. We believe both 
groups meet the definition of having a condition, about which the study will yield 
generalizable knowledge. 
Childhood and adolescent obesity is an enormously important problem for the US. 
Such children are at immediate risk for a number of comorbid conditions associated with 
obesity.141 The immediate consequences include orthopedic (slipped capital femoral 


 
 
47 
epiphysis and Blount's disease), neurologic (pseudotumor cerebri), pulmonary (asthma and 
sleep disorders including sleep apnea), gastroenterologic (gallstones and steatohepatitis), 
endocrinologic (insulin resistance, type 2 diabetes, hyperandrogenemia, early puberty, 
abnormalities in GH secretion, and menstrual abnormalities), metabolic (dyslipidemia), and 
cardiovascular (elevated blood pressure) disorders. Rates of childhood hypertension, type 2 
diabetes, hyperlipidemia, asthma, sleep apnea, and orthopedic disorders such as slipped 
capital femoral epiphysis are all climbing, in direct proportion with the increasing 
prevalence of obesity. Obese children are 9 times more likely to develop hypertension in 
adulthood, and 8 times more likely to have dyslipidemias that predispose them to heart 
disease. Children with excessive body weight are also at increased risk for cardiovascular 
and all-cause mortality in adulthood. There are also significant psychosocial and economic 
difficulties associated with pediatric obesity.142-145 Thus, there can be no question that 
obesity during childhood is a disorder.  
Evaluation of height is an important aspect of the pediatric examination. Height, and 
more importantly growth, are general indicators of overall well-being and health in children. 
Chronic disease often manifests with poor growth velocity and short stature. Compromised 
growth may be the only clinical sign of an underlying disorder, including Turner syndrome, 
hypothyroidism, renal tubular acidosis, and celiac disease. Additionally, isolated partial GH 
deficiency may be found during a short stature evaluation. Thus, short stature is an 
indication for further testing, which often includes GH axis evaluation.1 Short statue may 
also have behavioral effects. Short adults may have difficulty performing basic activities of 
daily living such as reaching the stove top or driving, and children show delay in visual-
motor skills.146 Psychological effects of short stature are not well established, but are often 
present in the cohort of children who are referred to pediatric endocrinology.147 Given that 
short stature may represent an underlying medical problem, may lead to physical 


 
 
48 
impairment, and should prompt testing and possible endocrine referral, short stature is a 
pediatric disorder.  
It is also clear that this protocol will yield generalizable data, since subject selection 
is not limited by race, ethnicity, or sex. 
Because administration of arginine, l-dopa, and niacin are likely to be considered 
greater than minimal risk but without the prospect of direct benefit to individual subjects, a 
normal weight, normal height control group (i.e., a group with no medical condition) could 
be studied only under section 45-CFR-46 subpart D 46.407 (Research not otherwise 
approvable which presents an opportunity to understand, prevent, or alleviate a serious 
problem affecting the health or welfare of children). This regulation requires approval of the 
Secretary of DHHS following a determination that the research presents a reasonable 
opportunity to further the understanding, prevention, or alleviation of a serious problem 
affecting the health or welfare of children. 
(d) Adequate provisions are made for soliciting assent of the children and permission 
of their parents or guardians, as set forth in 46.408 
Provision has been made for soliciting the assent of children and the permission of parents. 
The consent and assent forms for this study have been carefully reviewed. We believe they 
accurately portray the procedures being performed, and meet the requirements of 45-CFR-
46. Consent is obtained by the principal investigator or associate investigators.  
Because this study is proposed under Section 46.406 of 45CFR 46, Subpart D, namely 
greater than minimal risk with no prospect of direct benefit, but likely to yield generalizable 
knowledge about the subject's disorder or condition, both parents are required to provide 
permission for the minor's participation in the study unless one parent is deceased, unknown, 
incompetent, or not reasonably available, or when only one parent has legal responsibility 
for the care and custody of the child.  When the second parent is not present to sign a 


 
 
49 
witnessed consent form, one parent will sign the consent form and explicit written 
permission will be obtained (whenever possible) from the other parent of the child before 
any study procedures are carried out.  When only one parent is available to give permission 
for participation, this fact will be documented. 
 
iii Consent/Assent Process:   
Each participant will receive a written explanation of the purposes, procedures, and potential 
hazards of the study. Communication of this information and of the participant’s assent as well as 
the consent of the parents or guardians will be documented in the medical record. Written, active 
informed consent will be obtained in-person during the Outpatient Screening Visit from 
parents/guardians, and assent will be obtained from youth by the lead associate investigator or 
designated associate investigators/key personnel. All participants will be informed of their right to 
withdraw from the study. The purpose of the project, all testing procedures, and study components, 
and possible risks and inconveniences will be described in detail, in language understandable to the 
parent(s)/guardian(s). The investigator will also explain the study to the minor who is of a younger 
age and level of understanding. Sufficient time and opportunity will be given for discussion of the 
research as well as to answer any questions they may have, taking care to minimize or eliminate the 
perception of coercion or undue influence. When the NIH informed consent and assent forms are 
signed, a witness will sign the consent document to attest to the validity of the signature of the 
parent(s)/guardian(s). Parents or guardians will be given a signed copy of the consent and assent 
form for their records. In certain instances, the PI or designee will obtain informed consent by a 
witnessed telephone conversation with the parents/guardians of protocol-eligible subjects who 
cannot travel to the NIH Clinical Center for a considerable period of time. Consent may be obtained 


 
 
50 
via telephone and/or another electronic process, rather than in person. In such cases, the written 
signed consent will be faxed and/or mailed and made part of the patients' NIH records. 
iv. Non-English–Speaking Participants 
 
If a non-English speaking family is unexpectedly eligible for enrollment, the parent will be 
provided with the CC Short Written Consent Form for Non-English Speaking Research Participants 
in the participant’s native language and a verbal explanation of the purpose, procedures and risks of 
the study as described in MAS Policy M77-2, NIH HRPP SOP 12 and 45 CFR 46.117(b)(2). The 
IRB-approved English consent form will serve as basis for the verbal explanation of the study. The 
investigator will obtain an interpreter unless the investigator is fluent in the prospective participant’s 
language. Preferably, the interpreter will be someone who is independent of the participant (i.e., not 
a family member). Interpreters provided by the CC will be used whenever possible. The interpreter 
will interpret all oral communications (English to target language and conversely) between 
Investigator and Participant, facilitate discussions, and ensure understanding.  
The IRB-approved English consent form will be signed by the investigator obtaining 
consent and a witness to the oral presentation. The CC Short Written Consent Form will be signed 
by the participant and a witness who observed the presentation of information. The interpreter may 
sign the consent document as the witness and, in this case, will note “Interpreter” under the 
signature line. A copy of both signed forms will be provided to the participant to take home. The 
investigator obtaining consent will document the consent process in the participant’s medical 
record, including the name of the interpreter.  
We request prospective IRB approval of the use of the short form for up to a maximum of 5 
separate encounters in a given language and will notify the IRB at the time of continuing review of 
the frequency of the use of the Short Form. Should we reach the threshold of 5, we will notify the 
IRB of the need for an additional use of the Short Form and that we may have that consent 
document translated into the given inherent language.  


 
 
51 
 
g) Conflicts of Interest 
NIH guidelines on conflict of interest have been distributed to all investigators. There are no 
conflicts-of-interest to report for NIH or non-NIH investigators. Non-NIH investigators will abide 
by the conflict-of-interest policies of their own institutions. 
 
h) Monitoring Plan 
1.   Purpose 
 
The purpose of this Monitoring Plan is to describe the rationale and process for the collection, 
recording, and verification of data for NICHD Protocol #11-CH-0004 
 
2.   Objectives 
 
a. To establish a monitoring plan to ensure the protocol data are in compliance with Good 
Clinical Practice (GCP), NICHD Institutional Review Board (IRB) and Data Safety 
Monitoring Committee policies, and Federal regulations.  
b. To ensure the validity, accuracy and integrity of the data 
 
 
3.   Study Staff Responsibilities  
 
Jack A. Yanovski, MD, PhD (the principal investigator) is responsible for all aspects of the 
study.  
 
Delegation of responsibility will be documented on a study staff Signature and Delegation 
of Responsibility Log. 
 
STUDY STAFF NAME 
TITLE 
DELEGATED 
RESPONSIBILITIES 
Jack Yanovski, MD, PhD 
Co-investigator 
1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12 
 
 
 
*Delegated Study Tasks:    
1. Obtain Informed Consent 
2. Obtain Medical History 
3. Perform Physical Exam 
4. Assess Eligibility Criteria 
 
5. Prescribe Study Drug/device 
6. CRF Completion  
7. CRF Queries 
8. Query completion 
 
9. Maintain Regulatory Docs  
10. Maintain IRB documents  
11. Data Monitoring 
12. Safety Monitoring 
 
Hope Decederfelt, of the NIH Investigational Drug Management and Research Section 
(IDMS), will maintain records of randomized study medication dispensed, maintain records 
of subject identification codes assigned, and have responsibility for releasing randomized 


 
 
52 
codes to investigators at the conclusion of the randomized medication phase. IDMS will also 
have responsibility for the management of niacin and placebo capsules manufactured for the 
study by IDMS, including the performance of stability testing of drug. 
 
4.   Source Documentation and Case Report Forms 
 
Jack A. Yanovski, MD, PhD, is responsible for coordinating data collection and will review the data 
for accuracy and completeness within seven days of each subject visit.  
 
The Sponsor (Jack A. Yanovski, MD, PhD) will conduct initial monitoring. Patient consent 
documents, primary outcome and safety laboratory results and diagnostic test results will be 
monitored for accuracy, correct dating, and agreement between case report forms and source 
documents. As case report forms are entered electronically into the NICHD Clinical Trials 
Database, the computer system contains logs indicating changes made and the circumstances 
leading to these changes.  
 
The NICHD Data Safety Monitoring Committee will also review data from this trial. An 
outside monitor (Amarex) will also review study data periodically as directed by the NICHD 
Clinical Director. 
 
FDA regulatory requirements (annual reports, adverse events reporting, etc) related to IND # 
111512 (Niacin + L-dopa + L-arginine) will also be monitored. The medical records of 
active subjects (defined as subjects receiving study medication) will be monitored quarterly 
or more frequently as required.  The FDA issues will be monitored at least annually. Any 
major findings will be summarized in writing and reported to the NICHD Institutional 
Review Board, if indicated. Investigator credentials, training records, and the delegation of 
responsibility log will also be reviewed on an annual basis. 
 
5.   IRB and DSMC Documentation  
 
All IRB documentation can be found in PTMS. The Principal Investigator, Jack A. 
Yanovski, MD, PhD, is responsible for maintaining IRB and DSMC correspondence related 
to this protocol, including records of all reviews of the study and submissions to the IRB and 
DSMC.    
 
6.   FDA Documentation  
 
Jack A. Yanovski, MD, PhD is responsible for maintaining FDA correspondence, including 
forms 1571 and 1572 and other correspondence (e.g., annual reports, amendments, safety 
reports) in the electronic binder for IND #111512 (Niacin + L-dopa + L-arginine).  
 
Copies of all such correspondence are also maintained in PTMS as part of the NICHD 
protocol record.  
 
7.   Adverse Event Procedures and Documentation  
 


 
 
53 
Serious adverse events are defined by the FDA as any untoward medical occurrences that: 
(1) result in death, (2) are life threatening, (3) require (or prolong) hospitalization, (4) cause 
persistent or significant disability/incapacity, (5) result in congenital anomalies or birth 
defects, or (6) are other conditions which in the judgment of the investigators represent 
significant hazards. All serious adverse events will be reported by the PI verbally and in 
writing as soon as possible to the NICHD Clinical Director using a form provided by the 
Clinical Center.  All serious adverse events will also be reported to the Data Safety and 
Monitoring Committee (DSMC), the IRB, and the FDA within 7 calendar days for death or 
life-threatening adverse events, and within 15 days for all other serious adverse events. 
Adverse events are defined by the FDA as any unfavorable and unintended diagnosis, 
symptom, sign (including an abnormal laboratory finding), syndrome or disease which either 
occurs during the study, having been absent at baseline, or, if present at baseline, appears to 
worsen]. All adverse events (serious and non-serious, expected and unexpected) will be 
reported annually to the IRB and DSMC for review. Electronic data sheets or summary 
language will be supplied for IRB review of adverse event reports at continuing reviews. 
 
The PI will report adverse events in PTMS, to the IRB and to the DSMC. Jack A. Yanovski, 
MD, PhD will inform the FDA in writing.   
 
8. Study Completion 
 
Upon completion of the study Jack A. Yanovski, MD, PhD will retain possession of the 
electronic IND binder and electronic Protocol Binder in a secure location. FDA requires 
records be retained for at least 2 years after study completion. HHS regulations require that 
subjects’ records be maintained for at least three years after completion of a study. Since 
subjects of this investigation are children age 6-14 years, even longer record retention is 
required. All records will be retained until all participants have reached age 23 years.  
 


 
 
54 
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60 
Appendix A 
Medications Used in Growth Hormone Stimulation Testing131,148 
Test 
Dose 
Timing of 
peak GH 
Mechanism 
Side effects 
Cutoff GH 
value for  
≥ 90% 
sensitivity 
Cutoff GH 
value for  
≥ 90% 
specificity 
Arginine 
0.5 g/kg IV to max 
of 40 g,  
infuse over 30 min 
30-60 min 
Inhibits 
somatostatin 
Late 
hypoglycemia 
 
 
L-Dopa 
125 mg for  
< 13.5 kg 
250 mg for  
13.5-31.5 kg 
500 mg for  
> 31.5 kg 
20-120 min 
α-adrenergic 
stimulation of 
GHRH 
Nausea, 
emesis, 
headache 
26.6 
11.1 
GHRH 
1 or 2 mg/kg,  
infuse over 1 min 
15-30 min 
Stimulates pituitary 
somatotrophs 
Flushing 
 
 
Glucagon 
0.03 mg/kg to max 
of 1 mg,  
give IM or SC 
2-3 h 
Increases insulin 
Late 
hypoglycemia 
29.4 
7.5 
Insulin 
0.05-0.1 units/kg,  
give as bolus 
30-60 min 
Stress response to 
hypoglycemia 
presumed to 
decrease 
somatostatin 
Severe 
hypoglycemia 
23.4 
2.2 
Clonidine 
5 mcg/kg to max of 
250 mcg 
60 min 
α-2 agonist 
stimulates GHRH 
and inhibits 
somatostatin 
Drowsiness, 
hypotension 
30.5 
8.2 
 
 
 


 
 
61 
Appendix B 
 
Safety Monitoring for Niacin Growth Hormone Study 
Study Months 
Baseline Evaluation 
Dose-Establishing 
Studies Inpatient 
Admission 
Main Study 
Inpatient Admission 
 
Screening Visit: baseline blood work; 
Sign consent 
Yes 
 
 
Fasting baseline blood work 
Yes 
 
 
Urine pregnancy test 
Yes 
Yes 
Yes 
 
Medical history 
Yes 
Yes 
Yes 
 
Physical Exam 
Yes 
Yes 
Yes 
 
Bone age X-ray 
Yes (only for 
subjects in the main 
study) 
 
 
DXA scan 
 
 
Yes 
Adverse Drug Event Assessment  
Yes 
Yes 
Yes 
 
Review of systems 
Yes 
Yes 
Yes 
 
 


 
 
62 
Appendix C 
 
Flow Diagram for Niacin Growth Hormone Study 
 
DOSE-ESTABLISHING STUDY 1 
 
Recruitment Clinic Visit  
(performed at NIH Clinical Center): 
Medical history and physical examination.  
Fasting blood work 
Oral glucose tolerance test 
Bone age x-ray 
Study entry only if subject meets inclusion criteria, and subject 
has & HGBA1C of < 6.4%, fasting blood glucose of <100, 
and 2 hour post-dextrose glucose of <140 
Sign consent and assent forms 
 
Within 2 months 
 
Inpatient Stay: 
Admission Day: 
Admission to Clinical Center by 4:00 PM 
Review medical history  
Repeat physical exam 
Placement of intravenous line  
Begin fast at 10 pm 
Study Day: 
6am, 8am, and 10am: niacin (250 or 500 mg per dose) 
6am, 6:30am, 7am, 7:30am, 8am, 8:30am, 9am, 9:30am, 10am, 
10:30am, 11am, 11:30am, Noon: Blood draw 
Noon: completion of test, resume ad lib diet then discharge 
 
 
 
DOSE-ESTABLISHING STUDY 2 
 
Recruitment Clinic Visit  
(performed at NIH Clinical Center): 
Medical history and physical examination.  
Fasting blood work 
Oral glucose tolerance test 
Bone age x-ray 
Study entry only if subject meets inclusion criteria, and subject 
has & HGBA1C of < 6.4%, fasting blood glucose of <100, 
and 2 hour post-dextrose glucose of <140 
Sign consent and assent forms 
 
Within 2 months 


 
 
63 
 
Inpatient Stay: 
Admission Day: 
Admission to Clinical Center by 4:00 PM 
Review medical history  
Repeat physical exam 
Placement of intravenous line  
Begin fast at 10 pm 
Study Day: 
7:30am, 8:30am, 9:30am, 10:30am niacin (500 mg per dose) 
7:30am, 8am, 8:30am, 9am, 9:30am, 10am, 10:30am, 11am, 
11:30am: Blood draw (measuring FFA, insluin, GH, and 
glucose) 
7:30am, 8:30am, 9:30am, 10:30am, 11:30am: Blood draw 
(measuring Somatostatin and GHRH) 
Noon: completion of test, resume ad lib diet then discharge 
 
 


 
 
64 
MAIN STUDY 
 
Recruitment Clinic Visit  
(performed at NIH Clinical Center): 
Medical history and physical examination.  
Fasting blood work 
Oral glucose tolerance test 
Bone age x-ray 
Study entry only if subject meets inclusion criteria, and subject 
has & HGBA1C of < 6.4%, fasting blood glucose of <100, 
and 2 hour post-dextrose glucose of <140 
Sign consent and assent forms 
 
Within 2 months 
 
Inpatient Stay: 
Admission Day: 
Admission to Clinical Center by 4:00 PM 
Review medical history  
Repeat physical exam 
Placement of intravenous line  
Begin fast at 10 pm 
Day 1: 
7:30am and 8:30am: Placebo or niacin 500 mg 
7:30am, 8am, and 8:30am: Blood draw (Note GHRH and 
Somatostatin measured 7:30am and 8:30am) 
8:30am: Arginine stimulation test per routine protocol - 500mg/kg 
up to 30g 
8:30am, 9am, 9:15am, 9:30am: Blood draw (Note: GHRH and 
Somatostatin measured 9am) 
9:30am: Placebo or niacin 500 mg and start L-dopa stimulation 
test – 500 mg 
9:30am, 10am, 10:15am, 10:30am, 10:45am, 11am, 11:30am: 
Blood draw (Note: GHRH and Somatostatin measured 
9:30am, 10am, 10:30am, and 11:30am) 
10:30am: Placebo or niacin 500 mg 
11:30am: completion of test, resume ad lib diet 
Afternoon: DXA scan in nuclear medicine 
10pm: begin fast 
Day 2: 
7:30am and 8:30am: placebo or niacin 500 mg 
7:30am, 8am, and 8:30am: Blood draw (Note GHRH and 
Somatostatin measured 7:30am and 8:30am) 
8:30am: Arginine stimulation test per routine protocol - 500mg/kg 
up to 30g 
8:30am, 9am, 9:15am, 9:30am , : Blood draw (Note: GHRH and 
Somatosatin measured 9am) 


 
 
65 
9:30am: Placebo or niacin 500 mg and start L-dopa stimulation 
test – 500 mg 
9:30am, 10am, 10:15am, 10:30am, 10:45am, 11am, 11:30am: 
Blood draw (Note: GHRH and Somatostatin measured 9:30am 
10am 10:30am, and 11:30am) 
10:30am: Placebo or niacin 500 mg 
11:30am: completion of test, resume ad lib diet then discharge 
 
 
Outline of Main Study Blood Draws 
Time 
Study 
Hour 
Medication 
Time point 
Arginine 
Time point 
L-Dopa 
Blood Drawn 
7:30am 
0 
Niacin 
-60 
 
GHRH, Somatostatin, Insulin, GH, 
Glucose, FFA 
8:00am 
30 
 
-30 
 
Insulin, GH, Glucose, FFA 
8:30am 
60 
Niacin, 
Arginine 
0 
 
GHRH, Somatostatin, Insulin, GH, 
Glucose, FFA 
9:00am 
90 
 
+30 
-30 
GHRH, Somatostatin, Insulin, GH, 
Glucose, FFA 
9:15am 
 
 
+45 
 
Insulin, GH, Glucose, FFA 
9:30am 
120 
Niacin, L-dopa 
+60 
0 
GHRH, Somatostatin, Insulin, GH, 
Glucose, FFA 
10:00am 
150 
 
 
+30 
GHRH, Somatostatin, Insulin, GH, 
Glucose, FFA 
10:15am 
 
 
 
+45 
Insulin, GH, Glucose, FFA 
10:30am 
180 
Niacin 
 
+60 
GHRH, Somatostatin, Insulin, GH, 
Glucose, FFA 
10:45am 
 
 
 
+75 
Insulin, GH, Glucose, FFA 
11:00am 
210 
 
 
+90 
Insulin, GH, Glucose, FFA 
11:30am 
240 
 
 
+120 
GHRH, Somatostatin, Insulin, GH, 
Glucose, FFA 


 
 
66 
Appendix D 
 
Post-Test Questionnaire 
To be administered hourly from 6am-Noon during the inpatient stay of the dose-establishing study and at the 
end of the inpatient stay of the main study 
 
 
Please check off the symptoms that the patient experienced during the time the patient as staying at the NIH. 
Then indicate how long it lasted and how severe it was. 
Symptom 
Present? 
Duration 
Severity (please choose one) 
1 (mild) 
2 (moderate) 
3 (severe) 
Headache 
 
 
 
 
 
Flushing of face 
 
 
 
 
 
Feeling warm 
 
 
 
 
 
Nausea (feeling like vomiting) 
 
 
 
 
 
Vomiting 
 
 
 
 
 
Stomach ache 
 
 
 
 
 
Diarrhea or loose stools 
 
 
 
 
 
Tingling in arms or legs 
 
 
 
 
 
Light-headed or faint 
 
 
 
 
 
Itchiness 
 
 
 
 
 
Rash or skin problems 
 
 
 
 
 
Other (please list): 
 
 
 
 
 
  


 
 
67 
Appendix E: (completed once at baseline) 
 
Eating Behavior Questionnaire 
 
Participant’s Name: 
 
 
 
 
Date: 
 
Relationship of person completing questionnaire to subject (circle one): 
 
Mother  
Father  
Other ___________ 
 
 
 
(1) How upset does your child generally become when denied a desired food? 
 
___ Not particularly upset at all 
___ A little upset 
___ Somewhat upset 
___ Very upset 
___ Extremely upset 
 
(2) How often does your child try to bargain or manipulate to get more food at meals? 
 
___ A few times a year 
___ A few times a month 
___ A few times a week 
___ Several times a week 
___ Several times a day 
 
(3) Once your child has food on their mind, how easy is it for you or others to re-direct your child away from food to other 
things? 
 
___ Extremely easy, takes minimal effort to do so 
___ Very easy, takes just a little effort to do so 
___ Somewhat hard, takes some effort to do so 
___ Very hard, takes a lot of work to do so 
___ Extremely hard, takes sustained and hard work to do so 
 
(4) How often does your child forage through the trash for food? 
 
___ Never 
___ A few times a year 
___ 1–2 times a month 
___ 1–3 times a week 
___ 4  to 7 times a week 
(5) How often does your child get up at night to seek food? 
 
___ Never 
___ A few nights a year 
___ 1–2 nights a month 
___ 1–3 nights a week 
___ 4 to 7 nights a week 
 
(6) How persistent is your child in asking or looking for food after being told “no” or “no more”? 
 
___ Lets go of food ideas quickly and easily 
___ Lets go of food ideas pretty quickly and easily 


 
 
68 
___ Somewhat persistent with food ideas 
___ Very persistent with food ideas 
___ Extremely persistent with food ideas 
 
(7) Outside of normal meal times, how much time does your child spend talking about food or engaged in food-related 
behaviors? 
 
___ Less than 15 minutes a day 
___ 15 to 30 minutes a day 
___ 30 minutes to an hour 
___ 1 to 3 hours a day 
___ more than 3 hours a day 
 
(8) How often does your child try to steal food (that you are aware of?) 
 
___ A few times a year 
___ A few times a month  
___ A few times a week 
___ Several times a week 
___ Several times a day 
(9) When others try to stop your child from talking about food or engaging in food-related behaviors, it generally leads to: 
 
___ No distress or upset 
___ Mild distress or upset 
___ Moderate distress or upset 
___ Severe distress or upset 
___ Extreme distress, behaviors can’t usually be stopped 
 
(10) How clever or fast is your child in obtaining food? 
 
___ Not particularly clever or fast 
___ A little clever or fast 
___ Somewhat clever or fast 
___ Very clever or fast 
___ Extremely clever or fast 
 
(11) To what extent do food-related thoughts, talk, or behavior interfere with your child’s normal daily routines, self-care, 
school, or work? 
 
___ No interference 
___ Mild interference; occasional food-related interference in completing school, work, or hygiene tasks 
___ Moderate interference; frequent food-related interference in completing school, work, or hygiene tasks 
___ Severe interference; almost daily food-related interference in completing school, work, or hygiene tasks 
___ Extreme interference, often unable to participate in hygiene tasks or to get to school or work due to food-related 
difficulties 
 
(12) How old was your child when they first showed an increased interest in food? ____________ (write N/A if interest in food 
has never been a problem) 
 
(13) How variable is your child’s preoccupation or interest in food? 
 
___ Hardly ever varies 
___ Usually stays about the same 
___ Goes up and down occasionally 
___ Goes up and down quite a lot 
___ Goes up and down all the time 
 
Adapted from Dykens EM, et al. Obesity. 15(7):1816-1826 (2007). Used with permission