A Study to Evaluate Efficacy and Safety of Slow Release DHEA
Phase: PHASE2
Conditions: Asthma
Sponsor: Indiana University

IRB #26427 
Document Date: 10Jun2025 (Initial submission) 
 
Page 1 of 25 
 
Phase IIb Clinical Trial to Evaluate Efficacy 
and Safety of Slow Release DHEA 
 
Kirsten M. Kloepfer, MD, MS 
Associate Professor of Pediatrics 
Division of Pediatric Pulmonology, Allergy and Sleep Medicine 
Riley Hospital for Children at IU Health 
Indiana University School of Medicine 
 
Sub-Investigators: 
James F. Chmiel, MD, MPH 
Division Chief of Pediatric Pulmonology, Allergy and Sleep Medicine 
Professor of Pediatrics 
Riley Hospital for Children at IU Health 
Indiana University School of Medicine 
 
Benjamin E. Gaston, MD 
Professor of Pediatrics 
Vice Chair for Pediatric Research 
Riley Hospital for Children at IU Health 
Indiana University School of Medicine 
 
 
Support Provided by: 
National Institutes of Health 
 
IND#: 
162875 
 
 

IRB #26427 
Document Date: 10Jun2025 (Initial submission) 
 
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Table of Contents 
1 
Background and Rationale .................................................................................................................... 4 
2 
Clinical Significance ............................................................................................................................... 4 
3 
Study Objectives ................................................................................................................................... 5 
3.1 Primary Objective: ........................................................................................................................ 5 
3.2 Secondary Objective: .................................................................................................................... 5 
4 
Study Design.......................................................................................................................................... 5 
4.1 Multiple dose study ...................................................................................................................... 6 
4.2 Projected Study Enrollment .......................................................................................................... 6 
5 
Study Subject Eligibility ......................................................................................................................... 6 
5.1 Inclusion criteria ............................................................................................................................ 6 
5.2 Exclusion criteria ........................................................................................................................... 6 
6 
Scheduled Events .................................................................................................................................. 7 
7 
Description of Events ............................................................................................................................ 9 
8 
Description of Visits ............................................................................................................................ 11 
9 
Study Risks .......................................................................................................................................... 14 
10 Study Benefits ..................................................................................................................................... 15 
11 Withdrawal from study participation ................................................................................................. 16 
12 Data and Safety Monitoring ................................................................................................................ 16 
13 Safety Assessments ............................................................................................................................. 17 
14 Adverse Events and Severity Grading ................................................................................................. 17 
14.1 Adverse event assessment .......................................................................................................... 18 
14.2 Tracking of events ....................................................................................................................... 19 
14.3 Adverse event reporting ............................................................................................................. 19 
14.4 Follow up for Adverse Events ..................................................................................................... 19 
15 Study Monitoring ................................................................................................................................ 19 
16 Subject Rights and Confidentiality ...................................................................................................... 20 
16.1 Alternatives to Study Participation ............................................................................................. 20 
16.2 Financial Information .................................................................................................................. 20 
16.3 Research Related Injury .............................................................................................................. 20 
16.4 Use of Specimens ........................................................................................................................ 20 
16.5 Confidentiality ............................................................................................................................. 20 
16.6 Privacy ......................................................................................................................................... 20 

IRB #26427 
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16.7 Data/Sample confidentiality ....................................................................................................... 20 
16.8 Data/Sample security .................................................................................................................. 21 
16.9 Data Entry & Storage .................................................................................................................. 21 
17 Statistical Analysis ............................................................................................................................... 21 
18 Protocol Signature Page ...................................................................................................................... 25 
 
 
 

IRB #26427 
Document Date: 10Jun2025 (Initial submission) 
 
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1 
BACKGROUND AND RATIONALE 
Severe asthma results in significant mortality and morbidity, and in annual healthcare expenditures >$10 
billion (1). Glucocorticoids (GCs) are the mainstay of treatment but are only incompletely effective in 
this condition. There is a critical need for novel, targeted and corticosteroid-sparing therapies for 
patients with severe asthma. Since asthma is sexually dimorphic with women being more affected than 
men (2,3), since GC treatment suppresses endogenous dehydroepiandrosterone (DHEA) production (4), 
and since our preliminary data demonstrate a variety of protective DHEA effects on automatic exposure 
control (AEC) function and inflammatory responses, there is a strong biological rationale to test whether 
DHEA-based treatment strategies are beneficial in this condition. Our data suggest that patients with 
low dehydroepiandrosterone-sulfate (DHEA-S) levels and HSD3B1 AA or AC genotypes represent a 
subgroup that will derive particular benefit from DHEA treatment, suggesting an exciting new potential 
for personalized medicine strategies in severe asthma. Our experience with studying DHEA treatment in 
asthma (Marozkina (5)), HSD3B1 genotype-phenotype correlations in asthma (Zein (4)) and sex hormone 
signaling in lung disease (Lahm (6)), make us uniquely equipped to perform the proposed study. Our 
overall goal is to perform a randomized, placebo-controlled pilot study to evaluate DHEA effects on FEV1 
and FeNO. This study will allow us to gather critical baseline data for designing larger trials in the future. 
Ultimately, this will allow for developing novel and personalized therapies for severe asthma. 
Previous work has shown that the HSD3B1 genotype does not classically affect circulating DHEA-S levels, 
but rather affects tissue androgen levels (4, 8, 9). Based on our preliminary data and published reports 
(5), we anticipate that the maximal effect of DHEA will be observed in patients with the responsive 
genotype (4) and low DHEA-S levels (4) (Table 1). Because the homozygous HSD3B1(1245) AA genotype 
and heterozygous AC genotype in severe 
asthma populations are similar in lung 
function (4), and because the CC genotype is 
uncommon (12%; Table 2), we will focus on 
the “optimal response” cohort (AA/AC 
genotype & low DHEA-S levels). If we are 
successful, additional studies will be 
performed in subsequent, larger trials. 
Steady state levels in the pilot study were ~ 
725 µg/dL (5). Therefore, we will study 100 
mg of DHEA (10,11).  
2 
CLINICAL SIGNIFICANCE 
Severe asthma only accounts for ~10% of all asthma in the United States, but it accounts for nearly half 
of the annual mortality and cost of the disease (12-16). Estimates are that severe asthma takes over 
1,000 lives per year, and that the 
annual financial burden of severe 
asthma may be several billion 
dollars in the United States alone. 
Important improvements in 
asthma outcomes have been 
realized with antibody-based 
Table 1. Predicted biomarker response (based on 
previously published work from our group)(4,5). 
Table 2: HSD3B1(1245) genotype distribution in SARP I, II & III 

IRB #26427 
Document Date: 10Jun2025 (Initial submission) 
 
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therapies (for example, 17-19). However, these therapies are primarily effective for specific 
subpopulations of the Th-lymphocyte Type 2-high (“T2-high”) asthma population, are normally not 
indicated in the “T2 low” population (17-21) and are expensive. Here, we propose to investigate 
potentially less expensive, less invasive, personalized approaches to managing certain severe patients, 
particularly including those who are not candidates for, or have failed, conventional severe asthma 
therapies and biological approaches.  
3 
STUDY OBJECTIVES  
3.1 
PRIMARY OBJECTIVE:  
• 
Determine if slow-release DHEA in patients with asthma improves quality of life based on 
ACQ/ACT scoring.  
3.2 
SECONDARY OBJECTIVE:  
• 
Determine if slow-release DHEA increases FEV1 in patients with asthma. 
• 
Determine if SR DHEA in patients with asthma increases the change in pulmonary functions post 
maximum bronchodilator challenge.  
• 
Determine if slow-release DHEA in patients with asthma decreases FeNO. 
• 
Evaluate the safety and tolerability of DHEA in asthma.  
o Safety outcomes include changes in:  
▪ 
Adverse events (AEs) 
▪ 
Serious adverse events (SAEs) 
▪ 
Pulmonary function (FEV1, FVC, FEV1/FVC, FEF25-75)  
(An asthma exacerbation (physician decision to treat) will be considered an event of 
particular interest. Exacerbations not admitted to the hospital will be considered an AE. 
Exacerbations requiring admission will be considered a SAE.) 
4 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, cross-over study to determine if DHEA-S will 
increase FEV1 and decrease FeNO.  
 
 

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4.1 
MULTIPLE DOSE STUDY 
The dose of DHEA will be 100 mg via slow release (SR) capsules. Subjects will take one capsule daily at 
the same time each day. 
4.2 
PROJECTED STUDY ENROLLMENT 
The study cohort will consist of 30 subjects with asthma. 
5 
STUDY SUBJECT ELIGIBILITY 
5.1 
INCLUSION CRITERIA 
1. Adult male or female age ≥ 18 and ≤ 50 years at the time of enrollment 
2. Evidence of asthma demonstrated by reversibility at visit 0 or by historical methacholine or 
bronchodilator reversibility if testing was performed under either the 2017 ERS technical 
standard (22) or the 1999 ATS Guidelines (23) or outside studies, provided that full sets of flow 
volume loops have been reviewed and approved by the PI. These criteria are defined as one of 
the following: 
a. For bronchodilator reversibility: An increase in FEV1 ≥ 10% (24) compared to the 
baseline (and 200 ml) after up to 8 puffs of albuterol  
b. For historical methacholine responsiveness: Positive methacholine defined as PC20 ≤ 16 
mg/ml, or PD20 ≤ 400 mcg 
3. Physician diagnosis of asthma according to NHLBI guidelines 
4. Consistent use of an ICS inhaler for the prior 2 months 
5. Non-smoker 
6. Females must not be pregnant or breastfeeding 
7. Absence of non-allergic comorbidities 
5.2 
EXCLUSION CRITERIA 
1. Pregnant or actively trying to become pregnant; breastfeeding  
2. Positive urine pregnancy test 
3. Known lung disease other than asthma  
4. Acute (non-asthma related) dyspnea, viral respiratory illness or asthma exacerbation within 4 
weeks of screening  
5. Systemic glucocorticoid dosing for maintenance >10 mg/day of prednisone or equivalent 
6. Patients with significant non-allergic comorbidities (e.g. cerebral palsy, heart disease, kidney 
disease, liver disease, etc.)  
7. Patients with any know central or peripheral endocrine abnormality such as precocious puberty 
or diabetes  
8. Patients with any known previous adverse reaction to DHEA  
9. Current smoker or pack year history > 5 years (includes vaping/nicotine inhalation devices) 
10. Positive urine cotinine test (> 100 mg/mL) 
11. Use of prednisone or antibiotics in the last 4 weeks  
12. Use of any performance-enhancing drugs in the last 2 weeks  
13. Use of DHEA in the last 2 weeks  
14. Androgen use for any reason. 

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15. Any other condition or finding that would compromise the safety of the subject or the quality of 
the study data, or otherwise interfere with achieving the study objectives, as determined by the 
PI  
16. Menopausal amenorrhea by history 
17. Positive PSA (>4 ng/ml) (Prostate Specific Antigen) 
18. Prior diagnosis of vocal cord dysfunction, bronchopulmonary dysplasia, cystic fibrosis, chronic 
obstructive pulmonary disorder, or other lung disease  
19. Systolic blood pressure > 150 mm Hg and/or diastolic blood pressure >90 mm Hg 
20. Heart rates outside the range of 50 to 120 beats per minutes or with a pathologic irregularity 
21. Patients afflicted with any additional acute or chronic pathology that in the opinion of the 
screening physician makes them unsuitable for study or increases the risks associated with the 
study.  
6 
SCHEDULED EVENTS 
Assessments and 
Procedures 
Visit 0 
MCT 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Screenin
g Day 0 
Anytime 
between 
days 1-7; 
at least 3 
days prior 
to Visit 1 
Day 7 ± 3 
days 
Day 21 ± 
3 days 
(phone 
visit) 
Day 35 ± 
3 days 
Day 63 ± 
3 days 
Day 77 ± 
3 days 
(phone 
visit) 
Day 91 ± 
3 days 
Informed 
consent 
X 
 
 
 
 
 
 
 
Medical history 
and 
demographics 
X 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
 
X 
X 
X 
X 
X 
X 
Review 
inclusion/ 
exclusion criteria 
X 
 
 
 
 
 
 
 
Asthma Control 
Test (ACT) & 
Asthma Control 
Questionnaire 
(ACQ) 
X 
 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Weight, pulse 
oximetry, vital 
signs 
X 
X 
X 
 
X 
X 
 
X 
Urine pregnancy 
test (when 
applicable) 
X 
X 
X 
 
X 
X 
 
X 
Urine cotinine 
test 
X 
 
 
 
 
 
 
 

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Assessments and 
Procedures 
Visit 0 
MCT 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Screenin
g Day 0 
Anytime 
between 
days 1-7; 
at least 3 
days prior 
to Visit 1 
Day 7 ± 3 
days 
Day 21 ± 
3 days 
(phone 
visit) 
Day 35 ± 
3 days 
Day 63 ± 
3 days 
Day 77 ± 
3 days 
(phone 
visit) 
Day 91 ± 
3 days 
Prostate specific 
antigen test1 
(when 
applicable) 
X 
 
 
 
 
 
 
 
Spirometry with 
bronchodilator 
response 
(maximum 
bronchodilator) 
X 
 
 
 
 
 
 
 
Spirometry. If ≥ 
10% decrease in 
FEV1 from 
baseline, give 
bronchodilator 
and measure 
response  
 
 
X 
 
X 
X 
 
X 
Methacholine 
Checklista 
 
X 
 
 
 
 
 
 
Methacholine 
Challenge Test 
(MCT) 
(Asthma 
Participants 
Only)a 
 
X 
 
 
 
 
 
 
FeNO 
X 
 
X 
 
X 
X 
 
X 
Abbreviated 
physical exam 
X 
 
X 
 
X 
X 
 
X 
Blood draw 
X 
 
X 
 
X 
X 
 
X 
DHEA/placebo 
capsules 
dispensed in 
labeled bottle 
 
 
X 
 
 
X 
 
 
Collect any 
unused 
DHEA/placebo 
capsules 
 
 
 
 
X 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Give Dosing & 
Symptom Diary 
 
 
X 
 
 
X 
 
 
 
1 This test is for male subjects only. The prostate specific antigen is a protein made by the prostate and found in 
blood. If the result of this test is >4 nanograms per milliliter, subjects will be informed they are unable to 
participate in the study. We will also call them prior to their next visit to let them know and recommend that they 
follow-up with their regular primary care physician. 

IRB #26427 
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Assessments and 
Procedures 
Visit 0 
MCT 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Screenin
g Day 0 
Anytime 
between 
days 1-7; 
at least 3 
days prior 
to Visit 1 
Day 7 ± 3 
days 
Day 21 ± 
3 days 
(phone 
visit) 
Day 35 ± 
3 days 
Day 63 ± 
3 days 
Day 77 ± 
3 days 
(phone 
visit) 
Day 91 ± 
3 days 
Collect Dosing & 
Symptom Diary 
 
 
 
 
X 
 
 
X 
aThe MCT and MCT with checklist done only if: 1) participants with asthma fail to demonstrate 10% reversibility in 
FEV1 (max BD testing) and there is no historical MCT available 
7 
DESCRIPTION OF EVENTS 
Medical history and demographics, height, weight and vital signs  
Relevant medical history, including history of current disease, spirometry results, other pertinent 
respiratory history, and information regarding underlying diseases will be recorded. Demographic and 
baseline clinical characteristics including age, gender, and race will be recorded. Pulse oximetry, height 
(at screening only) and weight will be measured, as well as vital signs (blood pressure, temperature, 
heart rate and respiration rate). 
Concomitant medications  
All concomitant medications and concurrent therapies will be documented at visit 0. Dose, route, unit 
frequency of administration, and indication for administration and dates of medication will be captured 
for the 30 days prior to screening and during the study. The document will be reviewed and addended (if 
needed) at each visit. 
Asthma questionnaires  
Subjects will be asked to complete two questionnaires: the Asthma Control Test (ACT) and the Asthma 
Control Questionnaire (ACQ).  
• 
The ACT is a validated asthma assessment tool used to assess asthma symptoms over a 4-week 
period. Each item on the ACT has a possible score ranging from 0 to 5, and the total score is 
used to determine asthma control.  
• 
The ACQ includes six questions on symptoms, activity limitation and beta2-agonist use, with an 
optional assessment on airway caliber over a 7-day period. Each question is scored from 0 (well 
controlled) to 6 (extremely poorly controlled) with the total score being the average of the 
questions. 
Urine pregnancy test  
A urine pregnancy test will be performed at Visits 0 and Visit 1 (if not the same day as screening visit) if 
the subject is a female of child bearing potential. 
Urine cotinine test 
A urine cotinine test will be performed at Visit 0 for all subjects to measure cotinine levels.  

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Prostate specific antigen test 
Blood will be obtained from male subjects for PSA because administration of supplemental DHEA in 
people with prostate cancer could theoretically result in a flare-up of their prostate cancer.  
Spirometry with maximum bronchodilator response  
Pre-bronchodilator FEV1 and post-bronchodilator FEV1 will be measured using spirometry. The FEV1 is 
the volume of air which can be forcibly exhaled from the lungs in the first second, measured in liters. 
Spirometry will be done according to American Thoracic Society/European Respiratory Society 
procedural guidelines (25). Current reference equations (26) will be used.  
Airway Reversibility  
Airway reversibility will be demonstrated by measuring the change in FEV1 before and after inhalation of 
albuterol; reversibility testing should be attempted after withholding long-acting beta-agonist (LABA) 
therapy for at least 12 hours and short-active beta agonist (SABA) therapy for at least 6 hours. Up to 8 
puffs of albuterol should be used for reversibility testing, as tolerated. If a subject’s FEV1 improves at 
least 10% between the 2 tests, then he/she will be deemed as having airway reversibility. 
Methacholine Challenge Test (MCT) 
MCT will be performed only in participants with asthma who do not demonstrate reversibility and with a 
pre-diluent FEV1 of >50% predicted and at least 1.0 liter. A physician will be available during the 
challenge and testing will be performed according to standard of care. Participants will not be 
discharged until their FEV1 is within 10% of their baseline FEV1. 
FeNO 
FeNO stands for Fractional Exhaled Nitric Oxide and it is a non-invasive procedure that is considered to 
be an indirect measurement of airway inflammation. It involves taking a deep breath and blowing air out 
into a mouth piece at a constant pressure as directed by the study team. Measurements will be 
recorded.  
 
Medication withhold: 
To prepare for lung function testing, subjects will be asked to withhold certain medications so that 
screening procedures produce the most accurate results. Subjects will receive a list of medications that 
must be withheld prior to certain study visits, and length of withholding time.  
 
Abbreviated physical exam  
An abbreviated physical exam will consist of HEENT, cardiovascular system, chest/lung, abdomen, 
extremities, skin, and any other areas as appropriate. This exam will be performed by a physician.  
Blood collection 
Blood will be drawn at visits 0, 1, 3, 4, and 6. A CBC with differential and comprehensive metabolic panel 
will be performed as safety labs throughout the study. A prostate specific antigen (PSA) level will be 
measured in male subjects at the screening visit. DHEA-S levels will be measured at the screening visit 
and at the conclusion of the study. Blood will also be used for measurements including but not limited 
to: cytokine responses, hormone levels, PBMCs, genomics, and DHEA. The maximum amount of blood to 
be obtained at each visit is up to 40 ml.  

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Genotyping 
Single nucleotide polymorphism testing for HSD3B1 genotype will be performed from blood drawn at 
the screening visit and results must be available before the first dose of study drug. If a genotype test 
has been performed previously and is documented in the subject’s medical or research records, the 
subject's eligibility must be approved by the PI. If a historic genotype result is not available at screening 
or if the historic genotype result is not approved by the medical monitor, subjects will be tested for 
genotype at screening and the results must be reviewed before the first dose of study drug. Subjects will 
not receive the study drug if genotype is not confirmed by both an approved historic genotype and 
approval of medical monitor result OR by genotype testing at screening. Study subjects with HSD3B1 AA 
or AC specific variants will be enrolled in the study. No further genetic studies will be performed on the 
subject’s DNA. The subject will be fully informed of the genotype results relevant to this study.  
DHEA  
DHEA is available as an over-the-counter supplement that is available on the market without 
prescription. The DHEA used in this study will be formulated for slow release and will be dispensed at a 
compounding pharmacy by prescription only. They produce 100mg capsules that will be used for this 
study. The prescribed DHEA capsules will be received, stored and distributed by the Gaston Pediatric 
Translational Research Lab Group in the Herman B Wells Center for Pediatric Research. Accountability 
records will be maintained by the study team. 
Randomization 
Randomization will occur at the compounding pharmacy that manufactures DHEA and placebo. The 
study drug will be distributed with a code and study team will be blinded from code. Only the 
compounding pharmacy and the DSMB will have access to the unblinded data. 
Dosing and Symptom diary 
Subjects will complete a dosing and symptom diary at home starting after visit 1 until the end of the 
study.  
Adverse events (AEs)  
Information regarding the occurrence of AEs will be captured throughout the study from Visit 0 until the 
final visit. Subjects will be given a phone number to notify the study coordinator regarding an asthma 
exacerbation or other adverse event. 
8 
DESCRIPTION OF VISITS 
Below are the visits and the interventions that may occur at each of the visits. In addition to the 
following scheduled visits, we are also including an unscheduled visit that may be used for any reason 
when a subject needs to return to the study site to complete study activities. 
Visit 0 (Screening Visit)  
1. Review the study with the subject and obtain written informed consent and HIPAA authorization  
2. Assign the subject a unique subject id number  
3. Complete asthma control test and asthma control questionnaire 
4. Record demographics and other baseline data 

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5. Record medical and surgical history, including a history of asthma, diagnosis date, and asthma 
signs and symptoms 
6. Record concomitant medications  
7. Review inclusion/exclusion criteria  
8. Measure and record height and weight without shoes  
9. Perform and record vital signs, including blood pressure after the subject has been seated for 5 
minutes  
10. Perform and record oximetry  
11. Perform abbreviated physical exam 
12. Obtain urine to perform urine pregnancy test (when applicable) and urine cotinine test 
13. Obtain blood for prostate specific antigen test (when applicable) 
14. Perform spirometry with maximum bronchodilator response 
15. Perform FeNO  
16. Obtain blood  
17. Record any adverse events (AEs) that may have occurred since signing consent 
18. Schedule MCT or Visit 1 
MCT Visit, if needed (Anytime between days 1-7, must be at least 3 days prior to Visit 1) 
1. Confirm ongoing consent to participate 
2. Collect urine for pregnancy test if applicable 
3. Record vital signs and weight 
4. Complete MCT checklist 
5. Perform and record MCT 
6. Confirm eligibility criteria 
7. Record adverse events 
8. Schedule Visit 1 
 
Visit 1 (Day 7 ± 3)  
1. Complete asthma control test and asthma control questionnaire  
2. Review and record any changes to concomitant medications 
3. Record any adverse events (AEs) that may have occurred since last visit 
4. Measure and record weight without shoes  
5. Perform and record vital signs, including blood pressure after the subject has been seated for 5 
minutes  
6. Perform and record oximetry  
7. Perform abbreviated physical exam  
8. Obtain urine to perform urine pregnancy test (when applicable) 
9. Perform spirometry 
10. Perform FeNO 
11. Obtain blood 
12. Give subject a dosing and symptom diary and instructions on dosing intervals 
13. Randomize to receive placebo or DHEA-S 
14. Send home with 28 days of DHEA-S or placebo capsules 
15. Schedule visit 2 

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Visit 2 (Day 21 ± 3) phone visit 
1. Complete asthma control test and asthma control questionnaire  
2. Review and record any changes to concomitant medications 
3. Record any adverse events (AEs) that may have occurred since last visit 
4. Schedule visit 3 
Visit 3 (Day 35 ± 3) 
1. Complete asthma control test and asthma control questionnaire  
2. Review and record any changes to concomitant medications 
3. Record any adverse events (AEs) that may have occurred since last visit 
4. Review inclusion/exclusion criteria  
5. Measure and record weight without shoes  
6. Perform and record vital signs, including blood pressure after the subject has been seated for 5 
minutes  
7. Perform and record oximetry  
8. Perform abbreviated physical exam 
9. Obtain urine to perform urine pregnancy test (when applicable) 
10. Perform spirometry 
11. Perform FeNO 
12. Obtain blood  
13. Collect any unused capsules from visit 1 
14. Collect dosing and symptom diary 
15. Schedule visit 4 
 
Visit 4 (Day 63 ± 3) 
1. Complete asthma control test and asthma control questionnaire  
2. Review and record any changes to concomitant medications 
3. Record any adverse events (AEs) that may have occurred since last visit 
4. Measure and record weight without shoes  
5. Perform and record vital signs, including blood pressure after the subject has been seated for 5 
minutes  
6. Perform and record oximetry  
7. Perform abbreviated physical exam 
8. Obtain urine to perform urine pregnancy test (when applicable) 
9. Perform spirometry 
10. Perform FeNO 
11. Obtain blood 
12. Give subject a dosing and symptom diary and instructions on dosing intervals 
13. Randomize to receive placebo or DHEA-S (will enter whatever did not receive in visits 1-3) 
14. Send subject home with 28 days of 100 mg DHEA-S or placebo capsules to take daily 
15. Schedule visit 5 
 
Visit 5 (Day 77 ± 3) phone visit 
1. Complete asthma control test and asthma control questionnaire  

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2. Review and record any changes to concomitant medications 
3. Record any adverse events (AEs) that may have occurred since last visit 
4. Schedule visit 6 
Visit 6 (Day 91 ± 3) 
1. Complete asthma control test and asthma control questionnaire  
2. Review and record any changes to concomitant medications 
3. Record any adverse events (AEs) that may have occurred since last visit 
4. Measure and record weight without shoes  
5. Perform and record vital signs, including blood pressure after the subject has been seated for 5 
minutes  
6. Perform and record oximetry  
7. Perform abbreviated physical exam 
8. Obtain urine to perform urine pregnancy test (when applicable) 
9. Perform spirometry 
10. Perform FeNO 
11. Obtain blood  
12. Collect any unused capsules from visit 4 
13. Collect dosing and symptom diary 
9 
STUDY RISKS 
DHEA: DHEA is commercially available without a prescription. The DHEA capsules used in this study are 
formulated for slow release. Most of the known data pertaining to risks come from studies in adults with 
adrenal insufficiency who were treated with long courses of DHEA (e.g. 3-12 months). Many of these 
trials were included in a recent meta-analysis (27). This paper included 10 trials where 264 women 
treated with 20-50mg (most were 50mg) daily for 3-12 months (most were 4-6 months). None of the 
trials reported any serious adverse effects from prolonged therapy with DHEA. Minor side effects 
reported include greasy skin, hirsutism, acne, scalp itching and increased sweating. In two trials 
including 36 men, reported side effects included diarrhea (n=1), mild acne (n=1) and increased facial hair 
(n=1) (28, 29). In a study of 23 adolescent girls and young women (ages 13-25) treated with 25mg of 
DHEA for 1 year, adverse events were similar between DHEA and placebo (30). One girl developed mild 
hirsutism, and no subjects developed acne. We are aware of a single case report of a 55-year-old patient 
developing palpitations after 2 weeks of DHEA therapy (50mg/day) that were found to represent 
premature atrial and ventricular contractions (PACs and PVCs) that resolved with an oral beta-blocker 
therapy (31). Finally, we recently completed a pilot study of DHEA repletion in female asthma patients 
with DHEA-S levels <200 µg/dl. The short-term (2 week) regimen was associated with a significant 
improvement in post-bronchodilator FEV1, and no major side effects were observed (5).  These results 
support feasibility of the proposed trial and suggest that asthma patients with low DHEA-S plasma levels 
will tolerate DHEA treatment. 
Blood collection and genotyping: When blood samples are taken from a vein, subjects may have 
discomfort or pain where the blood was taken. Sometimes a person may become dizzy or faint when 
blood is taken. There is also a risk of infection (rare), bleeding, redness or bruising at the skin puncture. 

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Bleeding and bruising can usually be reduced by putting pressure on the place where the blood was 
taken. The chance of infection is lowered by using standard skin cleaning and sterile needles. 
Genotype data is obtained from blood analysis. The only risk specifically associated with genotyping is 
breach of confidentiality. Every effort will be made to maintain confidentiality and all study data will be 
treated as confidential information. No identifiable information released or shared with individuals 
outside the study team.  
Spirometry: There is a small risk of lightheadedness, wheezing, shortness of breath or increased cough 
when performing spirometry. These symptoms usually resolve quickly without the need for treatment. 
Withholding short-acting/long-acting beta-agonists prior to study visits: There is a risk of shortness of 
breath or breathing difficulty. Subjects will be advised that if they experience any worsening symptoms 
during the pre-visit withholding period, they should use their usual medication as needed and call the 
study team to cancel or reschedule the study visit.  
Methacholine Challenge Test (MCT): The volunteer may experience coughing, chest tightness, shortness 
of breath, and/or wheezing during this procedure. These symptoms typically resolve spontaneously 10-
15 minutes after testing without active intervention – recovery can be hastened as needed with 
administration of albuterol. 
FeNO: Such testing can cause a subject to become light-headed, dizzy or tired. In asthmatic subjects, 
testing may also induce or worsen wheeze, shortness of breath, and/or chest tightness. Rescue therapy 
with Albuterol will be administered as needed. The chance of these symptoms occurring is low and 
treatment will be readily available.  
Medication Withhold: Withholding medications may cause subjects to experience increased symptoms 
of the condition for which the medication is taken. Subjects will be advised that if they experience any 
unmanageable, worsening symptoms during the pre-visit withholding period, they should use their usual 
medication(s) as needed and call the study team to cancel or reschedule the visit.  
Urine Collection: Urine will be collected by clean-catch. There are no foreseeable risks to its collection. 
However, there is the risk of emotional distress if a subject discovers that she is pregnant. Our study 
coordinators are highly trained and experienced regarding advising women who discover that they are 
pregnant as part of a research protocol. 
Questionnaires: At any time during the study, subjects can stop answering or skip questions that feel too 
personal or make them uncomfortable. 
10 
STUDY BENEFITS 
There are no expected direct benefits to individual subjects participating in this research. The 
information obtained from this research study may prove helpful for future asthma patients and other 
pulmonary research projects. 

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11 
WITHDRAWAL FROM STUDY PARTICIPATION 
An individual subject will be withdrawn from the trial if the subject withdraws consent (the subject is not 
required to justify this decision). All withdrawals will be documented and the reason (if provided) for 
withdrawal will be recorded. There is no need to follow subjects after withdrawal. If a subject wishes to 
withdraw consent, the PI will have his/her stored specimens discarded. Specimens already tested or 
used by another researcher will not be destroyed. Information already learned from the testing of the 
sample will not be destroyed. If a subject starts taking the DHEA-S or placebo and then calls in prior to 
completion of the study to say that they want to stop taking it/withdraw from the study, we will ask the 
subject to come back for their final lab draw and return their unused capsules. 
In addition, a subject may be withdrawn from the study at any time if the PI feels that it is not in the 
subject’s best interest to continue. Possible reasons for study withdrawal include but are not limited to: 
• 
Subject withdrawal of consent 
• 
Subject is not compliant with or tolerating study procedures 
• 
Subject is not adherent to study drug schedule 
• 
Adverse event that, in the opinion of the PI, places the subject at increased risk 
• 
Lost to follow-up 
• 
Physician request for early termination of study 
• 
Subject becomes pregnant 
Being a part of this clinical trial while pregnant may expose the unborn child to significant risks. 
Therefore, pregnant women will be excluded from the study. A pregnancy test will be done at the 
beginning at every study visit for any women of childbearing potential, and it must be negative before 
they can enter and continue in this study. All subjects must agree to use appropriate contraceptive 
measures during the study. Medically acceptable contraceptives include: (1) surgical sterilization, (2) 
approved hormonal contraceptives such as birth control pills, (3) barrier methods (such as a condom or 
diaphragm) used with a spermicide, (4) abstinence, or (5) an intrauterine device (IUD). If they become 
pregnant during this study, they must inform a member of the research team immediately. In this 
scenario, study drug will be discontinued immediately, and the subject will be monitored throughout the 
pregnancy and for 1 year after study drug was discontinued. The baby will be monitored for adverse 
events for 1 year after birth. 
12 
DATA AND SAFETY MONITORING 
This study will have a Data and Safety Monitoring Board (DSMB). The DSMB will meet regularly to review 
reports of all adverse events. The DSMB may review all procedures, protocol changes, ICFs and annual 
reports. Notification of all Serious AEs will be sent to DSMB, the principal investigator and the study’s 
Steering Committee (comprised of research project leaders). The DSMB Chair also will function as an 
independent medical monitor and AE adjudicator. AEs will be reviewed and categorized as serious, non-
serious, drug related, or procedure related. Based on the safety data, the DSMB has the authority to 
request a modification to the study design. This overview is only meant to be used as a guideline by the 
DSMB to review the study and to make a recommendation to continue or modify the protocol, not 
necessarily a mandate to the board for study termination. The members will not be involved in the 
planned study but will have the requisite clinical expertise to oversee subject safety. The DSMB will 
meet at least once per year, will review a written report prepared annually by the study team, and in 
response, will prepare a written report of the results of these meetings. The PI will alert the DSMB, 

IRB #26427 
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Page 17 of 25 
along with the IRB, the study’s Steering Committee, and the NHLBI Program Officer of any serious AEs. 
Procedures and requirements for prompt reporting of AEs and unanticipated problems involving risk to 
subjects or others have been established by our IRB and will be adhered to for all aspects of this project. 
Any member of the study team will report any unexpected event or problem and any AE, either serious 
or non-serious, to the PI immediately upon discovery. The PI will then proceed to report the event 
within the specified timeframes mandated by the DSMB Charter, the IRB and the NHLBI. Any non-
serious AE, either study or not study related, can be reported by the research team at the date of the 
next continuing review. Current regulations require that any AE that is (1) unexpected (in terms of 
nature, severity, or frequency) given (a) the research procedures that are described in the study-related 
documents, and (b) the characteristics of the subject population being studied, (2) related or possibly 
related to study participation, AND (3) suggesting that the research places subjects or others at greater 
risk of harm than was previously known must be reported to the IRB within 5 business days. A SAE that 
is non-study related can be reported at the next continuing review.  
13 
SAFETY ASSESSMENTS  
The monitoring in place for assessing the subject’s responses will ensure that any untoward change in 
physiologic status is immediately known.  
This includes the following:  
1. Measuring pulmonary function at the beginning of each visit and measuring bronchodilator 
response if there is a drop ≥ 10% from baseline.  
2. Obtaining ACT scores at each visit to assess subjects’ asthma control.   
3. Performing an abbreviated physical exam at all visits. 
4. Checking vital signs, including pulse oximetry, to ensure the subject is at their baseline. 
5. Asking about interim history to ensure the subject has not had an asthma exacerbation since the 
previous visit.  
As a result of the study design, subjects will be monitored on a case-by-case basis by the study 
coordinator. The experimental design has each subject extensively monitored; any manner of medical 
intervention is immediately available, and the appearance of any suspected untoward effect will result 
in cessation of protocol procedures if decided by the principal investigator. 
Any applicable safety concerns will be reported as described above.  
14 
ADVERSE EVENTS AND SEVERITY GRADING 
The IU IRB and the FDA have well-established policies (and means) for prompt reporting of AEs and 
unanticipated problems involving risk to subjects and these policies will be strictly followed. 
Adverse and serious adverse events (AE and SAE, respectively) will be defined according to FDA and 
OHRP guidelines as per IU IRB and NIH requirements. 

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Page 18 of 25 
14.1 
ADVERSE EVENT ASSESSMENT 
All adverse events will be reported to the Indiana University IRB and FDA as required per their adverse 
event reporting policies. At the time of the annual review of the study, adverse events will be reported 
as per the Indiana University HRPP Reportable Events Policy and Guidance.  An Adverse Reaction 
Reporting Form will be completed for any serious and unexpected adverse reaction associated with the 
study, and the Indiana University IRB will be notified per IU HRPP Reportable Events Policy and 
Guidance.  
An IND safety report will be submitted to the FDA for an event that is a (1) suspected adverse reaction, 
(2) serious, and (3) unexpected, per FDA guidance.  
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
reasonable possibility’ means there is evidence to suggest a causal relationship between the 
drug and the adverse event. 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: Death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk 
information described in the protocol. 
Any unexpected fatal or life-threatening suspected adverse reaction will be submitted as an IND safety 
report to the FDA within seven (7) calendar days after initial receipt of information. Any potential 
serious risks (serious and unexpected suspected adverse reactions, findings from other studies, findings 
from animal or in vitro testing, or increased rate of occurrence of serious suspected adverse reactions) 
will be submitted as an IND safety report to the FDA within fifteen (15) calendar days after initial receipt 
of the information. 
All adverse events will be classified and recorded according to the NCI Toxicity Grading Scale. All study 
related toxicities will be graded (Grades 1, 2, 3 or 4) according to the Toxicity Grading Scale and will be 
employed along with potential study drug specific toxicities in the individual subject stopping rules. 
Subject and study stopping rules will be determined by the DSMB. If the DSMB recommends that the 
study change or be closed early for patient safety reasons or for slow accrual, the PI will act to 
implement the change as expeditiously as possible. If a recommendation is made to change the study 
for other than patient safety reasons or slow accrual, the DSMB will provide an adequate rationale for 
its decision. 

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Page 19 of 25 
Adverse events will be graded as follows: 
Grade 0 – No adverse effects 
Grade 1 - Mild adverse events 
Grade 2 – Moderate adverse events 
Grade 3 – Severe adverse events 
Grade 4 – Life threatening or disabling adverse events 
Grade 5 – Death related to adverse events 
Adverse events will be assessed using the NCI Common Toxicity Criteria guidelines listed in 
(http://ctep.cancer.gov/forms/CTCAEv3.pdf) along with potential study drug specific toxicities in the 
individual subject stopping rules. 
Deaths will be reported to the Indiana University IRB per their institutional guidelines if they occur 
within 30 days of study intervention. The principal investigator will be responsible for reporting adverse 
effects to the IRB and other relevant bodies. 
14.2 
TRACKING OF EVENTS 
The following AEs are discussed in the protocol, are discussed with patients as part of the informed 
consent process, and will be tracked as part of the protocol: 
• 
Complications of venipuncture, blood draw. 
• 
Complications related to study drug 
14.3 
ADVERSE EVENT REPORTING 
• 
Every event that is reported to either the PI or the designated research associates by the subject 
or medical staff caring for the subject and which meets the criteria will be documented.  
• 
An AE report will be generated for each event and each report will include: (1) description of the 
event; (2) when it was reported; (3) severity; and (4) a determination of attribution.  
• 
All SAE’s will be reported once the event has been verified, and determination of attribution has 
been completed in accordance with IU IRB reporting requirements and DSMB requirements. All 
other AEs will be reported according to the IU IRB reporting requirements. 
DSMB requirements are that SAE’s be reported to the board within 24 hours of learning of the 
confirmed event. DSMB will proceed to review, discuss and convey recommendations.  
14.4 
FOLLOW UP FOR ADVERSE EVENTS 
Subject follow-up will be on a case-by-case basis as directed by the PI and/or the IU IRB and the DSMB as 
appropriate. 
15 
STUDY MONITORING 
This is a single-site investigator-initiated study, taking place at University Hospital on the IU Indianapolis 
campus. This site will be monitored by representatives from the Indiana Clinical and Translational 
Sciences Institute. The Investigator grants permission to the monitoring office, and appropriate 

IRB #26427 
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Page 20 of 25 
regulatory authorities to conduct on-site monitoring and/or auditing of all appropriate study 
documentation. 
16 
SUBJECT RIGHTS AND CONFIDENTIALITY 
16.1 
ALTERNATIVES TO STUDY PARTICIPATION 
This is a voluntary study. The alternative is to choose to not participate. A subject’s decision will in no 
way influence any care a subject might receive at the respective hospital nor will it affect interactions 
with any of the study personnel. 
16.2 
FINANCIAL INFORMATION 
Subjects will be paid for their participation in this study. Details are provided in the informed consent 
form. 
16.3 
RESEARCH RELATED INJURY 
If injury occurs as a result of their involvement in this research, medical treatment is available from the 
respective hospital or another medical facility but the subject or their medical insurance will be 
responsible for the cost of this treatment. A research injury is an injury that happens as a result of taking 
part in this research study. There are no plans for payment of medical expenses or other payments, 
including lost wages, for any research related injury. 
16.4 
USE OF SPECIMENS 
Test results will not be used to guide clinical care, nor will they be used for purposes outside the scope 
of this research study. 
16.5 
CONFIDENTIALITY 
All study data will be treated as confidential information. Similarly, the subject’s medical history will also 
be treated as confidential with no identifiable information released or shared with individuals outside 
the study team. If the study results are published, subject names will not be used. Once all the results 
are collected any identifiers will be removed and the information assigned a code. The data will be 
identified by a study number and not by name or identifying information. The code assignment key will 
be maintained by the study team on a password-secured computer kept in a locked office. Access to the 
code key will be limited to a need-only basis. 
16.6 
PRIVACY 
Study team members are committed to protecting the privacy of research subjects. Recruitment 
discussions will be conducted with as much privacy as possible. The consent process will take place in a 
private room. Subjects will be assured that all study staff working on the study will make every effort to 
protect their privacy.  
16.7 
DATA/SAMPLE CONFIDENTIALITY 
The study team will make an ongoing effort to keep personal information of the subjects confidential. 
Personal information will be disclosed only if required by law. Subjects will be informed that they are 
assigned unique study identification numbers to protect their identity. Any paper and electronic files 

IRB #26427 
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Page 21 of 25 
containing study data, as well as any specimens, will be coded with the study identification number and 
not with the subject’s name. 
Study information, which does not identify the subjects, may be given to regulatory agencies and the 
Institutional Review Board (IRB). Staff members from these agencies have the right to review each 
subject’s medical and study records only as needed for safety purposes, to verify the data, assess 
compliance with the protocol and regulation, or to review the results of the study. By signing the study 
consent, subjects agree to let these organizations see their medical and study records. The records will 
not be used for any other purposes or disclosed to any other party without subject permission. Some of 
the records reviewed will contain identifying information; however, the study team are required to keep 
this information confidential. Efforts will be made to keep personal information in the subject’s research 
record private and confidential, but absolute confidentiality cannot be guaranteed.  
16.8 
DATA/SAMPLE SECURITY 
Health information/specimens will be labeled with subject ID number and any other pertinent 
information (e.g., study name, visit number, sample date). Subject records will be stored by the study 
coordinator. Specimens will be stored in the Pediatric Translational Research Lab in the Herman B. Wells 
Center for Pediatric Research, Pediatric Translational Lab, located in Walther Hall at 980 Walnut St, R3-
C115 or in the CCRC Lab, located in the Riley Hospital Children’s Clinical Research Center. Only study 
personnel for this study designated by the PI will have access to the data/specimens. Electronic files will 
be stored on password-protected IU systems. 
16.9 
DATA ENTRY & STORAGE 
The study team will adhere to 21 CFR Part 11 guidelines and requirements for data entry and storage 
practices. This study will use a secured, institutional REDCap database for data entry and storage, with 
original hard copy, paper documents maintained for cross reference. The institutional REDCap will be 
designed for this study.  
17 
STATISTICAL ANALYSIS 
Descriptive statistics of the study cohort will be summarized and used to determine safety. If an AE 
occurs, the maximum tolerable dose (MTD) will be determined following a design with intrapatient dose 
escalation. Mixed-effects models for repeated measures will be considered to test the significance of the 
difference at various measurement time points.  
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10.1164/ajrccm.159.1.9712108. PMID: 9872837.Alkatib AA, J Clin Endocrin Metab, October 
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18 
PROTOCOL SIGNATURE PAGE 
 
Protocol Title: 
Phase IIb Clinical Trial to Evaluate Efficacy and Safety of Slow Release DHEA 
IRB #: 
26427 
IND: 
162875 
Protocol Version/Date: 
10Jun2025 
 
The signature below constitutes approval of this study in full accordance with the provisions of this 
protocol and the attachments. I agree to conduct this study in compliance with the protocol, in-country 
and local regulatory requirements, applicable United States (US) Code of Federal Regulations (CFR) and 
ICH Good Clinical Practices (E6).  
I agree to conduct the study in accordance with the current protocol and will not make changes to the 
protocol without obtaining Sponsor and IRB approval, except when necessary to protect the safety, 
rights, or welfare of subjects. 
 
_______________________________________________ 
 
____________________ 
Printed Name of the Principal Investigator 
 
 
 
Date 
 
_______________________________________________ 
Signature of the Principal Investigator