Clinical trial NCT02421887
Conditions: Male Infertility
Sponsor: Yale University
Start date: 2015-12-01; Completion date: 2018-12-01
Enrollment: 171 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of the Males, Antioxidants, and Infertility (MOXI) Trial is to examine whether treatment of infertile males with an antioxidant formulation improves male fertility. The central hypothesis is that treatment of infertile males with antioxidants will improve sperm structure and function, resulting in higher fertilization rates and improved embryo development, leading to higher pregnancy and live birth rates. Findings from this research will be significant in that they will likely lead to an effective, non-hormonal treatment modality for male infertility. An effective treatment for men would also reduce the treatment burden on the female partner, lower costs, and provide effective alternatives to couples with religious or ethical contraindications to ART (Assisted Reproductive Technology). If antioxidants do not improve pregnancy rates, but do improve sperm motility and DNA integrity, they could allow for couples with male factor infertility to use less intensive therapies such as intrauterine insemination. Male fertility specialists currently prescribe antioxidants based on the limited data supporting their use. A negative finding, lack of any benefit, would also alter current treatment of infertile males.

Detailed description:

Arms: arm 1: Tablet: Vitamin C, 500 mg; Vitamin D3, 1000 IU; Vitamin E, 400 IU; Folic Acid 1000 mcg; Zinc, 20 mg; Selenium 200 mcg; Lycopene, 10 mg; Capsule: Vitamin D3, 1000 IU, L-Carnitine, 1000 mg arm 2: None
Interventions: intervention 1: Antioxidant Supplement intervention 2: Placebo
Intervention descriptions: intervention 1: An antioxidant combination including Vitamin C, Vitamin E, folic acid, selenium, zinc, and L-carnitine intervention 2: Placebo

Protocol documents:
Prot_SAP_ICF_000.pdf: 
RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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Reproductive Medicine Network 
Funded by Eunice Kennedy Shriver NICHD 
 
 
Males, Antioxidants, and Infertility (MOXI) Trial 
 
Protocol Leader: Anne Z. Steiner, MD, MPH 
Data and Coordination Leader: Heping Zhang, PhD 
Version: 4.0  
 
Prepared by: 
The RMN Data Coordination Center 
Collaborative Center for Statistics in Science 
Yale University School of Public Health 
300 George Street, Suite 523 
New Haven, CT 06511 
(203) 785-5185 
 
Last updated October 12, 2016 


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Protocol Subcommittee 
 
Group email address: rmn.moxi@mailman.yale.edu 
 
Name 
E-mail 
Anne Z. Steiner, MD, MPH 
anne_steiner@med.unc.edu  
Matt Coward, MD 
mcoward@med.unc.edu 
Esther Eisenberg, MD, MPH 
eisenbes@mail.nih.gov 
Stephen A. Krawetz, PhD 
steve@compbio.med.wayne.edu  
Puneet Masson, MD 
Puneet.Masson@uphs.upenn.edu  
Nanette Santoro, MD 
nanette.santoro@ucdenver.edu  
Jim Smith, MD, MS 
SmithJF@urology.ucsf.edu  
Peter Snyder, MD 
pjs@mail.med.upenn.edu  
J. C. Trussell, MD 
jctrussell1@verizon.net  
Heping Zhang, PhD 
heping.zhang@yale.edu   
 
 
 






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10 
REFERENCES ............................................................................................................................................ 59 
11 
INFORMED CONSENT ............................................................................................................................ 65 
11.1 
INFORMED CONSENT TEMPLATE – MALE PARTNERS ..................................................................................... 65 
11.2 
INFORMED CONSENT TEMPLATE – FEMALE PARTNERS .................................................................................. 83 
12 
APPENDIX A: MALE MEDICAL HISTORY QUESTIONNAIRE .................................................... 101 
13 
APPENDIX B: FEMALE MEDICAL HISTORY QUESTIONNAIRE ............................................... 116 
14 
APPENDIX C: LIST OF PROHIBITED CONCOMITANT MEDICATIONS .................................. 131 
15 
APPENDIX D: REVIEW OF ANTIOXIDANT FORMULATIONS ................................................... 134 
15.1 
COMMERCIALLY AVAILABLE FORMULATIONS ............................................................................................. 134 
15.2 
RESEARCH FORMULATIONS ......................................................................................................................... 135 
16 
APPENDIX E: RISK FACTORS FOR GENETIC DISORDERS ........................................................ 138 
17 
APPENDIX F: FEMALE SEXUAL FUNCTION INDEX (FSFI) ........................................................ 140 
18 
APPENDIX G: SF-12V2 HEALTH SURVEY ........................................................................................ 145 
19 
APPENDIX H: PATIENT HEALTH QUESTIONNAIRE (PHQ-9) .................................................... 148 
20 
APPENDIX I: FERTIQOL ...................................................................................................................... 150 
21 
APPENDIX J: EPWORTH SLEEPINESS SCALE ............................................................................... 151 
22 
APPENDIX K: STOP BANG QUESTIONNAIRE ................................................................................ 152 
23 
APPENDIX L: FEMALE SEXUAL DISTRESS SCALE (FSDS- REVISED 2005)............................ 153 
24 
APPENDIX M:  INTERNATIONAL INDEX OF ERECTILE FUNCTION (IIEF) .......................... 154 
25 
APPENDIX N: DIET HISTORY QUESTIONNAIRE II ...................................................................... 157 
26 
APPENDIX O: AUTOMATED SELF-ADMINISTERED 24-HOUR RECALL (ASA24) ................. 197 
27 
APPENDIX P: QADAM QUESTIONNAIRE ........................................................................................ 208 
28 
APPENDIX Q: PSYCHOSEXUAL DAILY QUESTIONNAIRE ......................................................... 209 
29 
APPENDIX R: SUN EXPOSURE AND BEHAVIOUR INVENTORY (SEBI V2) ............................. 210 
30 
APPENDIX S: INVESTIGATOR SIGNATURE OF AGREEMENT .................................................. 214 
31 
APPENDIX T: DATA AND SAFETY MONITORING PLAN ............................................................. 215 
 
Figure 1: Schema for the Participation Timeline .......................................................................... 17 
Figure 2: SAE flowchart ............................................................................................................... 44 
 
Table 1: Overview of Timing and Content of Data Collection for Primary Cohort ..................... 32 
Table 2: Sample size estimates under a variety of assumptions ................................................... 40 
Table 3: Power for subgroup analyses .......................................................................................... 40 
Table 4: Types of Serious Adverse Events and Their Reporting Requirements .......................... 43 
Table 5: Timeline for MOXI......................................................................................................... 50 
Table 6: RMN Publication Authorship ......................................................................................... 53 
Table 7: Authorship Order of the RMUs and Outside Sites ......................................................... 53 
 
 
 


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1 Acronyms 
Assisted Reproductive Technologies 
ART 
Intrauterine Insemination 
IUI 
Advisory Board    
AB  
Investigational New Drug 
IND 
American Congress of Obstetricians and 
Gynecologists 
ACOG 
National Institute of Child Health and 
Human Development 
NICHD 
Assessment of Multiple Intrauterine 
Gestations from Ovarian Stimulation 
AMIGOS 
Ovarian Hyperstimulation Syndrome 
OHSS 
Clinical Report Form 
CRF 
Principal Investigator 
PI 
Clomiphene Citrate 
CC 
Progesterone 
P4 
Code of Federal Regulations 
CFR 
Protected Health Information 
PHI 
Data and Safety Monitoring Board   
DSMB 
Quality Control 
QC 
Data Coordination Center 
DCC 
Randomized Controlled Trial 
RCT 
Deoxyribonucleic Acid 
DNA 
Reactive oxygen species 
ROS 
DNA fragmentation index      
DFI   
Reproductive Medicine Network 
RMN 
Ectopic Pregnancy 
EP 
Reproductive Medicine Unit 
RMU 
Follicle Stimulating Hormones 
FSH 
Serious Adverse Event 
SAE 
Food and Drug Administration 
FDA 
Single cell gel electrophoresis   
Comet 
Health Insurance Portability and 
Accountability Act 
HIPAA 
Sperm Chromatin Structure Analysis 
SCSA 
Human Chorionic Gonadotropin 
hCG 
Terminal Deoxynucleotide Transferase-
mediated dUTP Nick-end Labeling 
TUNEL 


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Human Investigation Committee 
HIC 
Time to Conceive   
TTC 
Identification 
ID 
Total and Free Testosterone 
T, FT 
In Vitro Fertilization 
IVF 
Ultrasound 
U/S 
Institutional Review Board 
IRB 
University of North Carolina 
UNC 
Intracytoplasmic sperm injection 
ICSI 
  
  
 
 
 
 


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2 Study Synopsis 
2.1 
Objectives 
The objective of the Males, Antioxidants, and Infertility (MOXI) Trial is to examine whether 
treatment of infertile males with an antioxidant formulation improves male fertility.  The central 
hypothesis is that treatment of infertile males with antioxidants will improve sperm structure 
and function, resulting in higher fertilization rates and improved embryo development, leading 
to higher pregnancy and live birth rates.  Findings from this research will be significant in that 
they will likely lead to an effective, non-hormonal treatment modality for male infertility.  An 
effective treatment for men would also reduce the treatment burden on the female partner, 
lower costs, and provide effective alternatives to couples with religious or ethical 
contraindications to ART.  If antioxidants do not improve pregnancy rates, but do improve sperm 
motility and DNA integrity, they could allow for couples with male factor infertility to use less 
intensive therapies such as intrauterine insemination.  Male fertility specialists currently 
prescribe antioxidants based on the limited data supporting their use.  A negative finding, lack of 
any benefit, would also alter current treatment of infertile males.  
2.2 
Patient population 
The population will consist of 790 heterosexual couples, who have been attempting to conceive 
for ≥12 months, recruited from the Reproductive Medicine Network (RMN) clinical sites and their 
surrounding communities over a two-year period. 
2.3 
Study design 
This will be a multi-center, randomized, placebo-controlled trial of antioxidant formulation, 
ConceptionXR Motility Support Formulation by Theralogix (“ConceptionXR”) for the male 
partner.  The randomization scheme will be stratified by participating site.  The study will contain 
an internal pilot study. 
2.4 
Treatment 
790 male subjects will be equally randomized via computer-generated randomization to receive: 
A) ConceptionXR Motility Support Formulation (Theralogix) containing an antioxidant 
combination including Vitamin C, Vitamin E, folic acid, selenium, zinc, and L-carnitine by oral 
ingestion twice daily or B) a placebo by oral ingestion twice daily in a double-blinded fashion.  
Treatment assignments will be randomized within each site by varying block size design.  
Treatment will occur for a minimum of 3 months and a maximum of 6 months.  Couples will 
attempt to conceive naturally during the first 3 months and with clomiphene citrate with 
intrauterine insemination in months 4 through 6. 


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2.5 
Primary outcome 
The primary outcome will be live birth rate following up to 6 months of treatment with 
antioxidants as compared to placebo. 
2.6 
Secondary outcome 
The secondary outcomes will be pregnancy rate, miscarriage rate, time to pregnancy, and semen 
parameters and DNA fragmentation at 3 months of treatment with an antioxidant as compared 
to placebo. 
2.7 
Internal Pilot 
We will be conducting an internal pilot study with a three-fold objective.  The objective of the 
internal pilot is 1) to determine the distribution of the semen abnormalities in the study 
population, 2) to examine the effect of our antioxidant formulation on male semen parameters 
and DNA integrity at 3 months of treatment compared to controls, and 3) to determine the 
feasibility of the proposed recruitment paradigm.  The first 120 men enrolled in the MOXI trial 
will be included in the internal pilot.  Assuming we fail to reject the null hypothesis that motility 
and DNA fragmentation percentage do not differ between the two treatment groups (antioxidant 
and placebo) at 3 months, the MOXI trial will stop enrolling subjects.  Assuming we reject the null 
hypothesis that motility and DNA fragmentation percentage do not differ between the two 
treatment groups (antioxidant and placebo) at 3 months, the MOXI trial will continue.  As the 
primary outcome will not be analyzed for the pilot, adjustments in significance levels will not be 
required for the primary analyses.  Feasibility will be assessed by recruitment pace.  We anticipate 
that the pilot enrollment will be completed by 6 months.  If we fail to meet this pace, the 
recruitment strategies may need to be altered or the study stopped at the conclusion of the pilot. 
2.8 
Statistical Analysis 
The primary outcome is a live birth resulting from a pregnancy that is conceived within the 6 
months from initiation of treatment.  Live birth is defined as a delivery of a live infant after 20- 
weeks gestation.  Secondary outcomes include pregnancy, defined by a positive home pregnancy 
test within the 6 months of treatment.  We will conduct an intent-to-treat analysis.  Cumulative 
incidence of live birth and pregnancy will be compared between those couples randomized to 
antioxidants and those couples randomized to placebo.  In addition, discrete-time hazard models 
will be used to compare time-to-pregnancy between the two treatment groups.  Subsequent 
subgroup analyses will be conducted to assess for effect modification by type of baseline sperm 
abnormality (asthenospermia, high DNA fragmentation, oligospermia).   
After transformations, if needed, semen parameter measures will be analyzed using a 
generalized linear mixed model (including random effects for site if necessary) or generalized 
linear model (if fixed effects for site are used).  Interaction terms will be used to determine the 


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extent to which the change in semen parameter measures differs by type of baseline sperm 
abnormality (asthenospermia, high DNA fragmentation, oligospermia).  If there is evidence of 
effect modification, change estimates will be determined for each type of baseline sperm 
abnormality. 
For the power analysis, we assume live birth rates of 35% in the antioxidant group and 25% in 
the control group, and 17% drop-out.  Under these assumptions, the power by using a two-sided 
chi square test at α=0.05 would be 0.80.    
2.9 
Regulatory Compliance 
The DCC is working with the Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD) to ensure that clinical study data and regulatory requirements are met 
regarding the Food and Drug Administration (FDA) code for federal regulations and 
Investigational New Drug (IND) submissions.   
This trial is registered on http://www.clinicaltrials.gov (NCT # 02421887), and has been issued 
IND # 125753. 
 
 
 
 


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3 Background and Significance 
3.1 
Background 
A variety of pathologic conditions including infection (1), varicocele (2), and cancer (3), along with 
environmental exposures including organic chemicals (4), pharmaceuticals, smoking (5), and 
radiation appear to increase oxidative stress, measured as reactive oxygen species (ROS), in 
semen.  The sperm plasma membrane and nuclear genomes are highly susceptible to damage 
due to ROS due to high levels of polyunsaturated fatty acids, deficiencies in intracellular 
antioxidant enzymes, and limited capacity for DNA repair in sperm (6).  ROS cause lipid 
peroxidation and thereby structural modifications to the membrane, which have been shown to 
interfere with sperm motility, the acrosome reactions, and sperm-oocyte fusion (7).  ROS damage 
the nuclear and mitochondrial genome by causing single and double DNA breaks, chemical 
modifications of bases, DNA crosslinks, and DNA protein crosslinks (8).  Damaged DNA may be 
repaired by endogenous repair mechanisms; however, if these are overwhelmed, the damaged 
DNA will be integrated into the embryo.  It has been proposed that this damaged DNA will impair 
embryonic development, lead to pregnancy loss, or result in birth defects or morbidity in the 
offspring.   
Given that ROS negatively affect the sperm plasma membrane, which is important for 
fertilization, and sperm DNA, which is important for normal embryonic and fetal development, it 
is logical that ROS will diminish a sperm's capacity to fertilize or lead to impaired embryo 
development.  Clinically this would be observed as reduced fertility and greater pregnancy loss 
in female partners of men with elevated levels of ROS.  While ROS are not commonly measured 
in semen, ROS damage to sperm, as measured by loss of motility and DNA fragmentation, can be 
quantified.  Sperm motility can be measured using a standard semen analysis.  DNA integrity is 
measured using a number of assays including Terminal Deoxynucleotide Transferase-mediated 
dUTP Nick-end Labeling (TUNEL), Sperm Chromatin Structure Analysis (SCSA), and single cell gel 
electrophoresis (Comet).  
In fact, previous studies have shown that low sperm motility and high DNA fragmentation, as 
measured by the SCSA, are associated with a longer time-to-pregnancy among couples trying to 
conceive (9).  Sperm motility lower than 32% is associated with 2.5 times the odds of infertility 
(10).  Evenson et al. found that couples that did not conceive had 30% more DNA fragmentation 
compared to couples that conceived within 3 months of attempt (9).  DNA fragmentation was 
also greater among those couples that did not conceive with intrauterine insemination and 
intracervical insemination compared to those that did conceive (11-13).  DNA fragmentation 
levels have not consistently been associated with live birth rates following ART.  Some studies 
have shown that fertilization and pregnancy rates are lower with high DNA fragmentation (14-
20), while others have not shown an association (11, 17, 21, 22).  These discrepancies may be 


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due to the variety of assays used to measure DNA fragmentation, the use of ICSI (ROS plasma 
membrane damage may be mitigated with intracytoplasmic sperm injection) (13-15, 23-25), and 
the variety of cut-off values used to define high DNA fragmentation.  In addition, sperm 
preparation techniques may decrease the percentage of sperm with fragmented DNA in the 
aliquots of sperm used for in vitro fertilization (26). 
Vitamin C, E, and other naturally occurring antioxidants are low molecular mass ROS scavengers 
found in semen (27).  Low levels of seminal vitamin C are associated with poor semen quality 
(27).  Seminal concentrations of antioxidants are lower in men with infertility compared to fertile 
men (28-30).  As antioxidants appear to lower ROS and ROS appear to negatively affect fertility, 
antioxidants have been proposed as a treatment for male factor infertility.   
The limited data suggest that antioxidants improve sperm motility and reduce DNA 
fragmentation.  A previous observational study showed that a health conscious diet is associated 
with a decrease in sperm DNA fragmentation, suggesting that natural antioxidants are beneficial 
to sperm (31).  However, another observational study using food frequency questionnaires failed 
to find an association between any antioxidant measure and DNA fragmentation, perhaps 
because the cohort was comprised of healthy volunteers (32).  Studies of supplements have 
tended to show an improvement in semen parameters with the use of antioxidants.  Benefits of 
Vitamin C (33), selenium (34), N-acetylcysteine (35), L-carnitine (36), and Zinc (37) on sperm 
motility have been seen after 3 months of treatment.  Unfortunately, most of these studies have 
been small and heterogeneous.  While most studies included only infertile men, some included 
those with normal baseline semen parameters and some with abnormal baseline semen 
parameters.  Only one clinical trial has compared DNA integrity between men treated with 
antioxidants (Vitamin C and Vitamin E) and a control group (38).  This study of 64 men found that 
after 2 months of treatment, men who received antioxidants had on average 14% (10.1-17.5%) 
less fragmented sperm.  DNA integrity needs to be assessed in addition to traditional semen 
parameters as a significant number of men will have high levels of DNA fragmentation despite a 
normal semen analysis (39-41). 
The paternal genome is thought to be activated between cleavage stage and blastocyst stage 
during embryonic development.  It has been suggested that sperm DNA fragmentation will alter 
embryonic development in these later stages (42).  Aberrant embryo development could lead to 
miscarriage or subsequent congenital abnormalities.  Meta-analyses of previous studies 
examining the association between DNA fragmentation and miscarriage suggest that high DNA 
damage as measured by TUNEL assay is associated with an increase in the risk of miscarriage 
(Mantel-Hansel Risk ratio (random effects model) 3.94 (95% CI 2.54, 6.32)(43).  The association 
was not as strong when the SCSA was used as the measure of DNA fragmentation (RR 1.47, 95% 
CI 1.04, 2.09).  Only one underpowered study examined the relationship between miscarriage 
and DNA fragmentation among couples conceiving naturally (9).  It is impossible to determine 


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the amount of DNA fragmentation in the fertilizing sperm in vivo and in vitro as assays to assess 
sperm DNA integrity preclude their use.  Thus it is assumed that the overall percentage of sperm 
with DNA damage in a given ejaculate reflects the probability that the DNA from the sperm that 
fertilized the egg was damaged.  It is possible that the probability of an embryologist selecting a 
sperm with DNA fragmentation to fertilize an oocyte in vitro would differ from the probability 
that a sperm with DNA fragmentation would fertilize an oocyte in vivo.   
Clinical studies of the use of antioxidants in the treatment of male infertility have been 
encouraging.  A recent meta-analysis found that use of antioxidants by males with infertility was 
associated with 4.85 times the odds (95% CI 1.92-12.24) of live birth following ART compared to 
men who did not use antioxidants (44).  While these findings are encouraging, they fail to provide 
a definitive answer as to whether antioxidants improve male fertility.  The meta-analysis included 
3 studies for a total of 214 participants and the quality of the evidence was graded as low.  These 
studies examined the antioxidants vitamin E (45, 46) and zinc (47), while studies using pregnancy 
as an outcome have shown L-carnitine to be promising (36, 48).  Finally, these studies all used 
antioxidants in combination with ART; it is certainly possible that the response to antioxidants 
will differ with in vivo fertilization.  
3.2 
Significance 
Although clinical trials suggest that antioxidants have a positive effect on sperm motility, DNA 
integrity, and pregnancy rates in couples undergoing assisted reproductive technologies, there 
are significant gaps in our knowledge of their impact on fertility (44).  Gaps exist due to limitations 
in existing literature.  1) A variety of antioxidants at varying doses and duration have been used, 
precluding a strong conclusion as to whether a specific regimen is beneficial.  2) Most studies 
have had small sample sizes, usually less than 50 subjects.  3) Studies have utilized heterogeneous 
populations, limiting ability to combine results of multiple studies.  4) Most studies have used 
changes in semen parameters or DNA integrity as the endpoint, rather than clinical outcomes. 5) 
Studies have used antioxidants in conjunction with in vitro fertilization with intracytoplasmic 
sperm injection (ICSI) when measuring effectiveness.  This has precluded the possibility of 
studying antioxidant effects on in vivo fertilization, which relies on normal sperm function.  Our 
proposed study will improve generalizability, but still allow for sufficient power to determine 
benefit among subgroups, and will look at reproductive endpoints including pregnancy, 
miscarriage, and live birth. 
Findings from this research will be significant in that they will likely lead to an effective, natural 
treatment modality for men with abnormal sperm. An effective, inexpensive, non-invasive 
treatment for male subfertility would be of significant benefit, as no such treatment has been 
clinically validated.  An effective treatment for men would also reduce the treatment burden on 
the female partner, lower costs, and provide effective alternatives to couples with religious or 
ethical contraindications to ART.  Even if antioxidants are found not to be of benefit to any 


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subgroup, this research will help us better understand the reproductive impact of sperm DNA 
integrity, leading to treatments that could improve fertility, pregnancy outcomes, and offspring 
health.  
Another important possible benefit of antioxidant use in males is their potential to reduce 
offspring morbidity.  Increasing evidence highlights a link between paternal age and offspring 
morbidities including autism (49), schizophrenia (50), and sporadic autosomal dominant 
disorders (51).  It is possible that these disorders may be attributable to DNA fragmentation due 
to increased ROS in aging males (15, 52).  While the proposed study will not directly address the 
therapeutic benefits of antioxidants in the prevention of these morbidities, it will address a 
potential mechanism and possibly suggest a preventative therapy by providing information about 
relationships between chronological age, DNA fragmentation, and relative effectiveness of 
antioxidant therapy in treating DNA fragmentation. 
3.3 
Innovation   
This proposal is innovative in that it 1) focuses on male infertility, 2) examines both primary 
clinical outcomes such as live birth, and intermediate outcomes, such as semen parameters, 3) 
seeks to discover a cure for male infertility that does not require ART, and 4) will use the highest 
quality study design, an adequately powered, randomized controlled trial.  While biologic 
evidence supports the hypothesis that antioxidants would improve male fertility, our unique 
study design will allow the RMN to ultimately determine if antioxidants improve male fertility 
without the use of ART.   
 
 


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4 Objectives 
4.1 
Primary Aim 
Our primary aim is to compare live birth rates in infertile couples (≥12 months of infertility) 
following up to 6 months of male treatment with antioxidants, as compared to placebo.  This is a 
randomized, multi-center trial in which couples receive clomiphene citrate and IUI in the second 
half of treatment.  The primary outcome measure will be cumulative incidence of live birth of 
pregnancies conceived following up to 6 months of male treatment with the antioxidant 
formulation or placebo. 
4.2 
Secondary Aim 
We will assess secondary outcomes including cumulative pregnancy rates with pregnancy 
defined as a positive pregnancy test, clinical pregnancy rates defined as presence of a fetus with 
cardiac activity, miscarriage rate, defined as the loss of a pregnancy prior to 20-weeks gestation, 
and time to pregnancy.  In addition, we will examine changes in semen parameters and DNA 
fragmentation at 3 months of treatment. 
4.3 
Tertiary Aims 
Subsequent subgroup analyses will be conducted to assess for effect modification by type of 
baseline sperm abnormality (oligospermia, asthenospermia, high DNA fragmentation).  
Additional questions that can be addressed with this cohort could include: 
1. Do high levels of DNA fragmentation increase the risk of miscarriage? 
2. Does DNA fragmentation increase with paternal age? 
3. Does DNA fragmentation increase time to pregnancy (and decrease fecundability)? 
4. How do SCSA and TUNEL assays for DNA fragmentation compare? 
4.4 
Internal Pilot 
While there are a number of small randomized controlled trials showing that antioxidants 
improve semen parameters and a few that show that they increase pregnancy rates following 
ART, the studies vary tremendously in their choice of antioxidant and formulation.  There are a 
number of commercial products marketed to improve male fertility.  No trials have been 
published in peer-reviewed journals using any of these formulations.  We have chosen a 
commercial antioxidant formulation, which includes the antioxidants that appear to improve 
semen parameters based on the existing literature.  For this reason, we will be conducting an 
internal pilot study.   
The objective of the internal pilot is to examine the effect of our antioxidant formulation, 
ConceptionXR, on male semen parameters and DNA integrity at 3 months of treatment compared 
to controls.  We hypothesize that motility will be significantly higher and DNA fragmentation 


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significantly lower among those men treated with antioxidants compared to placebo.  A 
secondary objective of the internal pilot is to determine the feasibility of recruitment into a male 
fertility study.  A tertiary objective, which will only be assessed if we fail to meet the primary and 
secondary objectives of the internal pilot, would be to compare live birth rates and pregnancy 
rates.   
 
 


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5 Study Design 
5.1 
Overview and Schema  
To achieve our objective, we will conduct the Males, Antioxidants, and Infertility (MOXI) Trial, a 
randomized controlled trial of the effect of antioxidants on semen parameters and male fertility.  
Couples will be recruited from the clinics and will undergo a screening visit.  At the female 
screening visit, she will provide consent, complete a questionnaire and any necessary screening 
tests, provide a blood sample, and complete a food frequency questionnaire.  At the male 
screening visit, he will provide consent, complete a questionnaire, provide a semen sample, if no 
semen analysis within the past 6 months is available, and complete a food frequency 
questionnaire.  A total of 790 couples will be enrolled.  At the first study visit the male partner 
will provide a semen sample and complete a dietary assessment.  The male will be randomized 
to the placebo or antioxidant arm.  Treatment will follow for 3 months.  If the couple has not 
conceived, treatment will continue for up to an additional 3 months and the female will receive 
up to 3 cycles of clomid and IUI.  Throughout the pre-conception window, women will use 
ovulation predictor kits and check a home pregnancy test with missed menses.  Men will provide 
a semen sample after 3 months of treatment.  Compliance will be assessed at 1, 3, and 6 months.  
An ultrasound will be performed between 7 and 9 weeks gestation and pregnancy outcomes 
determined. 
 
Figure 1: Schema for the Participation Timeline 
 
 
 






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Our exclusion criteria include a lower limit for sperm count.  Men with very low sperm counts are 
more likely to have hypogonadism or obstruction and would be unlikely to benefit from 
antioxidants.  Approximately 32% of males between the ages of 31 and 50 take a daily 
multivitamin (54).  Multivitamin use is more frequent among those with more education, higher 
incomes, healthier lifestyles and diets, and lower body-mass indexes (55).  For this reason, 
exclusion of men on vitamins 1) could possibly lead to selection bias and 2) might not be feasible.  
Thus the inclusion criteria call for a 1-month washout period for those men taking vitamins.   
5.3 
Recruitment 
A total of 790 men will be recruited over a 2-year period (approximately 30 men per month).  We 
will recruit subjects using methods previously proven effective in AMIGOS, which enrolled a 
similar study population.   
Hospital/Local Health Care Referrals  
Subjects will be recruited at each site from individual practice(s) as well as faculty/resident clinics. 
Ongoing contact with practice and faculty members as well as with residents will be made by the 
investigators and coordinators, reminding them of the inclusion criteria, importance of the study, 
etc. In addition, the investigators will describe the study to members of other departments in the 
hospital, primarily family practice, medical endocrinology, urology, and gynecology who also see 
and treat these patients. Contact with local physicians will be made and/or grand rounds will be 
given to disseminate information about the study.  
 
Local Publicity Office  
Investigators will meet with their local Public Relations offices and plan a news release about the 
study. They will also make themselves available for any newspaper, radio, or TV stories that may 
increase public awareness of the study. The full gamut of local media sources should be utilized. 
Often there is greater yield with more extensive coverage in smaller local outlets as opposed to 
brief mentions in outlets with larger circulation. News release will mention the uniqueness of the 
study, which may improve male fertility treatment.  
 
Local Advertisements  
Advertisements will be placed in local newspapers and will be continued on a regular basis if 
response is good. 
  
Contact with infertility support groups  
Contact will be made with both national and local support groups to spread information about 
the study through informational brochures and/or participation in local meetings.  The American 
Infertility Association also may be helpful in promoting awareness of this study.  
 
National Professional Organizations  
Contact will be made with the publicity office of The American Society for Reproductive Medicine, 
and other potentially helpful organizations to solicit their support and potential informational 
releases.  


RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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21 
 
 
Web sites  
The study will be prominently displayed on the RMN web site. Additionally, each RMN center 
should have a web page devoted to this study with general as well as contact information. 
Information should also be available at the NICHD web site with links to each RMN center. An ad 
should also be placed at “Center Watch” on the web. 
 
National Advertising  
We would consider placing a trial ad in the health section of a select or a series of selected 
national publications with all of our local numbers/contacts.  
 
IRB Approval  
It is expressly acknowledged that all informational material that could be construed to be 
advertising will be approved by the appropriate IRB prior to dissemination. 
5.4 
Screening 
Couples will be screened through a 3-part process.  The first step will be a review of medical 
records to assess for potential eligibility, when recruiting from the clinic.  
Both the female and the male partner will need a screening visit; however, these can be 
scheduled at the same time.  The screening visit will be conducted by the study coordinator and 
will include questionnaires and laboratory testing.  The screening visit will not require physician 
participation, unless a physical exam is needed.  Eligibility will be determined by review of 
responses to the questionnaire and results of the laboratory testing, and review of medical 
records. 
5.5 
Informed Consent 
We will obtain a limited waiver of HIPAA authorization to allow us to access and use protected 
health information to review eligibility criteria and contact potential subjects.  Female written 
consent including HIPAA is obtained at the screening visit for the female visit prior to any blood 
draws or questionnaires.  A medical records release form will be obtained at the pregnancy 
ultrasound.  Male written consent and HIPAA will be obtained at the male screening visit prior to 
the semen analysis and completion of questionnaires.  Both males and females will be asked to 
sign an optional consent form for storage of de-identified residual samples (semen, blood, and 
data). 
Randomization, Allocation, Masking:  A total of 790 men will be randomized to one of two 
treatment groups.  The randomization scheme will be generated using a computer generated 
random number sequence in randomly varying blocks of 4 and 6.  The allocation assignments will 




RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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23 
 
In general, the RCTs of Vitamin E and male fertility have tended to use higher doses than we 
propose.  However, Vitamin E will be just one of multiple antioxidants.  Second, an RCT of almost 
15,000 healthy men over 50 years of age showed that 400 IU of synthetic vitamin E use was 
associated with a significant increased risk of hemorrhagic stroke over 8 years of treatment (61).  
It should be noted that the men in the MOXI trial will be, on average, younger and will take the 
vitamin for a short interval (at most 6 months).  In another trial, the SELECT trial, of men over age 
50, synthetic vitamin E at 400 IU/day for 5.5 years was found to increase the risk of prostate 
cancer 1.5 years after cessation of therapy.  No differences in prostate cancer rates were seen 
during the 5.5 years of treatment (62).  In addition, a meta-analysis found an increased risk of 
death at doses of 400 IU/day (43).  Vitamin E can interact with anticoagulants increasing the risk 
of bleeding.  Therefore, men on anticoagulants will be excluded from participation.  Adverse 
effects of Vitamin E include fatigue, weakness, headache, nausea, diarrhea, flatulence and 
abdominal pain at high doses (over 1000 mg/day).  However, at lower doses as prescribed in this 
trial, Vitamin E is generally well tolerated.  
Selenium: The total daily dosage of selenium in the organic form of L-selenomethionine will be 
0.20mg.  Commercial products include selenium at doses between 0.05 mg and 0.133 mg. 
Randomized trials included doses ranging from 0.026 to 0.225mg, which the most common dose 
being 0.20mg (34, 56, 59, 60, 63).  These trials have shown that selenium increases sperm motility 
at 3 and 6 months (34, 63).  The tolerable upper limit intake level for selenium (from supplements 
and food) is 0.4 mg.  Levels above this are associated with hair and nail brittleness and loss.   
L-carnitine: The total daily dosage of L-carnitine in the form of L-carnitine-L-tartrate and L-
carnitine fumerate will be 1000 mg.  Commercial products include L-carnitine at doses between 
50 and 1000 mg.  Randomized controlled trials included doses ranging from 2000 to 3000 mg (48, 
58, 64, 65).  Common L-carnitine adverse effects include diarrhea, nausea, stomach cramps, and 
vomiting.  Uncommon serious adverse effects include seizures.  L-carnitine has been shown to 
increase pregnancy rates following IVF in small, randomized, placebo-controlled trials (36, 48). 
Zinc: The total daily dosage of zinc will be 20 mg.  Commercial products include zinc in the form 
of zinc amino acid chelate at doses of 10 to 70 mg.  Randomized controlled trials have included 
dosages ranging from 25 to 500 mg (37, 47, 56). These small trials have shown that zinc increased 
pregnancy rates following ART and improved sperm motility at 3 months.  The tolerable upper 
intake level for zinc is 40 mg per day.   
Folic acid: The total daily dosage of folic acid will be 1000 mcg.  Commercial products include folic 
acid at doses of 60 to 5000 mcg.  Randomized controlled trials (including combination 
formulations and isolated) have included dosages ranging from 500 to 5000 mcg (56, 66, 67). 
These small trials have suggested that folic acid improves sperm concentration. The tolerable 
upper intake level for folic acid is 1000 mcg per day.   












RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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29 
 
Visits for subjects will be conducted on an individualized basis until hCG administration.  When 
a decision has been made to give hCG on the next day, a follow up monitoring visit on that day 
is unnecessary. 
• Transvaginal ultrasound examination for endometrial and follicular monitoring 
• Adverse effects and concomitant medications query 
hCG administration day: 
1. 10,000 IU in 1 cc diluent delivered IM 
2. Transvaginal ultrasound examination for endometrial and follicular monitoring is not 
necessary if one has been performed within 2 days. 
 
Criteria for hCG administration: 
• First occurrence of lead follicle reaching 20 mm (in average diameter in two 
dimensions), or 
• First occurrence of two lead follicles greater than 18 mm diameter (in average diameter 
in two dimensions), or 
The day after the lead follicle reaching 18 mm (in average diameter in two dimensions), 
or the day of detection of presumptive ovulation by ultrasound 
Criteria for withholding hCG: 
• If a leading follicle does not reach a mean diameter of 18 mm after 18 days of 
treatment, or 
• Endogenous LH surge happens [which can lead to premature luteinization], or 
• Increased risk for OHSS and/or high-order multiple gestational pregnancy exists when 
more than 4 growing follicles develop (mean diameter >18 mm), or 
 
*Protocol medication adjustment: 
1. If no ovulation or development of at least one follicle ≥ 18 mm in average diameter, then 
increase dosage in the subsequent cycle. 
2. If only one follicle ≥ 18 mm in average diameter, the dosage increase for subsequent 
cycles will be left to physician’s discretion. 
3. If more than four follicles are ≥ 18 mm in average diameter, dosage will be reduced in the 
subsequent cycle. 
 
*Cancellation criteria: Cycles will be cancelled if significant adverse reactions develop in 
response to administered medications, if criteria for withholding hCG administration are 
encountered, or per patient’s request. 
 
Insemination day visit: 


RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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30 
 
1. Each site will perform its standard sperm processing and intrauterine insemination 
procedure. 
2. Record parameters of semen analysis before and after sperm preparation. 
3. Record time of insemination. 
4. Instruct patient to check urine pregnancy test 2 weeks after insemination and call with 
results. 
5. Provide clomiphene citrate for next cycle.  Counsel not to take it until instructed to do so. 
 
Pregnancy test: Patient is to do a home pregnancy test 2 weeks after insemination using the 
urine home pregnancy tests provided. 
 
Four possible outcomes: 
A. No pregnancy on urine pregnancy test 
B. Positive urine pregnancy test- serum βhcg level returns <5 mIU/ml- no pregnancy 
C. Positive urine pregnancy test- serum βhcg level returns >5 mIU/ml, retest for rising level 
in 2 days- no pregnancy  
D. Positive urine pregnancy test- serum βhcg level returns >5 mIU/ml, retest for rising level 
in 2 days- pregnancy  
 
 
A. Negative Urine Pregnancy Test/No pregnancy: Repeat cycles until pregnancy occurs or male 
completes a total of 6 months of treatment. 
Criteria to initiate Cycles 2 or 3 (Day 3 +/- 2 days): 
1. Negative urine pregnancy test,  
2. Male still on treatment. 
 
Cycle 2 and 3 will be identical to Cycle 1, except that there will be no Baseline Ultrasound visit.  
When the subject contacts the site with the results of her urine pregnancy test or start of menses, 
she will be instructed by the site to start her clomiphene citrate.  She will then return to the site 
for Monitoring Visit 1 (see above).  
In women who report a positive urine pregnancy test, obtain serum βhcg level.   
 
B &C. Positive Urine Pregnancy Test (no pregnancy) 
Patient will have a serum βhcg level checked.  If >5 mIU/ml, return in 2 days to check for a rising 
level in serum βhCG; if the first level is <5 mIU/ml or if there is not a rising level, patient will 
initiate Cycles 2 or 3.   
 
D. Positive Urine Pregnancy Test (pregnancy): Biochemical pregnancy will be defined as βhCG >5 
units/ml 2 weeks after insemination followed by a rising level two days later 
 








50102;,35272&2/9






 COMET 
One aliquot of raw semen will be sent to a central laboratory for the COMET assay.  The comet 
assay is one of the simplest methods to measure sperm DNA damage by quantifying the single 
and double strand breaks.  The principle of the assay is that the sperm nuclear DNA is separated 
in an electric field based on charge and size, which is viewed with a fluorescent DNA-specific dye. 
The resulting images, which resemble comets with an intact head and tail, determine the extent 
of DNA damage based on the intensity of staining and morphology of the comet.  The COMET 
assay will be conducted on the study visit 1 sample (prior to treatment) and study visit 3 sample.
6.2
Compliance 
Compliance and cross-over will be assessed via two mechanisms: 1) pill counts and 2) 
measurement of Vitamin E (alpha-tocopherol), L-carnitine, and zinc (and, if possible, Vitamin C 
and selenium) in blood.  Compliance and cross-over will be assessed by these 2 mechanisms at 
study visits 2, 3, and 4 (corresponding to months 1, 3, and 6 of treatment).  At study visit 1 (month 
0 of treatment), a baseline measurement will be established. 
 Measurement of vitamin levels
A random sample of 10% of blood samples (as done in the SU.VI.MAX study (83)) obtained at 
study visits 2, 3, and 4 will be shipped to a laboratory such as the Clinical Pharmacology Analytical 
Services Laboratory (CPAS) in the Department of Experimental and Clinical Pharmacology in the 
College 
of 
Pharmacy 
at 
the 
University 
of 
Minnesota 
(http://www.pharmacy.umn.edu/cpas/services/index.htm).  All three vitamins will be measured 
using a LC-MS/MS method.  Internal standards are commercially available.  These samples will 
allow us to assess for compliance.  As placebos will also be samples, we will also be able to assess 
for cross-over.   
6.3
Dietary assessment
A previous observational study showed that a health-conscious diet is associated with a decrease 
in sperm DNA fragmentation, suggesting that natural antioxidants are beneficial to sperm (31).
However, another observational study using food frequency questionnaires failed to find an 
association between any antioxidant measure and DNA fragmentation, perhaps because the 
cohort was comprised of healthy volunteers (32).  Therefore, to assess for possible effect 
modification by baseline dietary composition and vitamin intake, we will assess these through a 
24-hour recall during the 1st study visit and a food frequency questionnaire at baseline.  
Secondary analysis could be conducted to examine the relationship between baseline dietary 
composition and vitamin intake and semen parameters and couple fecundability and fertility over 
the study period.  A second 24-hour recall will be obtained at the 3-month study visit to 
determine if there were differential changes in dietary composition among treatment groups.   
To measure food intake, we will use the validated, self-administered, web-based, 24-hour recall 
questionnaire, ASA24 and Diet History Questionnaire II.  The method allows for collection of 
detailed intake and portion sizes.  It does not affect what an individual chooses to eat on a given 
day, due to its retrospective data collection.  It is administered in close proximity to the intake 




RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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35 
 
day minimizing recall issues.  The ASA24 format and design is based on a modified version of the 
interviewer-administered Automated Multiple Pass Method (AMPM) developed by the US 
Department 
of 
Agriculture. 
 
The 
ASA24 
consists 
of 
a 
respondent 
web 
site 
(https://asa24.westat.com/) 
and 
a 
researcher 
website 
(https://asa24.westat.com/researchersite.html).  The respondent website guides the participant 
through the completion of a 24-hour recall for the previous day from midnight to midnight using 
a dynamic user interface.  Information and instructions on the ASA24 can be found at 
https://asa24.westat.com/assets-r/docs/ResearcherSite_Instructions.pdf and a demonstration 
at http://asa24demo.westat.com/.  The male participants will complete the ASA24 on the day of 
study visit 1 and study visit 3.  
The Diet History Questionnaire II (DHQ II) is a food frequency questionnaire (FFQ) developed at 
the Risk Factor Monitoring Branch. The DHQ II consists of a respondent website and a researcher 
website. The respondent website guides the participant through the completion of a 
questionnaire regarding portion size, usual intake, and dietary supplements over the past year. 
Information 
and 
instructions 
on 
the 
DHQ 
II 
can 
be 
found 
at 
http://appliedresearch.cancer.gov/dhq2/ 
and 
a 
demonstration 
at 
https://appliedresearch.cancer.gov/cgi-bin/dhq2.pl?module=2&method=1. In summary, the 
DHQ has been validated as a measure of frequency and nutrient assessment.  The full and 
extensive list of the 176 nutrients, dietary constituents, and food groups assessed with the DHQ 
is available on the website.  Both male and female participants will complete the DHQ II at 
screening.   
6.4 
Male urinary testing for environmental contaminants 
Urine samples will be obtained from male participants at the visit 1 for future assessment for 
common environmental contaminants such as Bisphenol-A (BPA).  Samples will be collected into 
BPA-free collection containers at the clinical site and transferred to BPA-free cryovials by study 
staff.  Samples will be stored frozen until shipped in batches to a central laboratory for analysis. 
6.5 
Stress biomarker testing 
A first morning (basal) salivary sample will be obtained from male and female participants using 
a salivary collection device.  Participants will be told to collect the sample immediately upon 
awakening before eating, drinking, smoking or brushing their teeth.  Samples from males will be 
collected around the time of study visit one and returned at the time of study visit one or by 
prepaid overnight shipping.  Females will collect their sample shortly after their screening visit 
and return the sample via prepaid overnight shipping.  Samples will be stored at -20°C until 
analysis.  Samples will be analyzed for stress biomarkers such as amylase and cortisol.  
Participation in this part of the study will be optional. 
6.6 
Male laboratory testing (central core laboratory) 
The core lab will analyze the blood samples from the males at study visit 1 (prior to treatment) 
for total testosterone, LH, FSH and Vitamin D25-OH.  They will also analyze the blood samples 
from the males at study visit 3 for Vitamin D25-OH. 


RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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36 
 
6.7 
Male sunscreen usage 
There is increasing concern that benzophenone (BP)-type ultraviolet filters, used in sunscreens, 
are absorbed by the skin and act as endocrine disruptors (84).  Sunscreen ingredients have been 
demonstrated in vivo2 and in vitro3 to act as endocrine disruptors:  either affecting estrogen 
(those 
containing 
PB-2 
[tetrahydroxybenzophenone] 
and 
BP-8 
[hihydroxy-4-
methoxybgenzophenonoe]) (85,87) while other UV filters (13 of 29 filters), disrupted 
progesterone’s effect on sperm calcium ion channels (86).  While not all UV filters have been 
associated with a reduction in male fertility, the SEBI (Sun Exposure and Behaviour Inventory) 
(88) questionnaire will be used to evaluate whether or not men using more sunscreen will 
experience less fecundity.  Future analysis of repository blood or urine samples may be used to 
more accurately specify which UV filters are responsible for less fecundity. 
Sunscreens with PABA block the specific sunlight spectrum responsible for cutaneous synthesis 
of vitamin D (89).   Since the MOXI preparation contains vitamin D, the frequency and amount of 
both sun exposure and sunscreen usage should be documented.   
6.8 
Quality of Life (QOL) Measures 
Mood, quality of life, and sexual function will be assessed at baseline in both males and females.  
Quality of life will be assessed by the Medical Outcomes Survey (PHQ-9) and Short Form 12 (SF-
12).  Female sexual function will be assessed by the Female Sexual Function Inventory (FSFI) along 
with the Female Sexual Distress Scale (FSDS).  This measure is considered the “gold standard” 
paper and pencil assessment of sexual function and has excellent psychometric properties.  Male 
sexual response will be assessed by the International Index of Erectile Function (IIEF), a 
multidimensional scale for assessment of erectile dysfunction.  The measure addresses the 
relevant domains of male sexual function (erectile function, orgasmic function, sexual desire, 
intercourse satisfaction, and overall satisfaction).  We will assess hypogonadal symptoms with 
the Androgen Deficiency and the Aging Male quantitative (qADAM) questionnaire and 
psychosexual function with the Psychosexual Daily Questionnaire (PDQ).  We will assess quality 
of life relating to infertility and treatment with the FertiQoL survey.  There may also be some 
impact on fertility and we will investigate this in our study.  We will use two simple scales to 
evaluate sleep, the STOP BANG questionnaire for sleep apnea, and the Epworth Sleepiness Scale. 
(See Appendices) 
6.9 
Early Pregnancy Ultrasound 
A transvaginal ultrasound (standard for first trimester imaging), will be scheduled, ideally 
between 6 2/7 and 7 2/7 weeks of gestation; no later than 9 6/7 weeks.  This ultrasound confirms 
estimated date of delivery, and in the case of loss, documents likely developmental stage at the 
time of the loss (e.g. empty gestational sac, fetal pole not heart rate, normal fetal pole).  Presence 
and size of gestational sac, presence and size of yolk sac, presence of fetal pole and crown-rump 
length, and presence of cardiac motion and heart rate will be recorded.  With minimal costs, 
ultrasounds achieve 2 study goals.  They serve as an incentive to subjects for participation and 
compliance with study protocols and they provide estimates of miscarriage and clinical 
pregnancy rates. 


RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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37 
 
6.10 Ascertainment of Pregnancy Outcomes 
Participants will be encouraged to report outcome (miscarriage, ectopic, abortion, live birth) and 
answer follow-up questions specific to that outcome (for miscarriage: date miscarriage identified 
and for live birth: date of delivery, gestational number, birth weight, gender, and obstetrical 
complications).   
6.11 Pregnancy Registry 
All subjects who deliver will be encouraged to participate in our Pregnancy Registry which 
currently provides infant follow up till age 3.  This is currently a separate protocol and we will 
also obtain separate informed consent for participation in this protocol.   
6.12 Biologic Repository  
We will use the RMN biorepository as a biological specimen’s bank at baseline prior to 
randomization in both females and males.  This Biorepository will serve a two-fold purpose.  First, 
it can serve as a repository to run additional serum assays for novel markers of infertility or 
treatment success that are discovered while the study is ongoing.  Second, it will serve as a source 
of samples for further studies including proteomics, metabolomics, etc.  We will collect whole 
blood, serum, and urine from female and male participants, if consented.  We will also collect 
semen from male partners, if consented.  Subjects will be able to opt in or opt out of these studies 
via separate signature on the consent form.  We will also store leftover serum samples for 
additional post hoc studies.  Study subjects will be separately consented to store and use their 
leftover serum samples from the study and will similarly be able to opt out.  Further details of 
specimen processing can be found in the Manual of Operations and Procedures. 
6.13 Central Core Laboratory 
Screening labs to determine eligibility will be run in the local RMN site labs. Given the variability 
of assays between labs, assays will be performed in a central lab at the Ligand Assay Core lab at 
the University of Virginia.  
 
 


RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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38 
 
7 Data Analysis 
7.1 
Internal Pilot 
We will be conducting an internal pilot study with a three-fold objective.  The objective of the 
internal pilot is 1) to determine the distribution of various types of semen abnormalities in the 
study population, 2) to examine the effect of our antioxidant formulation on male semen 
parameters and DNA integrity at 3 months of treatment compared to controls, and 3) to 
determine the feasibility of the proposed recruitment paradigm.   
The first 120 men enrolled in the MOXI trial will be included in the internal pilot.  The 120 men 
will complete the entire MOXI protocol.  Once the first 120 men enrolled in MOXI have completed 
study visit 3, the DCC will complete the data analysis for the internal pilot.  After data cleaning 
and transformations, if needed, semen parameter measures will be analyzed using a generalized 
linear mixed model (including random effects for site if necessary) or generalized linear model (if 
fixed effects for site are used).  Interaction terms will be used to determine the extent to which 
the change in semen parameter measures differs by type of baseline semen abnormality 
(oligospermia, asthenospermia, high DNA fragmentation), if there is evidence of effect 
modification, change estimates will be determined for type. 
If we assume that 50% of the males will have low motility (<40%) after taking into account 
potential dropouts and that the drop-outs will be randomly distributed, we should have 30 men 
in each group. Based on Fedder et al. we can assume that the percentage of sperm motility at 
the end of treatment in antioxidant group can be increased by 32% (SD20%) from basement and 
that in the placebo group it will be increased by 20 % (SD12%)(83). Furthermore, Khadem et al. 
(38) reported that DNA fragmentation decreased from 22.1±7.7% to 9.1±7.2% in antioxidant 
group (38).  Under these assumptions, or pilot phase will have 80% power to detect the 
differences suggested in the literature with α=0.05. 
Feasibility will be assessed by recruitment pace.  We anticipate that the pilot enrollment will be 
completed by 6 months starting from when all the sites have been initiated to start the trial.  Thus 
120 couples will be recruited over the 6 months.  The pilot goal assumes that recruitment pace 
will increase over the course of the entire study period.   
Assuming we fail to reject the null hypothesis that motility and DNA fragmentation percentage 
do not differ between the two treatment groups (antioxidant and placebo), the MOXI trial will 
stop enrolling subjects.  Enrolled couples will complete the study protocol.  Data analyses will be 
conducted for the primary and secondary outcomes for the primary study.  These results could 
be used to power a future study should point estimates suggest that male partner treatment with 
antioxidants increases live birth or pregnancy rates. 
 


RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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39 
 
Assuming 1) we reject the null hypothesis that motility and DNA fragmentation percentage do 
not differ between the two treatment groups (antioxidant and placebo) and 2) we determine 
that the study is feasible, the MOXI trial will continue until a total of 790 couples have been 
enrolled.  Since the primary outcome will not be analyzed for the pilot, it is not thought that 
adjustments in significance levels will be required for these analyses. 
7.2 
Primary and Secondary Outcomes 
The primary outcome is a live birth resulting from a pregnancy occurring within the 6 months of 
treatment.  Live birth is defined as a delivery of a live infant after 20-weeks gestation.  Secondary 
outcomes include pregnancy, defined by a positive home pregnancy test within the 6 months of 
treatment.  We will conduct an intent-to-treat analysis.  Cumulative incidence of live birth and 
pregnancy will be compared between those couples randomized to antioxidants and those 
couples randomized to placebo.  In addition, discrete-time hazard models will be used to 
compare time-to-pregnancy between groups.  Subsequent subgroup analyses will be conducted 
to assess for effect modification by type of baseline sperm abnormality.  All analyses will include 
fixed or random effect terms as needed to account for potential site effects. 
7.3 
Sample Size and Statistical Power 
For the power analysis, we assume live birth rates of 35% in the antioxidant group and 25% in 
the control group, and 17% drop-out (based on drop-out rate in prior RMN trials).  A 25% live 
birth rate was estimated, assuming 5% live birth rate in the first 3 months of timed intercourse 
and a 20% live birth rate in the 3 clomid/IUI cycles.  The 20% live birth rate is the live birth rate in 
AMIGOS participants receiving up to 3 cycles of clomid/IUI and female partner under the age of 
35.  Under these assumptions, a sample size of 395 per group will yield 80% power using a two-
sided chi square test at α=0.05 (Table 2).   
 
 
 


RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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40 
 
Table 2: Sample size estimates under a variety of assumptions 
 
 
For subgroup analyses, power is dependent on the distribution of the sperm abnormalities, the 
control live birth rate and the treatment effect difference (see Table 3). 
 
Table 3: Power for subgroup analyses 
Proportion 
affected (%) 
Total N for 
subgroup 
Control Group 
Pregnancy 
Proportion (%) 
Treatment 
Effect 
Difference (%) 
Alpha 
Power (%) 
70 
552 
20 
10 
0.05 
78 
60 
474 
20 
10 
0.05 
71 
50 
394 
20 
10 
0.05 
63 
40 
316 
20 
10 
0.05 
54 
30 
236 
20 
10 
0.05 
43 
70 
553 
20 
15 
0.05 
98 
60 
474 
20 
15 
0.05 
96 
50 
395 
20 
15 
0.05 
92 
40 
316 
20 
15 
0.05 
85 
30 
237 
20 
15 
0.05 
74 
70 
553 
25 
15 
0.05 
97 
Proportion (%) 
of live birth in 
placebo group 
Proportion (%) of 
live birth in 
antioxidant group 
Power 
(%) 
Number of 
patients per arm 
with 0% dropout 
Total number 
of patients with 
0% dropout 
Total number of 
patients with 
17% dropout 
20 
30 
80 
294 
588 
708 
20 
30 
90 
392 
784 
944 
25 
35 
80 
328 
656 
790 
25 
35 
90 
440 
880 
1060 
30 
40 
80 
356 
712 
858 
30 
40 
90 
477 
954 
1150 
20 
35 
80 
138 
276 
332 
20 
35 
90 
185 
370 
446 
25 
40 
80 
152 
304 
366 
25 
40 
90 
203 
406 
490 


RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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41 
 
60 
474 
25 
15 
0.05 
94 
50 
395 
25 
15 
0.05 
89 
40 
316 
25 
15 
0.05 
82 
30 
237 
25 
15 
0.05 
69 
 
 
 


RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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42 
 
8 Technical Aspects 
8.1 
Reporting Adverse Events 
All serious adverse events (SAEs) that occur from the start of study drug through thirty days after 
the last dose of study medication must be reported or if the patient is pregnant, 6 weeks 
following delivery.  A serious adverse event is defined as: fatal or immediately life-threatening; 
severely or permanently disabling; requiring or prolonging inpatient hospitalization; overdose 
(intentional or accidental); congenital anomaly; pregnancy loss after 20-weeks gestation; 
neonatal death up to 6 weeks after delivery; or, any event adversely affecting the study’s 
risk/benefit ratio.  Additionally, any event that, based on appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention to prevent one 
of the outcomes listed above is considered an SAE. 
If an SAE occurs and is thought to be related to the study medication, the study medication will 
be discontinued.  Twenty-four hour unblinding will be available through the web-based 
randomization system to break the randomization code for the individual patient if this is 
required by the PI for proper treatment of the patient. 
The site PI will report the SAE by completing and signing the Serious Adverse Event Report Form 
[available in the “Study Forms” section of the RMN members-only website], and then emailing 
the document in PDF format to rmn.dcc@mailman.yale.edu.  Subjects will be identified by study 
number only.  No other identifying information will be included on the form.  The site PI must 
determine and record on the SAE form whether the SAE is unanticipated or anticipated, and if it 
is related, possibly related, or unrelated to participation in the research.  
DCC staff will enter the SAE information in the central database.  The Safety Surveillance team, 
consisting of the DCC, NICHD research scientist and lead PI of the protocol, will analyze the SAE 
to determine if it meets the criteria listed in the OHRP 45CFR46 and/or FDA 21CFR312.32 & 
3.14.80. 
These determinations will dictate timeframes for sites’ submission to the DCC, and the DCC’s 
submission to the DSMB: 
Upon receiving notification of an SAE, the DSMB will review it via a closed-session email or 
conference-call discussion arranged by the NICHD RMN Committee Coordinator (RMN CC).  The 
DSMB will send a report to the RMN CC within two weeks; reports for life-threatening SAEs will 
be submitted in one week.  The DSMB report will include: statement indicating what related 
information the DSMB reviewed; the review date; the DSMB’s assessment of the information 
reviewed; and the DSMB’s recommendation, if any, for the DCC.   


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Table 4: Types of Serious Adverse Events and Their Reporting Requirements 
TYPE 
SITE 
DCC 
Unanticipated and 
related/possibly related SAE, 
fatal or life-threatening 
Report to DCC within 1 business 
day of discovery 
Notify DSMB by end of next 
business day of receiving site 
report 
Other unanticipated and 
related/possibly related SAE 
Report to DCC within 1 business 
day of discovery 
Notify DSMB 5 business days of 
receiving site report 
Anticipated and related/possibly 
related SAE 
Report to DCC within 5 business 
days of discovery 
Notify DSMB 5 business days of 
receiving site report 
Unrelated SAE (anticipated or 
unanticipated 
Report to DCC within 10 
business days (no more than 3 
weeks) of discovery 
Notify DSMB within 10 business 
days (no more than 3 weeks) of 
receiving site report 
 
The RMN CC will then forward the DSMB report to the DCC for the record and appropriate 
distribution.  The DCC will forward reportable events to all RMN investigators, NICHD, and the 
FDA on behalf of the NICHD if the protocol is under IND.  The NICHD Project Scientist will review, 
sign, and return the IND safety report to the DCC within 2 business days, and will follow up with 
the site PI and DCC on the SAE until it is resolved.  The Protocol PI will evaluate the frequency and 
severity of the SAEs and determine if modifications to the protocol and consent form are 
required.  Site PIs will report the SAE to their site IRB according to local IRB requirements.  For 
more information, please see the RMN/DSMB Communication Procedure.   
Adverse events deemed non-serious will also be recorded throughout study participation from 
the start of study drug through one week after the last dose of study medication, and reported 
to the DCC.  If an anticipated serious adverse event occurs at a frequency greater than expected, 
the DCC will notify the DSMB by the end of the next business day of discovery and follow the 
procedures for reporting serious and unanticipated and related adverse events.  The DCC will 
forward relevant safety information to the DSMB.  If an adverse event not initially determined to 
be reportable to the FDA under 21CFR312.32 is so reportable, the DCC will report the adverse 
event to the FDA within 15 calendar days after the determination is made.  A flow chart for SAEs 
follows: 


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Figure 2: SAE flowchart 
 


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8.2
Data Collection and Management (including quality assurance/compliance measures) 
 Data Entry and Forms 
Case Report Forms (CRFs) will be developed as the protocol is developed.  They will also be 
implemented in a Web-based Oracle data management system.  The Web data entry forms will 
be similar to the paper forms with the same questions.  However, the Web forms usually have 
more flexibility than the paper forms, such as pull-down menus.   
 Features of Data Management System 
Features of the data management system include study definition; different types of data entry 
(including double entries and complete audit trail); forms control; query capture, reporting, and 
resolution; dictionary coding of Adverse Events (AEs) and medical terms; and clinical data review 
Tools; and prepares data and CRF images to FDA e-Submission Standards.  The end-
user/reporting/ad hoc query front-end uses a standard Web browser, so that data entry and 
browsing can be done from any machine with Internet access, without purchase of special 
software.  Login to this system will be through a secured Web server with the security under the 
protection of Yale Center for Clinical Investigations.  
 Data Security 
A data server and Web server will be used.  The data server will be managed by YNHH IT center 
and the website two servers will be separated and managed by Forte Research Systems.  The 
web server will be accessible through a secured login, but the data server can only be accessed 
through the web server.  For security purposes, no login to the data server will be permitted, and 
access to the back end is limited to authorized individuals.  PHI, including patient names and 
addresses, will be locked and secured at the participating sites, and data will be linked through a 
unique identification number, which will be assigned after a patient is screened or enrolled. 
Access will be limited to authorized individuals (21 CFR 11.10(d)).  Each user of the system will 
have an individual account.  The user will log into the account at the beginning of a data entry 
session, input information (include changes) on the electronic record, and log out at the 
completion of the data entry session.  The system will be designed to limit the number of log-in 
attempts and record unauthorized access log-in attempts.  Individuals will work only under their 
own access key, and not share these with others.  The system will not allow an individual to log 
onto the system to provide another person access to the system.  Access key Users will be asked 
to change their passwords at established intervals commensurate with a documented risk 
assessment.  This plan has been adapted from the guidelines for computerized systems used in 
clinical investigations established by the U.S. Department of Health and Human Services Food 
and Drug Administration.   
 Data Quality Control 
Competency to perform procedure/tests in the protocol 
The site PI will be responsible for ensuring that study related tests are performed by competent 
personnel.  The criteria for determination of competency may vary between sites in the study. 


RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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Attempts will be made to standardize operating procedures whenever possible to minimize inter-
site variation. 
Quality Control Steps 
Quality control of data will be handled on three different levels.  The first level is the real-time 
logical and range checking built into the web-based data entry system.  The research coordinators 
and data entry clerks at the participating sites are required to ensure the data accuracy as the 
first defense.  The second is the remote data monitoring and validation that is the primary 
responsibility of the data manager and programmer at the DCC.  The data manager will conduct 
monthly comprehensive data checks (SAS programs run on a regular basis as a systematic search 
for common errors and omissions), as well as regular manual checks (within the database 
system).  Manual checks will identify more complicated and less common errors.  The data 
manager will query sites until each irregularity is resolved.  The third level of quality control will 
be the site visits, where data in our database will be compared against source documents. 
Identified errors will be resolved between our center and clinical sites.  The visits will assure data 
quality and patient protection. 
An audit trail will be added as another security measure.  This will ensure that only authorized 
additions, deletions, or alterations of information in the electronic record have occurred and 
allows a means to reconstruct significant details about study conduct and source data collection 
necessary to verify the quality and integrity of data.  Computer generated, time-stamped audit 
trails will be implemented for tracking changes to electronic source documentation. 
Controls will be established to ensure that the system’s date and time are correct.  This is a multi-
center clinical trial and will be located in different time zones.  System documentation will explain 
time zone references as well as zone acronyms.  Dates and times will include the year, month, 
day, hour, and minute to the date provided by international standard-setting agencies (e.g. US 
National Institute of Standards and Technology).  The ability to change the date or time will be 
limited to authorized personnel, and such personnel will be notified if a system date or time 
discrepancy is detected.   
In addition to internal safeguards built into the computerized system, external safeguards will be 
implemented.  Data will be stored at the Data Coordination Center.  Records will be regularly 
backed up, and record logs maintained to prevent a catastrophic loss and ensure the quality and 
integrity of the data.  This plan has been adapted from the guidelines for computerized systems 
used in clinical investigations established by the U.S Department of Health and Human Services 
Food and Drug Administration.   
8.3 
Study Monitoring 
A monitoring plan that satisfies ICH/GCP guidelines for monitoring clinical trials will be used.  A 
Project Manager from the DCC will lead this effort, and report findings to the DCC PI.  The Project 
Manager will have full knowledge of the study protocol, Manuals of Procedures, and is familiar 
with the database system and is trained to review patient charts.  The Project Manager will be 
responsible for training and supervising other personnel.  


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Once personnel at participating site are trained to recruit patients, the Project Manager will be 
sent to the site to help initiate the study according to the study protocol, and to ensure that the 
clinical site meets the scientific, clinical, and regulatory requirements.  For example, the Project 
Manager will review all signed and dated forms required by the FDA (such as financial disclosure 
forms), the curriculum vitae and certifications of the investigators and personnel, CRF training, 
and the written IRB approval of the protocol and consent form.   
The on-site monitor will return to the clinical site after a defined number of patients are recruited 
(can be as early as the recruitment of the 2nd patient) or a certain time period has passed, 
depending on the duration of the protocol execution.  The schedule of visits will be discussed and 
agreed in the Steering Committee and we anticipate that the Project Manager will visit each 
participating site at least once. 
During the site visit, the clinical sites should provide to the monitor a space and access to all 
relevant records including medical records and regulatory binders, and there would be 
immediate verbal feedback provided to the site after original source documents are compared 
to entries in the CRF.  The clinical sites must agree to cooperate with the monitor to ensure that 
any problems detected in the course of these monitoring visits are resolved.  The on-site monitor 
will conduct an audit of a random sample of entered information against the source documents, 
a review of all regulatory documents, a review of all informed consents, and a review of all 
pharmacy logs.  The clinical site PI and coordinator should be available to meet the monitor 
during the visit.  The monitor will review electronic data from all sites, providing a method for 
identifying systematic errors or problems.  
To assure Good Clinical/Laboratory Practice, the monitor will control adherence to the protocol 
at the clinical sites and evaluate the competence of the personnel at the clinical sites including 
the ability to obtain written informed consents and record data correctly.  The monitor will 
inform the DCC PI, the Steering Committee, and NICHD regarding problems relating to facilities, 
technical equipment, or medical staff.  A thorough written report will follow each site-visit and 
will include a detailed itemization of discrepancies and items requiring follow-up or 
reconciliation.  This report will also be forwarded to the NICHD Research Scientist for review. The 
monitor will be responsible for maintaining regular contacts between the investigators in the 
clinical sites and the RMN.  When the study ends, the monitor will also visit the clinical site to 
provide assistance for close-out. 
8.4 
Data and Safety Monitoring Board 
The NICHD has established an independent DSMB to review and interpret data generated from 
RMN studies and to review protocols prior to their implementation.  Its primary objectives are to 
ensure the safety of study subjects, the integrity of the research data and to provide NICHD with 
advice on the ethical and safe progression of studies conducted in the RMN.  The DSMB advises 
on research design issues, data quality and analysis, and research participant protections for each 
prospective and on-going study.  A copy of the DSMB Charter can be found in the appendix. 
The DSMB members are appointed by the Director of NICHD in accordance with established NIH 
and NICHD policies.  DSMB members are experts in and represent the following fields: 


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biostatistics, epidemiology, infertility, gynecology, andrology and ethics.  The NICHD Committee 
Coordinator is responsible for scheduling regular committee meetings, recording all meeting 
minutes and summarizing the committee recommendations for the Steering Committee and 
NICHD.  Steering Committee members are prohibited from attending closed sessions of the 
DSMB.  Open sessions may be attended by Steering Committee members or Chairperson when 
requested by NICHD and the DSMB.   
The DSMB has quarterly teleconferences to review Network randomized trial protocols with 
respect to ethical and safety standards, monitors the safety of on-going clinical trials, monitors 
the integrity of the data with respect to original study design, and provides advice on study 
conduct.  The DSMB periodically monitors data quality, including protocol adherence and adverse 
events.  As outlined in the protocols, the DSMB will conduct interim evaluations of the data.  It 
may recommend protocol modifications based on concern for subject welfare and scientific 
integrity. 
8.5
Reporting 
Administrative Reports will be prepared by the DCC - which include monthly and quarterly 
reports on accrual, data quality and study compliance - and presented to the Steering Committee 
and DSMB.  Statistical reports include reports to the SC, DSMB and AB from the data analysis, 
and special reports for scientific manuscripts.  
Statistical Reports will be generated in SAS.  Reports are provided for DSMB reviews, and for final 
analysis of study results in preparation for scientific publications.  The content of the interim 
reports will be very complete, and will serve as the template for the final report of each study, 
which in turn will form the basis of the publication of the results.  Our proposed reports to the 
DSMB would include the following: a protocol description and history; accrual rates; site 
performance in terms of accrual; eligibility; protocol violations; data accuracy and minority 
representation; patient characteristics by treatment and site; and the rate of adverse 
experiences. 
8.6
Obligation of the Investigator 
 IRB Review 
The site PI is responsible for submitting the approved protocol and consent form to the IRB for 
review.  The IRB must approve all aspects of the study as detailed in the protocol, including the 
patient informed consent form. It is anticipated that there will be minor site-specific changes in 
the consent form.  The IRB must periodically review the status of the study at appropriate 
intervals not exceeding one year. The site PI will also be responsible for submitting revisions to 
the protocol to the IRB, as directed by the DCC, and promptly communicating serious adverse 
events that result during the study, to both the local IRB and the DCC. After the approval, the 
informed consent and IRB approval (or amendment) letters must be forwarded to the DCC. 
 Maintenance/Retention of site records 
In order to comply with Good Clinical Practice (GCP) requirements, the investigators must 
maintain the master patient log that identifies all patients entered into the study for a period of 


RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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49 
 
two years after the study ends so that the subjects can be identified by audit.  The PI must 
maintain adequate records pertaining to subjects’ files and other source data for a minimum of 
5 years after completion of the study. 
8.7 
Regulatory Requirements 
The DCC will work with NICHD staff by providing them with clinical study data, reports, and other 
support as required for AE Reporting and IND submissions. The Project Managers will work with 
NICHD colleagues in meeting all regulatory requirements including compliance with ICH and 
HIPAA requirements, FDA code for federal regulations (Title 21), and IND applications. For 
example, the DCC Project Managers will register this clinical trial in a timely manner with 
ClinicalTrials.gov via a web based data entry system called the Protocol Registration System (PRS). 
8.8 
Protocol Amendments 
Once the protocol is approved by the Steering Committee, it is then reviewed by an Advisory 
Board and a DSMB.  After all approvals, the DCC will finalize the protocol document that serves 
as the agreement among all members of the Network. In the meantime, because the DCC 
administers all patient care costs for the RMN, the DCC will promptly issue subcontracts to the 
participating sites based on the cost agreements made by the Steering Committee and NICHD.  
After the protocols are approved by the RMN and the Steering Committee decides that changes 
are necessary for scientific or clinical reasons, the DCC will facilitate the procedure in a timely 
and diligent fashion.  The RMN investigators and key personnel will participate in 
teleconferences and meetings, discuss, vote, and document circumstance and rationales for 
the changes as well as the implementation procedure for the changes.  These include revising 
study hypotheses, designs, sample sizes, data entry forms, and appropriate statistical 
analyses. Once the amendments are finalized and agreed to by the RMN, they will be 
submitted to the IRB and DSMB for review and approval. 
 
 
 


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8.9 
Timeline  
Table 5: Timeline for MOXI 
 
 
Study Activities 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
J-M A-J J-S 0-D J-M A-J J-S 0-D J-M A-J J-S 0-D J-M A-J J-S 0-D J-M A-J J-S 0-D 
IND exemption 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Formulate, test, package antioxidant and 
placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Finalize protocol, IRB revisions, interview 
modifications  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Active enrollment of participants 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment of participants 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Pregnancy Ultrasound 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Determination of Pregnancy Outcome  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Record Abstraction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clean and compile data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analyze data (begin with clinical 
fecundability) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prepare and disseminate results 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9 RMN Publications Policy 
The publications policy proposes guidelines for publications that originate from our collaborative 
Reproductive Medicine Network.  Decisions concerning publications shall be determined by 
consensus (majority vote) of the collaborating Principal Investigators (or designees) noted below 
as the "Network."  This policy is designed to promote prompt, exact, quality publications and 
presentations of Network studies with appropriate academic recognition of those with significant 
contributions.  Protocols are classified into three types: ‘Main Study’ (which may include major 
and minor publications), “Ancillary Study’, and ‘Pilot Study’.  Additionally, there may be 
publications from concepts or ideas generated by the RMN (“Related Publications”) or from other 
groups utilizing RMN data and/or specimens, known as “Outside Studies” (those utilizing data 
and/or specimens from the RMN studies).  Abstract submissions to national meetings will also 
follow the publications policy below.  The progress of publications (including presentations) will 
be a standing agenda note on all teleconferences and meetings.  The Steering Committee will 
make the final decision regarding disputes with respect to analysis request approval, 
prioritization, presentation, authorship and/or manuscript submission. 
9.1
Main Study 
A Main Study is a Network study designed prospectively by an investigator independent of other 
studies.  Generally, that investigator becomes Lead Investigator of the protocol and Chair of the 
Protocol Subcommittee.  At the end of each Main Study, a primary analysis resulting in the 
primary manuscript and a number of secondary analyses is produced based on the research 
questions stated in the protocol.  The Protocol Subcommittee Chair is the primary author of the 
primary analysis.  A Main Study can generate major (related to the major hypotheses) and minor 
publications (relating to secondary hypotheses). 
 Major Publications  
A major publication is defined as one reporting results of the major hypotheses tested.  (For 
example: Does hMG/IUI increase cyclic fecundity in couples with unexplained or male factor 
infertility?) 
a. Authorship 
Publications will include the names of investigators from each RMU and the DCC rather than 
merely identify the “Reproductive Medicine Network”.  Each RMU and the DCC will have up 
to two authors per publication, ordinarily the PI and the Co-PI, but this may at times involve 
another investigator who has contributed to the study at his/her site, in lieu of the PI or Co-PI.  
The Principal Investigator at each RMU will be responsible for submitting the names of the 
two authors from that unit and designating them as either the primary and secondary authors 
of the unit.  No more than 2 authors may represent a RMN site.  An ancillary site (such as a 
SCCPIR) may only have 1 investigator.  The Steering Committee Chair and NICHD Project 
Scientist will be authors.  Occasionally, additional authors, both within and outside the RMN 


RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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may be appropriate.  In these cases, the final decision will be by Network consensus (majority 
vote of the Steering Committee required).   
For the purpose of authorship, only one person from each site owns the primary PI status.  
This “PI” status is determined by the duration of the time from the start to end date of the site 
award.  It is determined by whoever has served longer.  There is NO automatic authorship for 
other PIs (new or old). They will be treated as any other RMN investigators, and their 
authorship would be resolved on a case-by-case basis per the current policy (i.e. based on the 
contribution to specific manuscripts and recommended by the first author and/or writing 
group).  The general order of the authorship is as follows: Group A (the protocol lead PI and 
site PIs), Group B (important and long term contributors such as some additional site PIs, 
CREST PIs, DCC second author, core lab author, some co-Investigators), Group C (nominated 
ad hoc co-authors such as some additional site PIs, DCC third author, and others), Group D (SC 
Chair, NICHD Project Scientist, and DCC PI), and finally the RMN. 
b. First Author 
The lead investigator initiating the protocol, chairing the Protocol Subcommittee will be the 
first author.  The first author will always be expected to prepare the initial draft of the 
manuscript, after receiving approval from the Network to proceed.  The author will prepare 
the first draft of the manuscript in a timely fashion after receiving all the relevant data analyses 
from the DCC.  The primary author will circulate the final draft to all authors prior to 
submission, with a timely turnaround of comments from other authors expected.  Final 
decision of the manuscript content will be determined by the Protocol Subcommittee.  In the 
event that the initiating protocol investigator declines first authorship or fails to meet the 
timeline determined by the Steering Committee (as determined by majority vote) and 
monitored monthly, the next RMU investigator in the rank order of authors (described below) 
will be the first author. 
c. Authorship Order 
All authorships are expected to meet reasonable criteria as set forth by the International 
Committee of Medical Journal Editors.  (Uniform requirements for manuscripts submitted to 
biomedical journals: http://www.icmje.org.  Updated February 2006.  Accessed April 4, 2007.) 
The overall authorship order will be 1) the primary author, 2) RMU investigators, additional 
outside investigators with a limit of one author per site (e.g. SCCPIR investigators if applicable), 
followed by the Steering Committee Chair, NIH Project Scientist, and then the authors of the 
DCC. 


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Table 6: RMN Publication Authorship 
Authorship Order 
Category 
Description 
1 
Lead Investigator of the Protocol (N = 1) 
2 
Primary RMN Investigators of the Protocol (N = 6); 
DCC Investigator (N = 1) 
3 
Outside Investigators (i.e. Primary Investigator of 
SCCPIR sites) (N = to be determined) 
4 
Additional Investigators (by Steering Committee 
vote) (N = to be determined) 
5 
Secondary RMN Investigators (N = 7) 
6 
Steering Committee Chair (N = 1) 
7 
NIH Project Scientist (N = 1) 
8 
DCC PI (N = 1)  
9 
“for the NICHD Reproductive Medicine Network” 
 
Table 7: Authorship Order of the RMUs and Outside Sites 
Investigative 
Sites 
# Subjects 
Rank 
Accuracy 
Rank 
Total Rank 
Authorship 
Order 
A 
1 
4 
5 
3 
B 
2 
7 
9 
6 
C 
3 
1 
4 
2 
D 
4 
2 
6 
4 
E 
5 
3 
8 
5 
F 
6 
5 
11 
7 
 


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It is anticipated that there will be up to 18-25 authors per major manuscript.  The authorship 
order of the RMUs and outside sites will be based upon subject recruitment, data accuracy 
and promptness of data report according to the chart below:  
Data accuracy will be ranked according to the rate of missing or false data entries/randomized 
subjects at each site.  Inquiries that show data was accurately entered will not count against 
this rate of data inaccuracy.  Each site’s PI will be responsible for documenting the 
contributions to the study of that site’s authors.  In the event the journal editor requires fewer 
authors even after written documentation of the authors’ contribution has been provided, the 
Steering Committee will vote on the authorship order which will include at a minimum the 
Lead Investigator and PI of the DCC (or his/her designee) in the positions listed above with the 
authorship order ending with the footnoted statement “for the Reproductive Medicine 
Network”.  The other authors will be referenced in the footnote and listed in the title page. 
d.Acknowledgement Section   
The acknowledgement section will include other investigators and study personnel who 
contributed substantially to the study by site, as well as members of the Advisory Board and 
the Data and Safety Monitoring Board.  The designation will list the initials of the individuals 
followed by their highest degree (e.g. C. L. Gnatuk, J.A. Ober, R.N., etc.).   
Significant contributions include but are not limited to protocol review, initiation and 
participation at each site, subject recruitment and enrollment, study conduct, data analysis, 
and preparation of the manuscript.   
 Minor Publications  
Minor studies are defined as those in which the hypotheses would not be the main elements of 
Network studies, but in which the study data base would be utilized to test secondary 
hypotheses.  (One example would be testing whether metformin use spares the dose of 
clomiphene resulting in lower dose needs.)  Ideas for "minor studies" will, in general, be proposed 
by a single individual, who would direct all efforts leading to publication and representation.  The 
results from minor studies would be handled similarly to those from major studies.  The 
“Protocol” is defined as the Concept Protocol/study design of the hypothesis resulting in the 
publication. 
Authorship will follow the Major Publications guidelines above with the exception that the 
individual leading the minor study would be the first author, followed by the ranked primary RMN 
investigators involved in developing the Concept Protocol.  The Lead Investigator of the minor 
publication can propose additional investigators who contributed to the study, whose inclusion 
in the authorship will be voted on by the Steering Committee (majority vote of SC required for 
inclusion in authorship).  Centers may wish to withdraw inclusion from authorship of publications 


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of minor studies in which only data are contributed, and this will be the decision of the individual 
site (RMU) PI. 
9.2
Ancillary Study  
An Ancillary Study is an observational study, conducted as a supplement to a Main Study.  By 
definition, an Ancillary Study involves all or a subset of patients enrolled in a Main Study.  An 
Ancillary Study does not involve any additional participants.  To be defined as an Ancillary Study, 
there must be a need for collection of additional data not already collected in the Main Study.  
An Ancillary Study may also be designed by another Network investigator, who would serve as 
the lead investigator and primary author of the paper.  Ancillary Studies may be a “single-center” 
or “multi-center”.   
A “single-center” Ancillary Study is a study in which all data are collected, stored and analyzed at 
a single center.  The center bears the additional cost of such a study.  The study requires approval 
of the Main Study Protocol Subcommittee and the Steering Committee.  The center conducting 
the study is responsible for the analysis and reporting of the results.  Abstracts and manuscripts 
resulting from data from the single-center Ancillary Study are not subject to the RMN Publications 
Policies. 
A “multi-center” Ancillary Study is defined as one for which data or material (such as specimens) 
are collected at more than one center, or additional funds for conduct of the study are provided 
by the NICHD RMN and the DCC provides data analysis.  Multi-center Ancillary Studies require 
the approval of the Main Study Protocol Subcommittee and the Steering Committee. 
Authorship will be as per Major Publications above with the exception that the individual leading 
the Ancillary Study and writing the paper would be the first author, followed by ranked RMN 
primary investigators, etc.  A center not participating in the Ancillary Study would not receive 
authorship unless by majority vote of the Steering Committee. 
 Publication Policy on Ancillary Papers 
Authorship 
1. RMN will be included as the group author and the acknowledgement will define the entire 
RMN roster as provided by all PIs. 
2. The SC Chair, the NICHD Project Scientist, and all PIs will be co-authors upfront. The order 
will be recommended by the lead author(s). 
3. Based 
on 
the 
ICJME 
statement 
for 
authorship 
(http://www.icmje.org/ethical_1author.html), 
anyone 
who 
makes 
additional 
contributions that are documented and substantive will be co-authors.  Correcting typos 
and making grammar suggestions may be below the threshold. 
4. The responsibilities of the lead authors and the DCC: 


RMN MOXI PROTOCOL V. 4.0 
 
 
 
 
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a) If the first and corresponding authorships are offered to a fellow and the PI at a site, 
this team will recommend the order of the others. The DCC prepares the data for a 
specific manuscript with a note from the SC that the data should not be used for 
‘mining’ other than answering the predefined questions. The site PI is responsible 
for the appropriate conduct of the analysis. 
b) The lead author or shared lead authors (at most two) from an RMN or CREST site is 
given the first choice of one authorship position and the DCC PI makes the second 
choice. These authors recommend the order of the others. The DCC will assist in the 
concepts, data preparation, data analysis, and manuscript section writing. If the lead 
author is not a site PI, the PI plays an administrative and logistic role to ensure that 
the lead author, whether within the institution, an affiliated CREST site or any other 
collaborating center, meets the timelines and expectations expressed below, and in 
return will be offered the second author, or the one preceding the DCC senior 
author position. 
 
Timeline and expectations 
1. The DCC prepares the data set within one month upon receiving the proper specification 
of the variables and cohort(s), assuming that the data exist in the database.  
2. Time from receipt of primary data to first draft is not expected to exceed 3 months.  Time 
from first draft to submitted manuscript is not expected to exceed 3 months.   
3. Co-authors are expected to return comments and edits on manuscript drafts within two 
weeks of the request unless otherwise stated.  Failure to respond within this time frame 
will lead to the assumption that the co-author fully approves the draft and has no 
comments or corrections.   
4. The lead author(s) will be responsible for updating the progress of manuscripts at his/her 
site (and any CREST sites affiliated with that RMN site) on the Publication Subcommittee 
conference calls (which will replace Recruitment Subcommittee conference calls) to 
ensure that reasonable progress is occurring. The Publication Subcommittee can vote to 
change the authorship if the progress remains slow (e.g., exceeding the timeline 
expressed above) after two warnings. 
9.3 
Pilot Study 
A Pilot Study is a preliminary study that generates data to help in the design of a Main Study and 
is the responsibility of the Main Study Protocol Subcommittee.  The DCC collaborates with the 
Protocol Committee to complete the analysis, which may or may not generate an abstract for 
presentation and/or a manuscript for publication.  The DCC writes a Final Report if there is 
sufficient data to justify one.  It is not expected that there will be any secondary analyses resulting 
from a Pilot Study.  


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9.4 
Related Publications 
A related publication is one that has had significant input from members of the RMN Steering 
Committee at formal meetings in terms of study significance and design.  It is distinct from an 
ancillary publication in that a related publication reports on a study, concept or new methodology 
that has not been subjected to formal DSMB review and approval. Generally, “Related 
Publications” will arise from ideas and studies discussed with the Steering Committee, but not 
voted upon to become formal protocols.  
The investigator who initiates, conducts and writes the study, and those whom he/she names 
will be the sole authors. The authors should acknowledge the contribution of the NICHD 
Reproductive Medicine Network in the author line of the publication according to the format of 
the journal.  
9.5 
Outside Studies 
Outside studies will result from the sharing of intellectual property, data and/or specimens with 
investigators whose protocols have been approved by the Steering Committee, and who comply 
with all components of those policies.  All publications will acknowledge the assistance of the 
NICHD, the RMN, and the Protocol Subcommittee in making the database available on behalf of 
the project.  In addition, however, a disclaimer will need to be included stating, “The contents of 
this report represent the views of the authors and do not represent the views of the NICHD 
Reproductive Medicine Network.”  The authors will be requested to cc the submitted manuscript 
to the NICHD program official to ensure compliance.  These policies apply to both Network 
centers and outside centers. 
9.6 
Presentations   
Network data should be presented before national organizations by the Lead Investigators of 
Main Studies, Ancillary, and Pilot studies.  Organizations that might be appropriate include the 
American Fertility Society, the Society for Gynecologic Investigation, the American College of 
Obstetricians and Gynecologists, the American Urology Society and other urology or andrology 
societies.  All presentations will be approved by the Publications and Presentations Committee.  
Once data are published in at least abstract form, all members of the Network can cite them 
publicly in lectures.  
However, investigators should avoid citing specific numbers in review articles and chapters, for 
this could jeopardize peer review publication.  Authorship, First Author, and Author Order are as 
described for Major Publications, and if there is an authorship limit to the abstract, we will follow 
the plan above under Major Publications.  Oral and poster presentations, including those 
resulting from secondary analyses at professional societies, must list all authors and participating 
institutions.  In addition, they must include both the NICHD RMN logo and NIH Department of 
Health and Human Services logos that can be found on the Network web site.  


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9.7 
Timelines 
After conclusion of each protocol, the initiating investigator, designated as first author, will 
consult with the DCC for data analysis and conclusions.  The investigator will draft an abstract for 
distribution to the Network and discussion at the next teleconference or Steering Committee 
meeting.  This should be completed within two months of study completion.  Presentation of 
such abstract may be discussed at this time. 
The first author will prepare a draft manuscript within 3 months of data analysis for Network 
distribution.  After incorporating network comments, discussion at the next Steering Committee 
meeting should allow preparation for publication to ensue in the following 3 months, such that 
submission will be possible 6 months after data analysis is complete. 
9.8 
NICHD Clearance 
Prior to submitting an abstract for presentation or publication for journal review, the document 
should be sent to the Project Scientist for submission for NICHD Clearance. 
 
 
 
 
 
 
 


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Silver EW. Effect of antioxidant intake on sperm chromatin stability in healthy 
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Ciftci H, Verit A, Savas M, Yeni E, Erel O. Effects of N-acetylcysteine on semen 
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Omu AE, Al-Azemi MK, Kehinde EO, Anim JT, Oriowo MA, Mathew TC. Indications of the 
mechanisms involved in improved sperm parameters by zinc therapy. Med Princ Pract 
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Greco E. Reduction of the incidence of sperm DNA fragmentation by oral antioxidant 
treatment. Journal of andrology 2005;26:349-53. 
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damage impairs human fertility. The Danish First Pregnancy Planner Study Team. Fertil Steril 
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Zini A. Reactive oxygen species in semen of infertile patients: levels of superoxide 
dismutase- and catalase-like activities in seminal plasma and spermatozoa. International 
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sperm DNA fragmentation on miscarriage rates: a systematic review and meta-analysis. Human 
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Showell MG, Brown J, Yazdani A, Stankiewicz MT, Hart RJ. Antioxidants for male 
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blind randomized placebo cross-over controlled trial using the antioxidant vitamin E to treat 
reactive oxygen species associated male infertility. Fertil Steril 1995;64:825-31. 
46. 
Suleiman SA, Ali ME, Zaki ZM, el-Malik EM, Nasr MA. Lipid peroxidation and human 
sperm motility: protective role of vitamin E. J Androl 1996;17:530-7. 


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47. 
Omu AE, Dashti H, Al-Othman S. Treatment of asthenozoospermia with zinc sulphate: 
andrological, immunological and obstetric outcome. Eur J Obstet Gynecol Reprod Biol 
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2003;79:292-300. 
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Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap S et al. Advancing 
paternal age and autism. Arch Gen Psychiatry 2006;63:1026-32. 
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Sipos A, Rasmussen F, Harrison G, Tynelius P, Lewis G, Leon DA et al. Paternal age and 
schizophrenia: a population based cohort study. BMJ 2004;329:1070. 
51. 
Zhu JL, Madsen KM, Vestergaard M, Olesen AV, Basso O, Olsen J. Paternal age and 
congenital malformations. Hum Reprod 2005;20:3173-7. 
52. 
Hammiche F, Laven JSE, Boxmeer JC, Dohle GR, Steegers EAP, Steegers-Theunissen RPM. 
Sperm Quality Decline Among Men Below 60 Years of Age Undergoing IVF or ICSI Treatment. J 
Androl 2011;32:70-6. 
53. 
Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HWG, Behre HM et al. World 
Health Organization reference values for human semen characteristics. Human Reproduction 
Update 2010;16:231-45. 
54. 
Bailey RL, Gahche JJ, Lentino CV, Dwyer JT, Engel JS, Thomas PR et al. Dietary 
supplement use in the United States, 2003-2006. J Nutr 2011;141:261-6. 
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multivitamin/mineral supplements and chronic disease prevention. Am J Clin Nutr 
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effect of an antioxidant (Menevit) on pregnancy outcome during IVF-ICSI treatment. Aust N Z J 
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Galatioto GP, G.L. G, Angelozzi G, Sacchetti A, Innominato PF, Pace Gea. May antioxidant 
therapy improve sperm parameters of men with persistent oligospermia after retrograde 
embolization for varicocele? World Journal of Urology 2008;26:97-102. 
58. 
Li Z, Chen GW, Shang XJ, Bai WJ, Han YF, Chen B et al. [A controlled randomized trial of 
the use of combined L-carnitine and acetyl-L-carnitine treatment in men with 
oligoasthenozoospermia]. Zhonghua Nan Ke Xue 2005;11:761-4. 
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Keskes-Ammar L, Feki-Chakroun N, Rebai T, Sahnoun Z, Ghozzi H, Hammami S et al. 
Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen 
quality in infertile men. Arch Androl 2003;49:83-94. 
60. 
Nozha CF, Leila AK, Zouhir S, Hanen G, Z. K, Tarek R. Oxidateive stress and male 
infertility:comparative study of combined vitamin E/selenium treatment versus vitamin B. Hum 
Reprod 2001;17:111-2. 
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Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J et al. Vitamins E and 
C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized 
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Klein EA, Thompson IM, Jr., Tangen CM, Crowley JJ, Lucia MS, Goodman PJ et al. Vitamin 
E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). 
JAMA;306:1549-56. 


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Safarinejad MR, Safarinejad S. Efficacy of selenium and/or N-acetyl-cysteine for 
improving semen parameters in infertile men: a double-blind, placebo controlled, randomized 
study. J Urol 2009;181:741-51. 
64. 
Lombardo F, Gandini L, Agarwal A, Sgro P, Dondero F, Lenzi A. A prospective double 
blind placebo controlled cross over trial of carnitine therapy in selected cases of male infertility. 
Fertil Steril 2002;78 Suppl 1:68-9. 
65. 
Sigman M, Glass S, Campagnone J, Pryor JL. Carnitine for the treatment of idiopathic 
asthenospermia: a randomized, double-blind, placebo-controlled trial. Fertil Steril 
2006;85:1409-14. 
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Raigani M, Yaghmaei B, Amirjannti N, Lakpour N, Akhondi MM, Zeraati H et al. The 
micronutrient supplements, zinc sulphate and folic acid, did not ameliorate sperm functional 
parameters in oligoasthenoteratozoospermic men. Andrologia. 
67. 
Azizollahi G, Azizollahi S, Babaei H, Kianinejad M, Baneshi MR, Nematollahi-mahani SN. 
Effects of supplement therapy on sperm parameters, protamine content and acrosomal 
integrity of varicocelectomized subjects. J Assist Reprod Genet;30:593-9. 
68. 
Zareba P, Colaci DS, Afeiche M, Gaskins AJ, Jorgensen N, Mendiola J et al. Semen quality 
in relation to antioxidant intake in a healthy male population. Fertil Steril;100:1572-9. 
69. 
Balercia G. Placebo-controlled double-blind randomized trial on the use of L-carnitine, L-
acetylcarnitine, or combined L-carnitine and L-acetylcarnitine in men with idiopathic 
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Biagiotti G, Cavallini G, Modenini F, Vitali G, Magli C, Ferraretti A. Prostaglandins pulsed 
down-regulation enhances carnitine therapy performance in severe idiopathic 
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Cavallini G, Ferraretti AP, Gianaroli L, Biagiotti G, Vitali G. Cinnoxicam and L-
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72. 
Lenzi A, Sgro P, Salacone P, Paoli D, Gilio B, Lombardo F et al. A placebo-controlled 
double-blind randomized trial of the use of combined l-carnitine and l-acetyl-carnitine 
treatment in men with asthenozoospermia. Fertil Steril 2004;81:1578-84. 
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antioxidants dietary supplementation on the oxidative DNA damage of the human 
spermatozoa. ESHRE 14th annual meeting Goteborg 1998:270-1. 
74. 
Blomberg Jensen M, Jorgensen A, Nielsen JE, Bjerrum PJ, Skalkam M, Petersen JH et al. 
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spermatozoa may serve as a novel marker of semen quality. Int J Androl;35:499-510. 
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Yang B, Sun H, Wan Y, Wang H, Qin W, Yang L et al. Associations between testosterone, 
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Henkel R, Hoogendijk CF, Bouic PJD, Kruger TF. TUNEL assay and SCSA determine 
different aspects of sperm DNA damage. Andrologia 2010;42:305-13. 
80. 
Evenson DP, Larson KL, Jost LK. Sperm chromatin structure assay: its clinical use for 
detecting sperm DNA fragmentation in male infertility and comparisons with other techniques. 
J Androl 2002;23:25-43. 
81. 
Sharma RK, Sabanegh E, Mahfouz R, Gupta S, Thiyagarajan A, Agarwal A. TUNEL as a Test 
for Sperm DNA Damage in the Evaluation of Male Infertility. Urology 2010;76:1380-6. 
82. 
Sergerie M, Laforest G, Bujan L, Bissonnette F, Bleau G. Sperm DNA fragmentation: 
threshold value in male fertility. Hum Reprod 2005;20:3446-51. 
83. 
Fedder MD, Jakobsen HB, Giversen I, Christensen LP, Parner ET, Fedder J. An extract of 
pomegranate fruit and galangal rhizome increases the numbers of motile sperm: a prospective, 
randomised, controlled, double-blinded trial. PLoS One 2014;9:e108532. 
84. 
Louis GMB, Kannan K, Sapra KJ, Maisog J, Sundaram R.  Urinary concentrations of 
Benzophenone-Type Ultraviolet Radiation Filters and Couples’ Fecundity.  Am J Epidem 
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85. 
Louis GMB, Chen Z, Kim S, Sapra KJ, Bae J, Kannan K.  Urinary concentrations of 
benzophenone-type ultraviolet light filters and semen quality.  Fertil Steril 2015;104:989-996. 
86. 
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ScienceDaily April 1, 2016.  www.sciencedialy.com/releases/2016/04/160401111847.htm 
87. 
Niederberger C.  Editorial.  Re:  Urinary concentrations of benzophenone-type 
ultraviolet light filters and semen quality.  J Urology 2015;194(6):1711-1712. 
88. 
Jennings L, Karia PS, Jambusaria-Pahlajani A, Whalen FM, Schmults CD.  The Sun 
Exposure and Behaviour Inventory (SEBI):  validation of an instrument to assess sun exposure 
and sun protective practices.  J Eur Acad Dermatol Venereol 2013;27(6):706-15.   
89. 
Matsouka LY, Wortsman J, Hanifan N, Holick MF.  Chronic sunscreen use decreases 
circulating concentrations of 25-hydroxyvitamin D.  A preliminary study.  Arch Dermatol 
1988;124(12):1802-4. 
 
 
 
 
 
 


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11 Informed Consent 
11.1 Informed Consent Template – Male Partners 
 
University of North Carolina 
Research Subject  
Combined Informed Consent and HIPAA Authorization Form 
 
Protocol Title:   
Males, Antioxidants, and Infertility (MOXI) Trial 
Principal 
Investigator: 
Anne Steiner, MD, MPH 
4007 Old Clinic Bldg, CB 7570 
Chapel Hill, NC 27599 
919-966-5283 
Emergency 
Contact: 
919-966-5283 Monday to Friday, 9AM to 5PM  
919-966-4131 During non-business hours (Ask for 
the Reproductive Endocrinologist on call) 
 
 
Why am I being asked to volunteer? 
 
You are being invited to participate in a research study. Your participation is voluntary 
which means you can choose whether or not you want to participate. If you choose not 
to participate, there will be no loss of benefits to which you are otherwise entitled. 
Before you can make your decision, you will need to know what the study is about, the 
possible risks and benefits of being in this study, and what you will have to do in this 
study. The research team is going to talk to you about the research study, and they will 
give you this consent form to read. You may also decide to discuss it with your family, 
friends, or family doctor. You may find some of the medical language difficult to 
understand. Please ask the study doctor and/or the research team about this form. If 
you decide to participate, you will be asked to sign this form.  
 
 


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What is the purpose of this research study? 
The purpose of this research study is to learn if taking antioxidants can improve male 
fertility. After 1 year of trying, some couples will not become pregnant. This is called 
infertility. Male infertility can be caused by DNA damage in sperm. The DNA damage 
affects the sperm’s ability to move or fuse with the egg.  Earlier studies have shown that 
taking antioxidants such as vitamin C, vitamin E, selenium, N-acetylcysteine, L-
carnitine, and Zinc might improve this DNA damage. While we know that taking 
antioxidants might improve DNA damage, we don’t know if taking antioxidants can help 
couples get pregnant. This study will try to determine if taking antioxidants can help 
infertile couples achieve pregnancy. 
You are being invited to participate in this research study because you are an adult 
male and you and your partner are currently experiencing infertility. To participate in this 
study you must be trying to get pregnant and living with your female partner.  
 
How many people will take part in this study? 
 
A total of approximately 790 couples at six institutions will take part in this study, 
including approximately 50 people from this institution. 
 
How long will I be in the study?  
 
You will be enrolled in the study for a minimum of 3 months or a maximum of 6 months.   
 
What am I being asked to do? 
 
If you decide to take part in this study, you and your partner will be asked to complete a 
brief eligibility questionnaire by phone or in person. If you and your partner qualify to 
take part in research, you and your partner will be scheduled to come into one of the 
study centers for a screening visit. This consent form will be reviewed by you and the 
study coordinator. The purpose of the study, all procedures involved, the risks, and the 
time commitment related to this study will be discussed. Once all questions have been 
answered, you will sign this consent form. A copy of this signed consent form will be 
given to you for your records. Your partner will also sign a separate consent form for 
participation in this study. 
 
Your screening visit will include the following tests and assessments: 
• Complete a questionnaire about your medical history, current medications, 
infertility history, demographic information, and family history. 


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• You will be asked to provide a semen sample if you have not had a semen 
analysis within the past 6 months, which will be used to determine if you are 
eligible for the study.  If you have previously had a semen analysis test done 
within the past 6 months, we will ask you to sign a medical release form so we 
can obtain those results. 
If you are considered eligible, you will be given 8 questionnaires to complete. A Medical 
Outcomes Survey (PHQ-9) and the Short Form 12 (SF 12 will assess your daily 
activities.  A Risk Factor for Genetic Disorders questionnaire is completed to determine 
if you have an increased risk of fathering a child with a genetic disorder.  FertiQOL will 
assess how your infertility affects your thoughts and feelings.  The Stop Bang 
Questionnaire and Epworth Sleepiness Scale (ESS) will assess your sleep habits.  The 
Diet History Questionnaire will be completed to assess your food choices over the past 
year.  The International Index of Erectile Function Survey (IIEF), Psychosexual Daily 
Questionnaire (PDQ) and qADAM questionnaire will assess your sexual function. The 
Sun Exposure and Behaviour Inventory (SEBI) will assess your sunscreen usage.  You 
will be free to skip any questions that you would prefer not to answer. 
If both you and your partner are considered eligible for the study, you will return to the 
study center to begin study treatment. You will be randomized by a computer system to 
receive either an antioxidant formulation or placebo.  A placebo is a pill that looks just 
like the antioxidant tablets but does not contain any active medication.  
Neither you nor your study team will know which treatment you will receive. Half of 
participants are expected to receive placebo. You will take the study drug for at least 
three and up to six months. You will be asked to provide a semen sample at study visit 
1 and 90 days later, at study visit 3. We will also obtain approximately 15mL of blood (2 
teaspoons) from your vein at study visits 1, 2, 3 and 4. If you and your partner have not 
become pregnant by the end of three months of study treatment, your partner will 
receive up to three cycles of infertility treatment in the form of clomiphene citrate and 
intrauterine insemination (IUI). You will be given an additional 3 months of study 
medication to take during this time. 
This study will include the following tests and assessments: 
Questionnaires 
You will be required to complete the questionnaires described above at your screening 
visit. In addition, you will also complete the ASA24, which asks you questions about the 
food you have eaten over the past 24 hours. You will be asked to complete the ASA24 
twice throughout this study, at study visit 1 and study visit 3. 
Blood Draws 


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We will collect approximately 15mL of blood (2 teaspoons) from your vein at four 
different times throughout the study. These blood draws will be used to look at certain 
reproductive hormones and vitamin levels in your blood. You will not be given these 
results. 
Urine sample 
You will provide a urine sample at the first study visit.  The urine sample will be used to 
test for common environmental pollutants.  You will not be given these results. 
Semen Collection 
You will be asked to provide a semen sample at screening (if necessary), study visit 1, 
study visit 3, and for each insemination cycle up to 3 cycles.  For this semen analysis 
test, it is important to not have sex or masturbate for 48 hours prior to collecting your 
samples. 
The following are the instructions you will follow to collect your sample. There is a 
private room near the lab where specimens can be collected. 
1. Wash your hands and genitals in the normal way and dry thoroughly. 
2. Use the cup provided by the study coordinator or the lab. Do not open the 
container until you are ready to produce the sample. 
3. Collect the sample by masturbation, putting the entire specimen directly into the 
cup. 
4. Do not use lubricants or condoms, as these are harmful to sperm. 
5. Seal the cup immediately with the lid. 
 
Once you have completed your collection, a semen analysis will be performed to 
determine the concentration of sperm, motility (moving) and morphology (appearance). 
You will be given your results.  
  
Repository Semen and Blood Specimen Collection 
 
If you consent to the optional part of the study, an additional 2 tablespoons of blood will 
be drawn for future testing. A portion of your semen will also be collected and stored as 
part of the repository. These will only be collected if you have consented to the optional 
part of the study. 
 
Study Timeline 
Study visit 1 
• Complete a food intake questionnaire (ASA24) online 


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• Height / Weight 
• Measurement of neck, waist and hip circumference 
• Provide a semen sample 
• Provide a urine sample 
• Provide a blood sample 
• Randomization 
• Pick up one month’s supply of study medication 
Study visit 2 (approximately 30 days after visit 1) 
• Provide a blood sample 
• Give old study pill packages, including any leftover pills to study staff 
• Pick up 2 month’s supply of study medication 
• Pick up ovulation strips and pregnancy tests 
• Schedule next study visit 
Study visit 3 (approximately 60 days after visit 2) 
• Complete a food intake questionnaire (ASA24) online 
• Give old study pill packages, including any leftover pills to study staff 
• Provide a semen sample 
• Provide a blood sample 
• Pick up 3 month’s supply of study medication 
 
If you and your partner have not become pregnant: 
Clomiphene Citrate + Intrauterine Insemination Cycles (up to 3) 
• Assist your partner with the injection of hCG trigger medication 
• Provide semen for IUI 
Study visit 4 (approximately 90 days following visit 3) 
• Provide a blood sample 
• Give old study pill packages to study staff, including any leftover pills 
The following study procedures will be performed once you and your partner 
have become pregnant:  
• Pregnancy Ultrasound (between 6 to 9 weeks gestation) 


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• Pregnancy Status Update: Women will be contacted by study staff (usually 
between 20 and 22 weeks gestation) to get an update on where she is receiving 
prenatal care and where she expects to deliver her baby. 
• Pregnancy Outcome: Study staff will contact you or your partner after the 
planned delivery date to obtain pregnancy outcome information such as birth 
weight, date of delivery, or delivery complications. 
 
What will happen to the blood sample that I donate to the study? 
 
The sample of blood you donate to the study will not have your name on it and will be 
stored in a freezer with other samples.  The samples will be stored until they are used 
by the investigators at The University of North Carolina, or their collaborators. The blood 
will be tested for certain reproductive hormones and vitamin levels in your blood.  You 
will not be able to remove your sample once it is donated.  
 
What are the possible risks or discomforts?  
 
You may experience minimal discomfort, bruising, and a low risk of infection with the 
blood draw. We understand that you may not want others to know that you and your 
partner are trying to get pregnant. We will do our best to protect your confidentiality. In 
addition, there may be uncommon or previously unknown risks related to the study 
medication or study procedures. You should report any problems to the researcher.  
The doses of antioxidants in the supplement have been shown to be safe.  Do not take 
any vitamins in addition to the supplement you are provided as you may then exceed 
the safe dosage of each vitamin. 
 
Risks of Genetic Testing:  
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally 
makes it illegal for health insurance companies, group health plans, and most 
employers to discriminate against you based on your genetic information.  
This law generally will protect you in the following ways: 
Health insurance companies and group health plans may not request your genetic 
information that we get from this research. 
Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums. 


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Employers with 15 or more employees may not use your genetic information that we 
get from this research when making a decision to hire, promote, or fire you or when 
setting the terms of your employment. 
Be aware that this Federal law does not protect you or your family against genetic 
discrimination by companies that sell life insurance, disability insurance, or long-term 
care insurance.  Also, GINA does not prohibit discrimination of individuals with a genetic 
disorder that has been diagnosed.  However, in order to do everything possible to keep 
this from happening, the results of this test will NOT be given to anyone outside the 
study staff. This means that it will not be made available to you, your family members, 
your private physician, your employer, your insurance company or any other party as 
allowed by law. 
 
What if new information becomes available about the study? 
During the course of this study, we may find more information that could be important to 
you. This includes information that, once learned, might cause you to change your mind 
about being in the study. We will notify you as soon as possible if such information 
becomes available. 
 
What are the possible benefits of the study?  
 
You will not benefit personally from being in this research study. Research is designed 
to benefit society by gaining new knowledge. 
 
What other choices do I have if I do not participate?  
 
You do not have to participate in this study to receive treatment for your infertility. 
Choosing not to participate will not have any effect on your clinical care. 
 
Will I be paid for being in this study? 
 
You will not be paid to be in the study but you will receive study medications 
(antioxidant pills or placebo) free of charge.  You and your partner will receive six free 
pregnancy tests and 21 ovulation strips while participating in this study. If you and your 
partner do not become pregnant following 3 months of study treatment, your partner will 
receive infertility treatment in the form of clomiphene citrate and intrauterine 
insemination. If your partner becomes pregnant during the study, you will receive an 
ultrasound of your baby. You will not have to pay for the antioxidant, placebo, 
clomiphene citrate, the IUI procedures, or the pregnancy ultrasound. 
 


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Will I have to pay for anything? 
 
For costs of tests and procedures that are only being done for the research study: 
• The semen analysis will be provided by the Reproductive Medicine Network at no 
cost to you.  
• You and/or your insurance company will not be charged for the cost of any tests or 
procedures that are required as part of the research.  
• The research-related tests and procedures that will be provided at no cost to you 
include: semen analysis and research-related blood work and urine collection.   
 
For costs of medical services for care you would receive even if you were not in this 
research study: 
• You and/or your insurance company will be responsible for the cost of routine 
medications, tests and procedures that you would receive even if you were not in 
this research. 
• You and/or your insurance company will be billed for the costs of these routine tests 
and procedures in the usual manner. 
• You will be responsible for any co-payments, co-insurance and deductibles that are 
standard for your insurance coverage.  
• You will be responsible for any charges not reimbursed by your insurance 
company. 
• Some insurance companies will not pay for routine costs for people taking part in 
research studies. Before deciding to be in this research you should check with your 
insurance company to find out what they will pay for. 
If you have any questions about costs and insurance, ask the research study doctor or a 
member of the research team about putting you in touch with a financial counselor to 
determine exactly what the deductible and co-pay will be for you; this is highly variable 
depending on your type of insurance.”  
 
What happens if I am injured from being in the study?  
 
All research involves a chance that something bad might happen to you.  This may 
include the risk of personal injury. In spite of all safety measures, you might develop a 
reaction or injury from being in this study. 
 
We will offer you the care needed to treat injuries directly resulting from taking part in 
this research.  We may bill your insurance company or other third parties, if appropriate, 


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for the costs of the care you get for the injury, but you may also be responsible for some 
of them. 
There are no plans for the University of North Carolina to pay you or give you other 
compensation for the injury.  You do not give up your legal rights by signing this form.   
If you think you have been injured as a result of taking part in this research study, tell 
the person in charge of the research study as soon as possible.  The researcher’s name 
and phone number are listed in the consent form. 
 
When is the Study over?  Can I leave the Study before it ends? 
 
This study is expected to end after all participants have completed all visits, and all 
information has been collected.  This study may also be stopped at any time by your 
physician, the study Sponsor, or the Food and Drug Administration (FDA) without your 
consent because: 
• 
The Primary Investigator feels it is necessary for your health or safety.  
Such an action would not require your consent, but you will be informed 
if such a decision is made and the reason for this decision. 
• 
You have not followed study instructions.  
• 
The Sponsor, the study Principal Investigator, or the Food and Drug 
Administration (FDA) has decided to stop the study. 
If you decide to participate, you are free to leave the study at any time.  Withdrawal will 
not interfere with your future care.   
 
What information about me may be collected, used or shared with 
others? 
 
The following information may be used or disclosed for this research project: 
• Name, address, telephone number, email address, date of birth 
• Medical record number 
• Information from your medical records pertaining to your medical history, 
pregnancy outcome, and information related to all assessments and treatments 
for this pregnancy 
 
Why is my information being used? 
 
Your information is used by the research team to contact you during the study. Your 
information and results of tests and procedures are used to: 
• do the research 


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• oversee the research 
• see if the research was done right.   
 
Who may use and share information about me?   
 
The following individuals may use or share your information for this research study: 
Representatives of the following people/groups within The University of North Carolina 
may use your health information and share it with other specific groups in connection 
with this research study. 
• The principal investigator, Anne Steiner, MD, MPH 
• The University of North Carolina-Chapel Hill Institutional Review Board 
• The University of North Carolina-Chapel Hill Human Subjects Protection Office 
• The members of the research team working with Anne Steiner 
• Other authorized personnel at The University of North Carolina who may have 
access to your information to perform their daily duties (laboratory personnel, 
financial personnel, etc.). 
Who, outside of the School of Medicine, might receive my 
information?  
The above people/groups may share your health information with the following 
people/groups outside The University of North Carolina for their use in connection with 
this research study. These groups, while monitoring the research study, may also 
review and/or copy your original The University of North Carolina records. 
• The Office of Human Research Protections in the U.S. Department of Health and 
Human Services 
• Food and Drug Administration 
• Data Coordination Center at Yale University 
• Reproductive Medicine Network of the Eunice Kennedy Shriver National Institute 
of Child Health and Human Development  
• National Institute of Health 
• The University of Pennsylvania Institutional Review Board 
• The University of Pennsylvania Human Subjects Protection Office 
Once your personal health information is disclosed to others outside the School of 
Medicine, it may no longer be covered by federal privacy protection regulations.   
The Principal Investigator or study staff will inform you if there are any additions to the 
list above during your active participation in the trial. Any additions will be subject to The 
University of North Carolina procedures developed to protect your privacy. 


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How long may the School of Medicine use or disclose my personal 
health information?  
Your authorization for use of your personal health information for this specific study 
does not expire.  
Your information may be held in a research database.  However, the School of Medicine 
may not re-use or re-disclose information collected in this study for a purpose other than 
this study unless: 
• You have given written authorization  
• The University of Pennsylvania’s Institutional Review Board grants permission 
• The University of North Carolina’s Institutional Review Board grants permission 
• As permitted by law  
• As permitted by law 
 
Who is sponsoring this study? 
 
This research is funded by the Eunice Kennedy Shriver National Institute of Child Health 
and Human Development. This means that the research team is being paid by the 
sponsor for doing the study. The researchers do not, however, have a direct financial 
interest with the sponsor or in the final results of the study. 
 
Can I change my mind about giving permission for use of my 
information? 
 
Yes. You may withdraw or take away your permission to use and disclose your health 
information at any time. You do this by sending written notice to the investigator for the 
study. If you withdraw your permission, you will not be able to stay in this study. 
 
Who can see or use my information?  How will my personal 
information be protected? 
 
The investigators and the research team will be able to see your medical records as 
authorized by you. Results of laboratory tests and clinical procedures done for the 
monitoring or treatment of your infertility will be placed in your medical record and will 
be accessible to employees of the health system that are not part of the research team. 
This information may also be viewed by your insurance company during routine audits. 
 
Privacy and confidentiality measures: 


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Your records that are used in the research at The University of North Carolina will 
include your study identification number, your initials, and visit date and will be kept in a 
secured area in a locked file cabinet. Your samples collected for research purposes will 
be labeled with your study identification number, initials, and visit date and will be stored 
in a -80 degree freezer. 
For research records sent to the Data Coordination Center at Yale University, you will 
be identified by your study identification number and study visit date. Your blood 
specimens will not identify you and you cannot be linked to your specimen.  The list that 
matches your name with your code number will be kept in a secured area in a locked 
file cabinet or in a password-protected electronic document at University of North 
Carolina. 
To help protect your privacy, a Certificate of Confidentiality will be obtained from the 
federal government. This Certificate means that the researchers cannot be forced (for 
example by court subpoena) to share information that may identify you in any federal, 
state, or local civil, criminal, administrative, legislative, or other proceedings.  The 
researchers will use the Certificate to resist any demands for information that would 
identify you, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the 
U.S. government that is used for checking or evaluation of federally funded projects or 
for information that must be disclosed in order to meet the requirements of the federal 
Food and Drug Administration (FDA).  
The Certificate, however, does not prevent you or a member of your family from 
voluntarily releasing information about yourself or your involvement in this research. If 
an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers may not use the Certificate to withhold that 
information. This means that you and your family should actively protect your own 
privacy.  
The Certificate of Confidentiality does not prevent researchers from disclosing 
voluntarily, without your consent, information that would identify you as a participant in 
the research project under the following circumstances: child abuse, intent to harm 
yourself or others, or if you have reportable communicable disease that state or federal 
law requires us to report such as Tuberculosis, HIV infection, or Syphilis.  
 


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In the event of any publication or presentation resulting from the research, no personally 
identifiable information will be shared. Your de-identified information may be used in the 
future for other research.  Your de-identified data will be shared with the National Institute 
of Child Health and Human Development on the Data and Specimen Hub which is a 
resource for investigators to share de-identified research data from studies. 
A copy of this consent form will go in to your medical record.  This will allow the doctors 
caring for you to know what study medications or tests you may be receiving as a part 
of the study and know how to take care of you if you have other health problems or 
needs during the study. 
We will do our best to make sure that the personal information obtained during the 
course of this research study will be kept private. However, we cannot guarantee total 
privacy. Your personal information may be given out if required by law. If information 
from this study is published or presented at scientific meetings, your name and other 
personal information will not be used. If this study is being overseen by the Food and 
Drug Administration (FDA), they may review your research records. 
If you test positive for reportable infectious diseases, by law we have to report the 
infection to the City of Philadelphia Health Department/PA Department of Health. We 
would report your name, gender, racial/ethnic background, and the month and year you 
were born.  
Electronic Medical Records and Research Results  
What is an Electronic Medical Record?  
An Electronic Medical Record (EMR) is an electronic version of the record of your care 
within a health system. An EMR is simply a computerized version of a paper medical 
record.  
If you are receiving care or have received care within the University of North Carolina 
Health System (outpatient or inpatient) and are participating in a University of North 
Carolina research study, results of research-related procedures (i.e. laboratory tests, 
imaging studies and clinical procedures) may be placed in your existing EMR 
maintained by UNC.  
If you have never received care within UPHS and are participating in a University of 
North Carolina research study that uses UNC services, an EMR will be created for you 
for the purpose of maintaining any results of procedures performed as part of this 
research study.  The creation of this EMR is required for your participation in this study. 
In order to create your EMR, the study team will need to obtain basic information about 
you that would be similar to the information you would provide the first time you visit a 


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hospital or medical facility (i.e. your name, the name of your primary doctor, the type of 
insurance you have). Results of research procedures performed as part of your 
participation in the study (i.e. laboratory tests, imaging studies and clinical procedures) 
may be placed in this EMR.  
Once placed in your EMR, these results are accessible to appropriate UNC workforce 
members that are not part of the research team.  Information within your EMR may also 
be shared with others who are determined by UNC to be appropriate to have access to 
your EMR (e.g. health insurance company, disability provider, etc.).  
 
Who can I call with questions, complaints or if I’m concerned about 
my rights as a research subject? 
If you have questions, concerns or complaints regarding your participation in this 
research study or if you have any questions about your rights as a research subject, you 
should speak with the Principal Investigator listed on page one of this form. If a member 
of the research team cannot be reached or you want to talk to someone other than 
those working on the study, you may contact the Institutional Review Board with any 
question, concerns or complaints at the University of North Carolina by calling 919-966-
3113 or by email to IRB_subjects@unc.edu. 
 
 
 


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When you sign this form, you are agreeing to take part in this research study. This 
means that you have read the consent form, your questions have been answered, 
and you have decided to volunteer.  Your signature also means that you are 
permitting the University of North Carolina to use your personal health information 
collected about you for research purposes within our institution. You are also 
allowing the University of North Carolina to disclose that personal health 
information to outside organizations or people involved with the operations of this 
study. 
 
A copy of this consent form will be given to you.  
 
 
________________________       ____________________________________ 
Name of Subject (Please Print)  Signature of Subject  
 
           Date 
 
________________________ 
_____________________________________ 
Name of Person Obtaining 
Signature                                  
 
Date 
Consent (Please Print) 
 
 
______________________________________________________________ 
 
Optional part(s) of the study 
In addition to the main part of the research study, there is another part of the research. 
You can be in the main part of the research without agreeing to be in this optional part. 
Optional Collection of Saliva for Biomarkers of Stress 
As part of an optional part of the study, you will provide us with a sample of saliva.  This 
saliva sample will be tested for biomarkers of stress such as amylase and cortisol.  You 
will be asked to collect the sample upon wakening using a kit provided to you.  There 
are no risks or pain associated with the collection.  The sample can be returned in 
person or via prepaid overnight shipping.  Neither you nor your doctor will receive the 


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results of these tests.  There is no cost to you to participate in this optional portion of the 
study. 
You should initial below to indicate your preference for the collection of your saliva for 
testing: 
________ I give my permission for my saliva to be collected and tested for stress 
biomarkers. 
________ I decline my permission for my saliva to be collected and tested for stress 
biomarkers. 
 
Optional Storage of Blood for RMN Biologic Repository  
As part of an optional study, we are obtaining a sample of your blood to be stored in a 
Biologic Repository by the Reproductive Medicine Network for future use. If you agree, 
approximately 2 tablespoons of your blood will be collected at the randomization visit and 
shipped to the RMN Biologic Repository (a central location) and stored for a minimum of 5 
years, and perhaps into the future. Your sample will be tested for DNA and to measure 
other substances in your blood. If you agree to allow us to collect and store a blood sample 
from you for future use in the repository, your sample will be labeled with a bar code label 
and unique identifier.  These samples will be stored in a locked laboratory at The University 
of North Carolina, until shipment to the repository. If you consent to the collection of your 
blood for the repository, it will be kept indefinitely or until the sample is exhausted by the 
Reproductive Medicine Network.  Once your blood has left The University of North 
Carolina, there is no way to have it returned or withdrawn for testing. You will not be able to 
withdraw your permission for the use of your blood sample for future use at this time. 
We are also collecting blood and urine as a part of this study.  If you agree, we would like to 
retain any leftovers after their use in the study for future use, including measuring other 
substances from your blood and urine.  If you agree to let us retain these samples they will 
be stored in a locked laboratory at The University of North Carolina, until shipment to the 
repository. If you consent to the retention of these samples blood and urine for the 
repository, they will be kept indefinitely or until the sample is exhausted by the 
Reproductive Medicine Network.  Once your blood and urine has left the University of North 
Carolina, there is no way to have it returned or withdrawn for testing. You will not be able to 
withdraw your permission for the use of your blood and urine sample for future use at this 
time.   
 
• These future studies may be helpful in understanding male infertility and the vitamins 
used in this trial.  


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• It is unlikely that these studies will have a direct benefit to you.  
• The results of these tests will not have an effect on your care.  
• Neither your doctor nor you will receive results of these future research tests, nor will 
the results be put in your health record.  
• It is possible that your blood might be used to develop products or tests that could 
be patented and licensed. There are no plans to provide financial compensation to 
you should this occur. If you have any questions, you should contact a member of 
the research team. 
 
You should initial below to indicate your preference for the collection of your blood and 
urine for the repository: 
________ I give my permission for my blood sample to be collected and sent to the 
repository for future testing. 
________ I decline my permission for my blood sample to be collected and sent to the 
repository for future testing. 
 
You should initial below to indicate your preference for your leftover blood and urine to be 
retained and sent to the repository: 
________ I give my permission for my leftover blood and urine sample(s) to be retained 
and sent to the repository for future testing. 
________ I decline my permission my leftover blood and urine sample(s) to be retained 
and sent to the repository for future testing. 
 
Optional Storage of Semen for Future Use in Research 
As part of an optional study, we want to obtain a sample of your semen to be stored by 
the RMN for future testing in the RMN Biologic Repository. If you agree, your semen 
sample will be collected at the screening visit after informed consent.  We are also 
collecting semen as a part of this study.  If you agree, we would like to retain any 
leftover semen not used for the primary study for future research.  
 
Your sample will be stored for a minimum of 5 years, and perhaps further into the future. 
Your sample will be tested for the chemicals that make up all of your genes and contain 
your genetic information. These samples can be used for other research in the future 


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after this study is over. Your sample will not be labeled with any of your personal 
information, such as your name or a code number. The sample for the repository is 
labeled with a bar code and cannot be directly linked back to you. They will be available 
for use in future research studies indefinitely and cannot be removed due to the inability 
to identify them. 
• These future studies may be helpful in understanding male fertility and the vitamins 
used in this trial.  
• It is unlikely that these studies will have a direct benefit to you.  
• The results of these tests will not have an effect on your care.  
• Neither your doctor nor you will receive results of these future research tests, nor will 
the results be put in your health record.  
• It is possible that your semen sample might be used to develop products or tests 
that could be patented and licensed. There are no plans to provide financial 
compensation to you should this occur. If you have any questions, you should 
contact a member of the research team. 
 
You should initial below to indicate your preference for the collection of your semen 
sample for the repository: 
 
________ I give my permission for a portion of my semen sample to be collected and 
sent to the repository for future testing. 
________ I decline my permission for a portion of my semen sample to be collected and 
sent to the repository for future testing. 
 
 


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11.2 Informed Consent Template – Female Partners 
 
 
University of North Carolina 
Research Subject  
Combined Informed Consent and HIPAA Authorization Form 
 
Protocol Title:   
Males, Antioxidants, and Infertility (MOXI) Trial 
Principal 
Investigator: 
Anne Steiner, MD, MPH 
4007 Old Clinic Bldg, CB 7570 
Chapel Hill, NC 27599 
919-966-5283 
Emergency 
Contact: 
919-966-5283 Monday to Friday, 9AM to 5PM  
919-966-4131 During non-business hours (Ask for 
the Reproductive Endocrinologist on call) 
 
 
 
Why am I being asked to volunteer? 
 
You are being invited to participate in a research study. Your participation is voluntary 
which means you can choose whether or not you want to participate. If you choose not 
to participate, there will be no loss of benefits to which you are otherwise entitled. 
Before you can make your decision, you will need to know what the study is about, the 
possible risks and benefits of being in this study, and what you will have to do in this 
study. The research team is going to talk to you about the research study, and they will 
give you this consent form to read. You may also decide to discuss it with your family, 
friends, or family doctor. You may find some of the medical language difficult to 
understand. Please ask the study doctor and/or the research team about this form. If 
you decide to participate, you will be asked to sign this form. 
 
 


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What is the purpose of this research study? 
The purpose of this research study is to learn if taking antioxidants can improve male 
fertility. After 1 year of trying, some couples will not become pregnant. This is called 
infertility. Male infertility can be caused by DNA damage in sperm. The DNA damage 
affects the sperm’s ability to move or fuse with the egg.  Earlier studies have shown that 
taking antioxidants such as vitamin C, vitamin E, selenium, N-acetylcysteine, L-
carnitine, and Zinc might improve this DNA damage. While we know that taking 
antioxidants might improve DNA damage, we don’t know if taking antioxidants can help 
couples get pregnant. This study will try to determine if taking antioxidants can help 
infertile couples achieve pregnancy. 
You are being invited to participate in this research study because you are an adult 
female and you and your partner are currently experiencing infertility. To participate in 
this study, you must be trying to get pregnant and living with your male partner. 
How many people will take part in this study? 
 
A total of approximately 790 couples at six institutions will take part in this study, 
including approximately 50 people from this institution. 
 
How long will I be in the study? 
 
If you achieve pregnancy during this study, you will be enrolled in this study from the 
time you sign this consent form until you have your early pregnancy ultrasound.  Study 
staff will contact you to obtain information about your pregnancy outcome.  If you and 
your partner do not become pregnant, you will be enrolled in this study from the time 
you sign this consent form to the time your partner has completed six months of study 
treatment. 
 
What am I being asked to do? 
 
If you decide to take part in this study, you and your partner will be asked to complete a 
brief eligibility questionnaire by phone or in person. If you and your partner qualify to 
take part in research, you and your partner will be scheduled to come into one of the 
study centers for a screening visit. This consent form will be reviewed by you and the 
study coordinator. The purpose of the study, all procedures involved, the risks, and the 
time commitment related to this study will be discussed. Once all questions have been 
answered, you will sign this consent form. A copy of this signed consent form will be 
given to you for your records. Your partner will also sign a separate consent form for 
participation in this study. 


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Your screening visit will include the following tests and assessments: 
• Your past medical and menstrual history will be recorded.  This form will ask a 
series of questions about your medical health, family health history, reproductive 
and gynecological history, pregnancy history, and current use of medications.  
• Your height, weight, vital signs (blood pressure and pulse) and neck circumference 
will be collected and your body mass index (BMI) will be calculated.  
• You will be given 9 questionnaires to complete. A Risk Factor for Genetic Disorders 
questionnaire is completed to determine if you have an increased risk of having a 
baby with a genetic disorder.  Any potential problems that may lead to 
complications during pregnancy will be addressed at this time and we may refer 
you to a genetics counselor prior to starting the study.  The Female Sexual 
Function Index (FSFI) and Female Sexual Distress Scale (FSDS) will assess your 
sexual function.  A Medical Outcomes Survey (PHQ-9) and the Short Form 12 (SF 
12) will assess your daily activities.  FertiQOL will assess how your infertility affects 
your thoughts and feelings.  The Stop Bang Questionnaire and Epworth Sleepiness 
Scale (ESS) will assess your sleep habits.  The Dietary History Questionnaire II will 
be completed to assess your current dietary intake.  You will be free to skip any 
questions that you would prefer not to answer.  
• The following tests will be done if you have not had them done previously.  If you 
have had them done, you will need to sign a medical record release so that we may 
obtain these results. 
o Blood work may be drawn to determine your eligibility for the study. Tests 
that may be drawn are a progesterone level, FSH, estradiol, or AMH level. 
 
o If you have had not had a test within the past 3 years to determine that your 
fallopian tubes are open, a sonohysterogram (SHG) or hysterosalpingogram 
(HSG) will be completed. During the SHG, sterile saline fluid is injected 
through an intrauterine catheter that contains a balloon. The balloon is 
inflated and the shape of your uterus can be seen and the fluid that 
accumulates in the back area of your uterus determines that at least one 
fallopian tube is open. If it can’t be determined by the SHG, it will be 
necessary for a different procedure to be performed. An HSG procedure is 
done in the radiology department using radio-opaque contrast dye that is 
injected into the uterus and is visualized flowing through the fallopian tube. If 
you have been pregnant within the last three years and your pregnancy and 
delivery were uncomplicated, the SHG or HSG may not be necessary.  
o A physical exam will be performed by the physician if not done within the 
past 12 months.   
o A pap smear will be collected if you are 21 or older and have not had one 
within the time period specified by current guidelines. 
 


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If you consent to the optional part of the study, an additional 2 tablespoons of blood will be 
drawn and a urine sample collected for the biological repository. 
If you and your partner are considered eligible for the study, your partner will return to 
the study center to begin study treatment. Your partner will be randomized by a 
computer system to receive either an antioxidant formulation or placebo.  A placebo is a 
pill that looks just like the antioxidant tablets but does not contain any active 
medication.  
Neither you, your partner, nor your study team will know which treatment he will receive. 
Half of participants are expected to receive placebo. He will take the study drug for at 
least three and up to six months. If you are not pregnant by the end of the third month of 
study treatment, you will receive up to three cycles of infertility treatment in form of 
clomiphene citrate and intrauterine insemination (IUI) while he is on treatment. 
The following procedures will be performed if you and your partner have not become 
pregnant following the third study visit (after 3 months of study treatment): 
Baseline Visit – Infertility Treatment (clomiphene citrate + IUI) 
You will call on the first day of your next menstrual period following your partner’s third 
study visit to schedule your baseline visit for infertility treatment between menstrual 
cycle day 1-5. At this visit the following procedures will occur: 
• Transvaginal Ultrasound. This involves inserting an ultrasound probe into your 
vagina to visualize your ovaries and uterus. Measurements and ultrasound pictures 
will be recorded of your ovaries and uterus. 
• Your medications will be given to you at this time. You will receive clomiphene 
citrate. You will be instructed to begin your medications if your urine pregnancy 
test is negative and your ultrasound results are within a normal range. You will 
also receive hCG injection medication to be used when directed by your 
physician prior to your insemination. You and your partner will be taught the 
technique for administering an intramuscular injection.  
 
Monitor Visits (cycle day 8 to 12 and then beyond as required) 
 
You will be required to return to the clinic within 3 days after completing your 5 day 
treatment of clomiphene citrate. A transvaginal ultrasound will be performed. You may 
be required to return to the clinic regularly for additional monitoring visits until you have 
met the criteria for hCG administration. These visits will be individualized and based on 
your physician’s discretion. 
 


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When your main follicle (cyst which contains an egg) gets to a certain size, you will be 
instructed to self or partner-administer an injection of hCG at a dose of 10,000 IU. A 
cycle may be cancelled if the lead follicles become too large or too small after 18 days 
of monitoring.  
 
Intrauterine Insemination Visit 
 
You must return to the clinic within 44 hours of the hCG shot. Your partner will provide a 
semen sample. This sample will be washed and prepared for the insemination. A 
speculum will be placed in your vagina and a thin flexible catheter will be placed into 
your cervix. The sperm will be injected through the catheter and into your uterus. 
Urine Pregnancy Test 
Two weeks after insemination you will do a urine pregnancy test at home and call the 
study coordinator with your results.   
If you have a positive urine pregnancy test, you will be required to return to the clinic for 
a blood pregnancy test (quantitative bhCG). If your bhCG is positive you will return 2 days 
later for repeat bhCG to check for a rising level. If the level is not rising, you will begin the 
next cycle of treatment with the start of your menstrual cycle. If the bhCG level has risen, 
you will be schedule for an ultrasound approximately 14-21 days after the positive result.  
 
Follow up Initiation of Cycle 2 & 3 
If your urine pregnancy test is negative after a cycle, you may start another cycle of 
treatment. You may participate for a maximum of 3 cycles.  A cycle may be cancelled if 
any significant adverse reactions develop in response to the medications, if you are 
unable to have the hCG injection, or if you request the cycle to be cancelled. The study 
coordinator will provide you with instructions to start your medication on cycle day 3 (+ 
or – 2 days). The study physician may change the start dose of your Clomiphene 
Citrate. You will be scheduled for a return monitoring visit during menstrual cycle day 8-
12. 
The following study procedures will be performed once you and your partner have 
become pregnant:  
• Pregnancy Ultrasound (between 6 to 9 weeks gestation) 
• Pregnancy Status Update: Women will be contacted by study staff (usually 
between 20 and 22 weeks gestation) to get an update on where she is receiving 
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• Pregnancy Outcome: Study staff will contact you or your partner after the 
planned delivery date to obtain pregnancy outcome information such as birth 
weight, date of delivery, or delivery complications. 
 
Pregnancy Ultrasound: 
This transvaginal ultrasound will determine the location of your pregnancy, number of 
gestational sacs and to assess fetal heartbeat.  
Pregnancy Care: 
You may need additional ultrasounds done to evaluate the progress of the pregnancy if 
necessary. Pregnancy care is not part of this study. You will be scheduled with your 
obstetrician for follow up prenatal care. If you do not have a doctor who delivers babies, 
you will be referred to one. Before being released from the study, you will be asked to 
sign a medical release form so the study coordinator can obtain your pregnancy and 
delivery information. You will be contacted between 12 and 22 weeks to see how your 
pregnancy is progressing. 
What will happen to the blood sample that I donate to the study? 
 
The sample of blood you donate to the study will not have your name on it and will be 
stored in a freezer with other samples. The samples will be stored until they are used by 
the investigators at The University of North Carolina, or their collaborators. The blood 
will be tested for certain reproductive hormones and vitamin levels in your blood. You 
will not be able to remove your sample once it is donated.  
 
What are the possible risks or discomforts? 
 
You may experience minimal discomfort, bruising, and a low risk of infection with the 
blood draw. You may experience abdominal or pelvic discomfort due to the transvaginal 
ultrasound used in this study.  
Risks associated with the sonohystogram/hysterosalpingogram include pain, bleeding, 
damage to the uterus, pelvic infection, interrupting an unrecognized pregnancy, small 
amount of radiation exposure, allergic reaction to the radio-opaque dye. 
Risks associated with clomiphene citrate: visual changes (such as blurring of vision, 
double vision, light sensitivity), abdominal pain, nausea, vomiting, constipation, mood 
changes, depression, headache, hot flashes, respiratory difficulty, fatigue, abnormal 
endometrial thickening, multiple pregnancies, formation of ovarian cyst causing ovarian 
hyperstimulation syndrome, ovarian enlargement, breast discomfort, abnormal uterine 


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bleeding, bloating, hair loss, arrhythmias, chest pain, allergic reaction, palpitations, and 
stroke or pulmonary embolism. 
Risks associated with intrauterine insemination include Vasovagal response (feeling 
lightheaded, dizzy, sweating); possible infection.  
We understand that you may not want others to know that you and your partner are 
trying to get pregnant. We will do our best to protect your confidentiality. In addition, 
there may be uncommon or previously unknown risks related to the study medication or 
study procedures. You should report any problems to the researcher. 
Risks of Genetic Testing:  
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally 
makes it illegal for health insurance companies, group health plans, and most 
employers to discriminate against you based on your genetic information.  
This law generally will protect you in the following ways: 
• 
Health insurance companies and group health plans may not request your 
genetic information that we get from this research. 
• 
Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums. 
• 
Employers with 15 or more employees may not use your genetic information that 
we get from this research when making a decision to hire, promote, or fire you or 
when setting the terms of your employment. 
Be aware that this Federal law does not protect you or your family against genetic 
discrimination by companies that sell life insurance, disability insurance, or long-term 
care insurance.  Also, GINA does not prohibit discrimination of individuals with a genetic 
disorder that has been diagnosed.  However, in order to do everything possible to keep 
this from happening, the results of this test will NOT be given to anyone outside the 
study staff. This means that it will not be made available to you, your family members, 
your private physician, your employer, your insurance company or any other party as 
allowed by law. 
What if new information becomes available about the study? 
During the course of this study, we may find more information that could be important to 
you. This includes information that, once learned, might cause you to change your mind 
about being in the study. We will notify you as soon as possible if such information 
becomes available. 


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What are the possible benefits of the study?  
You will not benefit personally from being in this research study.  Research is designed 
to benefit society by gaining new knowledge.   
What other choices do I have if I do not participate?  
You do not have to participate in this study to receive treatment for your infertility. 
Choosing not to participate will not have any effect on your clinical care. 
 
Will I be paid for being in this study? 
You will not be paid to be in this study. You and your partner will receive 6 free 
pregnancy tests and 21 ovulation strips while participating in this study. If you and your 
partner do not become pregnant following 3 months of study treatment, you will receive 
infertility treatment in the form of clomiphene citrate, human chorionic gonadotropin, and 
intrauterine insemination. If you become pregnant during the study, you will receive an 
ultrasound of your baby. You will not have to pay for the clomiphene citrate, human 
chorionic gonadotropin, the IUI procedures, or the pregnancy ultrasound. 
Will I have to pay for anything? 
For costs of tests and procedures that are only being done for the research study: 
• The Clomiphene Citrate and hCG injection will be provided by RMN at no cost to 
you.  
• You and/or your insurance company will not be charged for the cost of any tests or 
procedures that are required as part of the research.  
• The research-related tests and procedures that will be provided at no cost to you 
include:  
• All study required blood tests 
• Physical exam 
• Transvaginal ultrasound (s) 
• Tests ordered for the study to determine tubal patency such as a 
sonohystogram  
• Intrauterine inseminations 
• Ovulation predictor kits 
• Urine pregnancy tests 
• Supplies for injection medication such as; syringes, alcohol swabs, 
gauze, and band-aids 


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• 1 Pregnancy Ultrasound 
 
For costs of medical services for care you would receive even if you were not in this 
research study: 
• You and/or your insurance company will be responsible for the cost of routine 
medications, tests and procedures that you would receive even if you were not in 
this research. 
• You and/or your insurance company will be billed for the costs of these routine tests 
and procedures in the usual manner. 
• You will be responsible for any co-payments, co-insurance and deductibles that are 
standard for your insurance coverage.  
• You will be responsible for any charges not reimbursed by your insurance 
company. 
• Some insurance companies will not pay for routine costs for people taking part in 
research studies. Before deciding to be in this research you should check with your 
insurance company to find out what they will pay for. 
 
The following is a list of the non-covered services related to this study: 
• Prior testing 
• Rubella, Varicella, & HIV testing 
• Pap Smear 
• Carrier screening for genetic diseases 
• Doxycycline prescription for after the HSG procedure, if necessary 
• Remaining obstetrical ultrasounds after the first one 
• Pregnancy care and delivery costs 
 
If you have any questions about costs and insurance, ask the research study doctor or a 
member of the research team about putting you in touch with a financial counselor to 
determine exactly what the deductible and co-pay will be for you; this is highly variable 
depending on your type of insurance. 
 
What happens if I am injured from being in the study?  
All research involves a chance that something bad might happen to you.  This may 
include the risk of personal injury. In spite of all safety measures, you might develop a 
reaction or injury from being in this study.  


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We will offer you the care needed to treat injuries directly resulting from taking part in 
this research.  We may bill your insurance company or other third parties, if appropriate, 
for the costs of the care you get for the injury, but you may also be responsible for some 
of them. 
 
There are no plans for the University of North Carolina to pay you or give you other 
compensation for the injury.  You do not give up your legal rights by signing this form.   
 
If you think you have been injured as a result of taking part in this research study, tell 
the person in charge of the research study as soon as possible.  The researcher’s name 
and phone number are listed in the consent form. 
 
When is the Study over?  Can I leave the Study before it ends? 
This study is expected to end after all participants have completed all visits, and all 
information has been collected.  This study may also be stopped at any time by your 
physician, the study Sponsor, or the Food and Drug Administration (FDA) without your 
consent because: 
• 
The Primary Investigator feels it is necessary for your health or safety.  Such an 
action would not require your consent, but you will be informed if such a decision is 
made and the reason for this decision. 
• 
You have not followed study instructions.  
• 
The Sponsor, the study Principal Investigator, or the Food and Drug Administration 
(FDA) has decided to stop the study. 
If you decide to participate, you are free to leave the study at anytime.  Withdrawal will 
not interfere with your future care.   
 
What information about me may be collected, used or shared with 
others?  
The following information may be used or disclosed for this research project:  
• Name, address, telephone number, email address, date of birth 
• Medical record number 
• Information from your medical records pertaining to your medical history, 
pregnancy outcome, and information related to all assessments and treatments 
for this pregnancy 
  
Why is my information being used? 


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Your information is used by the research team to contact you during the study. Your 
information and results of tests and procedures are used to: 
• do the research 
• oversee the research 
• see if the research was done right.   
 
Who may use and share information about me?   
The following individuals may use or share your information for this research study: 
Representatives of the following people/groups within The University of North Carolina 
may use your health information and share it with other specific groups in connection 
with this research study. 
• The principal investigator, Anne Steiner, MD, MPH 
• The University of North Carolina Institutional Review Board 
• The University of North Carolina Human Subjects Protection Office 
• The members of the research team working with Anne Steiner 
• Other authorized personnel at The University of North Carolina who may have 
access to your information to perform their daily duties (laboratory personnel, 
financial personnel, etc.) 
 
Who, outside of the School of Medicine, might receive my 
information?  
 
The above people/groups may share your health information with the following 
people/groups outside The University of North Carolina for their use in connection with 
this research study. These groups, while monitoring the research study, may also 
review and/or copy your original The University of North Carolina records. 
• The Office of Human Research Protections in the U.S. Department of Health and 
Human Services 
• Food and Drug Administration 
• Data Coordination Center at Yale University 
• Institutional Review board at The University of Pennsylvania 
• Reproductive Medicine Network of the Eunice Kennedy Shriver National Institute 
of Child Health and Human Development  
• National Institute of Health 
• City of Chapel Hill Health Department/NC Department of Health 
Once your personal health information is disclosed to others outside the School of 
Medicine, it may no longer be covered by federal privacy protection regulations.   


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The Principal Investigator or study staff will inform you if there are any additions to the 
list above during your active participation in the trial. Any additions will be subject to The 
University of North Carolina procedures developed to protect your privacy. 
How long may the School of Medicine use or disclose my personal 
health information? 
Your authorization for use of your personal health information for this specific study 
does not expire.  
Your information may be held in a research database.  However, the School of Medicine 
may not re-use or re-disclose information collected in this study for a purpose other than 
this study unless: 
• You have given written authorization  
• The University of Pennsylvania’s Institutional Review Board grants 
permission 
• The University of North Carolina’s Institutional Review Board grants 
permission 
• As permitted by law  
• As permitted by law 
 
Who is sponsoring this study? 
 
This research is funded by the National Institute of Child Health and Human 
Development. This means that the research team is being paid by the sponsor for doing 
the study. The researchers do not, however, have a direct financial interest with the 
sponsor or in the final results of the study. 
 
Can I change my mind about giving permission for use of my 
information? 
Yes. You may withdraw or take away your permission to use and disclose your health 
information at any time. You do this by sending written notice to the investigator for the 
study. If you withdraw your permission, you will not be able to stay in this study. 
Who can see or use my information?  How will my personal 
information be protected?   
The investigators and the research team will be able to see your medical records as 
authorized by you. Results of laboratory tests and clinical procedures done for the 


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monitoring or treatment of your infertility will be placed in your medical record and will 
be accessible to employees of the health system that are not part of the research team.  
This information may also be viewed by your insurance company during routine audits. 
 
Privacy and confidentiality measures: 
Your records that are used in the research at The University of North Carolina will 
include your study identification number, your initials, and visit date and will be kept in a 
secured area in a locked file cabinet. Your samples collected for research purposes will 
be labeled with your study identification number, initials, and visit date and will be stored 
in a -80 degree freezer. 
For research records sent to the Data Coordination Center at Yale University, you will 
be identified by your study identification number and study visit date. Your blood 
specimens will not identify you and you cannot be linked to your specimen.  The list that 
matches your name with your code number will be kept in a secured area in a locked 
file cabinet or in a password-protected electronic document at University of North 
Carolina 
To help protect your privacy, a Certificate of Confidentiality will be obtained from the 
federal government. This Certificate means that the researchers cannot be forced (for 
example by court subpoena) to share information that may identify you in any federal, 
state, or local civil, criminal, administrative, legislative, or other proceedings.  The 
researchers will use the Certificate to resist any demands for information that would 
identify you, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the 
U.S. government that is used for checking or evaluation of federally funded projects or 
for information that must be disclosed in order to meet the requirements of the federal 
Food and Drug Administration (FDA).  
The Certificate, however, does not prevent you or a member of your family from 
voluntarily releasing information about yourself or your involvement in this research. If 
an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers may not use the Certificate to withhold that 
information. This means that you and your family should actively protect your own 
privacy.  
The Certificate of Confidentiality does not prevent researchers from disclosing 
voluntarily, without your consent, information that would identify you as a participant in 


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the research project under the following circumstances: child abuse, intent to harm 
yourself or others, or if you have reportable communicable disease that state or federal 
law requires us to report such as Tuberculosis, HIV infection, or Syphilis. 
In the event of any publication or presentation resulting from the research, no personally 
identifiable information will be shared. Your de-identified information may be used in the 
future for other research.  Your de-identified data will be shared with the National Institute 
of Child Health and Human Development on the Data and Specimen Hub which is a 
resource for investigators to share de-identified research data from studies. 
A copy of this consent form will go in to your medical record.  This will allow the doctors 
caring for you to know what study medications or tests you may be receiving as a part 
of the study and know how to take care of you if you have other health problems or 
needs during the study. 
We will do our best to make sure that the personal information obtained during the 
course of this research study will be kept private.  However, we cannot guarantee total 
privacy.  Your personal information may be given out if required by law.  If information 
from this study is published or presented at scientific meetings, your name and other 
personal information will not be used. If this study is being overseen by the Food and 
Drug Administration (FDA), they may review your research records.   
 
 
If you test positive for reportable infectious diseases, by law we have to report the 
infection to the City of Chapel Hill Health Department/NC Department of Health. We 
would report your name, gender, racial/ethnic background, and the month and year you 
were born.  
This is to keep track of how many people in the U.S. have HIV infection. It is also to 
make sure that states get enough money from the federal government to support the 
medical care of people living with HIV.  The Health Department does not share the 
names of HIV infected people with anyone else. It removes all personal identifiers, such 
as your name, before giving information on the number of HIV infections to the federal 
government. 
 
Electronic Medical Records and Research Results  
What is an Electronic Medical Record?  


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An Electronic Medical Record (EMR) is an electronic version of the record of your care 
within a health system. An EMR is simply a computerized version of a paper medical 
record.  
If you are receiving care or have received care within the University of North Carolina 
(outpatient or inpatient) and are participating in a University of North Carolina research 
study, results of research-related procedures (i.e. laboratory tests, imaging studies and 
clinical procedures) may be placed in your existing EMR maintained by UNC 
Healthcare.  
If you have never received care within UNC and are participating in a University of North 
Carolina research study that uses UNC services, an EMR will be created for you for the 
purpose of maintaining any results of procedures performed as part of this research 
study.  The creation of this EMR is required for your participation in this study. In order 
to create your EMR, the study team will need to obtain basic information about you that 
would be similar to the information you would provide the first time you visit a hospital or 
medical facility (i.e. your name, the name of your primary doctor, the type of insurance 
you have). Results of research procedures performed as part of your participation in the 
study (i.e. laboratory tests, imaging studies and clinical procedures) may be placed in 
this EMR.  
Once placed in your EMR, these results are accessible to appropriate UNC workforce 
members that are not part of the research team.  Information within your EMR may also 
be shared with others who are determined by UNC to be appropriate to have access to 
your EMR (e.g. health insurance company, disability provider, etc.).  
 
Optional part(s) of the study 
In addition to the main part of the research study, there is another part of the research. 
You can be in the main part of the research without agreeing to be in this optional part. 
 
Optional Collection of Saliva for Biomarkers of Stress 
As part of an optional part of the study, you will provide us with a sample of saliva.  This 
saliva sample will be tested for biomarkers of stress such as amylase and cortisol.  You 
will be asked to collect the sample upon wakening using a kit provided to you.  There 
are no risks or pain associated with the collection.  The sample can be returned in 
person or via prepaid overnight shipping.  Neither you nor your doctor will receive the 
results of these tests.  There is no cost to you to participate in this optional portion of the 
study. 


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You should initial below to indicate your preference for the collection of your saliva for 
testing: 
________ I give my permission for my saliva to be collected and tested for stress 
biomarkers. 
________ I decline my permission for my saliva to be collected and tested for stress 
biomarkers. 
 
Optional Storage of Blood and Urine for RMN Biologic Repository  
As part of an optional study, we are obtaining a sample of your blood and urine to be stored 
in a Biologic Repository by the Reproductive Medicine Network for future use. If you agree, 
approximately 2 tablespoons of your blood will be collected at the randomization visit and 
shipped to the RMN Biologic Repository (a central location) and stored for a minimum of 5 
years, and perhaps into the future. Your sample will be tested for DNA and to measure 
other substances in your blood and urine. If you agree to allow us to collect and store a 
blood and urine sample from you for future use in the repository, your sample will be 
labeled with a bar code label and unique identifier.  These samples will be stored in a 
locked laboratory at The University of North Carolina, until shipment to the repository. If you 
consent to the collection of your blood and urine for the repository, it will be kept indefinitely 
or until the sample is exhausted by the Reproductive Medicine Network.  Once your blood 
and urine has left University of North Carolina, there is no way to have it returned or 
withdrawn for testing. You will not be able to withdraw your permission for the use of your 
blood and urine sample for future use at this time. 
 
• These future studies may be helpful in understanding male infertility and the vitamins 
used in this trial.  
• It is unlikely that these studies will have a direct benefit to you.  
• The results of these tests will not have an effect on your care.  
• Neither your doctor nor you will receive results of these future research tests, nor will 
the results be put in your health record.  
• It is possible that your blood might be used to develop products or tests that could 
be patented and licensed. There are no plans to provide financial compensation to 
you should this occur. If you have any questions, you should contact a member of 
the research team. 
 


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You should initial below to indicate your preference for the collection of your blood and 
urine for the repository: 
 
________ I give my permission for my blood and urine sample to be collected and sent to 
the repository for future testing. 
________ I decline my permission for my blood and urine sample to be collected and 
sent to the repository for future testing. 
Who can I call with questions, complaints or if I’m concerned about 
my rights as a research subject? 
If you have questions, concerns or complaints regarding your participation in this 
research study or if you have any questions about your rights as a research subject, you 
should speak with the Principal Investigator listed on page one of this form.  If a 
member of the research team cannot be reached or you want to talk to someone other 
than those working on the study, you may contact the Institutional Review Board with 
any question, concerns or complaints at the University of North Carolina by calling 919-
966-3113 or by email to IRB_subjects@unc.edu. 
 
When you sign this form, you are agreeing to take part in this research study. 
This means that you have read the consent form, your questions have been 
answered, and you have decided to volunteer.  Your signature also means that 
you are permitting the University of North Carolina to use your personal health 
information collected about you for research purposes within our institution. You 
are also allowing the University of North Carolina to disclose that personal health 
information to outside organizations or people involved with the operations of this 
study. 
 
By signing below, you also indicate that you have read the information written 
above and have indicated your choices for the optional part(s) of the research 
study.  
 
A copy of this consent form will be given to you.  
 
________________________       ____________________________________ 
Name of Subject (Please Print)  Signature of Subject  
 
           Date 
Your signature below means that you have explained the optional part(s) to the 
research to the subject or subject representative and have answered any questions 
he/she has about the research. 


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________________________ 
_____________________________________ 
Name of Person Obtaining 
Signature                                  
 
Date 
Consent (Please Print) 


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12 Appendix A: Male Medical History Questionnaire 
  
 
Male Medical History 
 
 
Source Document 
 
 
Reproductive Medicine Network 
Males, Antioxidants, and Infertility (MOXI) Trial 
 
 
 
Do you have a history of any of the following medical conditions or problems? 
 
Body System 
Response      
(If NO, skip to 
next 
question) 
 
Condition/Problem 
 
Currently 
Symptomatic 
 
Requires 
Medication
1. Problems with 
your head, ears, 
eyes, nose or 
throat?  
 Yes   
 No 
 Hearing loss 
 Blindness 
 Sinus  
 Surgery (specify):___________ 
 Other (specify):_____________ 
 Yes   
 
 
 
 
 Yes 
 
 
 
 
2. Problems with 
your brain, nervous 
system or any 
psychiatric 
conditions? 
 Yes   
 No 
 Stroke 
 Migraines 
 Seizures 
 CVA/TIA 
 Depression 
 Anxiety 
 Bipolar disorder 
 Schizophrenia/Psychosis  
 Obsessive-Compulsive Disorder 
 ADD/ADHD 
 Eating Disorder (anorexia, bulimia) 
 Yes   
  
 
 
 
 
 
 
 
 
 
 Yes 
  
 
 
 
 
 
 
 
 
 
MEDICAL HISTORY 


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 Post-Traumatic Stress 
 Acute Stress Disorder 
 Substance/Alcohol Abuse 
 Phobia/Agoraphobia 
 Surgery (specify):___________ 
 Other (specify):_____________ 
 
 
 
 
 
 
 
 
 
 
 
 
3. Problems with 
your respiratory 
system? 
 Yes   
 No 
 Asthma 
 Pneumonia 
 COPD 
 Emphysema 
 TB 
 Surgery (specify):____________ 
 Other (specify):______________ 
 Yes   
  
 
 
 
 
 
 Yes 
  
 
 
 
 
 
4. Problems with 
your heart or 
cardiovascular 
system? 
 Yes   
 No 
 Previous heart attack 
 Congenital heart defect 
 Palpitations 
 Arrhythmias 
 Valve disease 
 Angina 
 CHF 
 Hypertension 
 Syncope 
 Blood clot in leg, lung, brain 
 Surgery (specify):____________ 
 Other (specify):______________ 
 Yes   
  
 
 
 
 
 
 
 
 
 
 
 Yes 
  
 
 
 
 
 
 
 
 
 
 
 


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5. Problems with 
your muscles, joints, 
bones or 
musculoskeletal 
system? 
 Yes   
 No 
 Arthritis 
 Lupus 
 Osteoporosis 
 Gout 
 Disc disease 
 Surgery (specify):_____________ 
 Other (specify):_______________ 
 Yes   
  
 
 
 
 
 
 Yes   
  
 
 
 
 
 
6. Problems with 
your gastrointestinal 
system? 
 Yes   
 No 
 Irritable bowel 
 GI cancer 
 Liver disease 
 Peptic ulcer 
 GERD 
 Hepatitis 
 Pancreatitis 
 Surgery (specify):_____________ 
 Other (specify):_______________ 
 Yes   
  
  
 
 
 
 
 
 Yes   
  
  
 
 
 
 
 
7. Problems with 
your blood and 
metabolic system? 
 Yes   
 No 
 Clotting 
 Anemia 
 Hyperlipidemia 
 Diabetes 
 Hyper/hypothyroidism 
 Surgery (specify):_____________ 
 Other (specify):_______________ 
 Yes   
  
  
 
 
 
 
 Yes   
  
  
 
 
 
 
8. Problems with the 
whole body? 
 Yes   
 No 
 Cancer 
 Alcoholism 
 Drug abuse 
 Yes   
  
 
 Yes   
  
 


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 Allergies 
 Fatigue 
 Weakness 
 Surgery (specify):_____________ 
 Other (specify):_______________ 
  
  
  
  
   
  
  
  
  
 
 
9. Have you ever been treated for cancer?  
 Yes 
No  Skip to Question #10 
9a. If yes, specify type of cancer:  
 
 Testicular 
 
 
 
 
 
 
 Hodgkin’s 
 
 
 
 
 
 
 Lymphoma 
 
 
 
 
 
 
 Leukemia 
 
 
 
 
 
 
 Bladder 
 
 
 
 
 
 
 Prostate 
 
 
 
 
 
 
 Other  
 
(specify):__________________ 
 
9b. Was surgery used for treatment? 
 
 Yes 
 No 
 
9c. Was chemotherapy used for treatment? 
 Yes 
 No  Skip to Question #9d 
 
9c1. If yes, specify type: (check all that apply) 
 Cisplatinum chemotherapy  
 
 
 
 
 
 
      
     (Platinol) 
       
 
 
 
 
 
 
 Cyclophosphamide (Cytoxan) 
 
 
 
 
 
 
 
 Busulfan (Myleran) 
 
 
 
 
 
 
 
 Nitrosoureas (Carmustine,  
 
 
 
 
 
 
     Lomustine) 
 
 
 
 
 
 
 
 L-phenylalanine mustard   
 
 
 
 
 
 
     (Alkeran) 
 
 
 
 
 
 
 
 Bleomycin (Blenoxane,  
 
 
 
 
 
 
 
     Bleomycin) 
 
 
 
 
 
 
 
 Chlorambucil (Leukeran) 
 
 
 
 
 
 
 
 Procarbazine (Natulan,Matulane) 
 
 
 
 
 
 
 
 Nitrogen mustard  (Mustargen) 
 
 
 
 
 
 
 
 
 Other  
 
(specify):__________________ 


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 Unknown 
 
9d. Was radiation used for treatment? 
 
 
 Yes 
 No  Skip to Question 
#10 
 
9d1. If yes, specify location:  
 
 Pelvic 
 
 
 
 
 
 
 
 Brain 
 
 
 
 
 
 
 
 Total body irradiation 
 
 
 
 
 
 
 
 Other 
(specify):__________________ 
 
10. Have you had a high fever (>103 oF) in the last six months? 
 Yes 
 No  
 
 
11. Have you ever been diagnosed with a sexually transmitted infection/disease? 
 
 
 
 
 
 
 
 
 
 Yes 
 No  Skip to Question #12 
11a. Type of STD/STI: (check all that apply) 
 
 
 Gonorrhea 
 
 
 
 
 
 
 
 
 Chlamydia 
 
 
 
 
 
 
 
 
 Syphillis 
 
 
 
 
 
 
 
 
 Herpes Simplex Virus  
 
 
 
 
 
 
 
     (HSV) 
 
 
 
 
 
 
 
 
 Human Papillomavirus  
 
 
 
 
 
 
 
     (HPV) 
 
 
 
 
 
 
 
 
 Trichomoniasis (Trich) 
 
 
 
 
 
 
 
 
 Other  
 
 
 
 
 
 
 
(specify):__________________  
11b. Did you receive treatment?  
 
 
 Yes 
 No 
 
12. Have you ever had a urinary tract infection (bladder infection)?  
 
 
 
 
 
 
 
 
 
 
 
 
 Yes 
 No  Skip to Question #13 
12a. Indicate number of times: 
 
 
 
 
__ __  
 
13. Have you ever had epididymitis?  
 
 
 Yes 
 No  Skip to Question #14 
13a. Indicate number of times: 
 
 
 
 
__ __ 
 
 
14. Have you ever had prostatitis? 
 
 
 
 Yes 
 No  Skip to Question #15 
14a. Indicate number of times:   
 
 
__ __ 
 


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15. Have you ever had testicular torsion (twist)? 
 
 Yes 
 No  Skip to Question #16 
15a. Indicate number of times: 
 
 
 
 
__ __ 
 
 
16. Have you ever been treated for an undescended testicle? 
 
 
 
 
 
 
 
 
 
 
 
 
 Yes 
 No  Skip to Question #17 
 
16a. Indicate type: 
 
 
 
 
 Bilateral 
 Unilateral 
 
17. Do you have a varicocele? 
 
 
 
 Yes 
 No  Skip to Question #18 
 
17a. Indicate type: 
 
 
 
 
 Unilateral 
 
 
 
 
 
 
 
 
 Bilateral 
 
 
 
 
18. Have you ever used cigarettes?  
 
 
 Never  Skip to Question #19 
 
 
 
 
 
 
 
 
 
 Current  
 
 
 
 
 
 
 
 
 
 Former 
Current or former users, proceed to questions 18a through 18g. 
 
18a. Are you currently smoking?  
 
 
 Yes 
 No 
 
18b. On average, how many cigarettes do/did you smoke 
   per day? 
 
 
 
 
 
 
 1-10 
 21-40 
 
 
 
 
 
 
 
 
 11-20 
 >40 
 
18c. On days that you can/could smoke cigarettes  
  freely, how soon after you wake up do you smoke  
  your first cigarette of the day? 
 
 
 minutes  
 hours 
 
18d. How many years have/had you smoked?  
 <1 year 
 6-10 years  
 
 
 
 
 
 
 
 
 1-5 years 
 >15 years 
ENVIRONMENTAL EXPOSURES 


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18e. How many of times have you tried to quit smoking  
 
   (ever)? 
 
 
 
 
 
 
__ __ times 
 
18f. How long ago did you quit smoking? 
 
 <1 year 
  
 11-15 years 
 
 
 
 
 
 
 
 
 1-5 years   
 >15 years 
 
 
 
 
 
 
 
 
 6-10 years  
 NA- currently  
 
 
 
 
 
 
 
 
 
 
 
smoking 
 
18g. Do/did you use any other forms of tobacco? 
 
 Yes 
 No  Skip to 
Question #19  
18g1. If yes, please indicate other tobacco products:     
 
 Cigars 
     
 Pipes 
 
 
 
 
 
 
 
 
 
 Snus/snuff/dip 
 Chew 
 
 
 Electric Cigarettes 
 
 
 
 
 
 
 
 
 
 Dissolvables 
 
 
 
 
 
 
 
 
 
 
 Hookah/water pipe 
 
 
 
 
 
 
 
 
 Other (specify):_______________ 
 
19. On a scale of 1 thru 7, are you around smokers much of the time? 
 
 
 
 
 
 
 
 
 
 
 
 
 1- Not at all true of me 
 
 
 
 
 
 
 
 
 
 2 
 
 
 
 
 
 
 
 
 
 3 
 
 
 
 
 
 
 
 
 
 4 
 
 
 
 
 
 
 
 
 
 5 
 
 
 
 
 
 
 
 
 
 6 
 
 
 
 
 
 
 
 
 
 7- Extremely true of me 
 
20. How many people who live in your household use 
tobacco? (Do not count yourself) 
 
 
 
 
__ __ people 


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21. Does your spouse or partner currently use tobacco? 
 Yes 
 No 
 
22. Have you used any recreational drugs or non-prescribed prescription medicines in the last 3 
months?  
 
 
 
 
 
 Yes 
 No  Skip to Question #23 
 
 
22a. If yes, indicate what type:   
 
 Marijuana 
 
 
 
 
 
 
 
 Cocaine 
 
 
 
 
 
 
 
 Methadone / Narcotics 
 
 
 
 
 
 
 
 Other (specify):_________________ 
 
23. During the last 12 months, how often did you usually have any kind of drink containing 
alcohol? Choose only one. 
(By a drink we mean half an ounce of absolute alcohol (e.g. a 12 ounce 
can or glass of beer or cooler, a 5 ounce glass of wine, or a drink containing one shot of liquor))  
 
 
 
 
 
 
 
 
 Everyday 
 
 
 
 
 
 
 
 5 to 6 times a week 
     
 
 
 
 
 
 
 
 
 3 to 4 times a week 
 
 
 
 
 
 
 
 twice a week 
.  
 
 
 
 
 
 
 once a week  
 
 
 
 
 
 
 
 
 2 to 3 times a month 
 
 
 
 
 
 
 
 
 
 once a month 
 
 
 
 
 
 
 
 3 to 11 times in the past year 
 
 
 
 
 
 
 
 1 or 2 times in the past year 
 
If any of the responses are checked above, proceed to Question #24. 
 I did not drink any alcohol in the past year, but I did drink in the past  
 Skip to Question #23a. 
 I never drank any alcohol in my life  
 Skip to Question #23b.  


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23a. During your lifetime, what is the maximum number of drinks containing alcohol that 
you drank within a 24-hour period? 
 
    
 
 
 
 
 
 36 drinks or more 
 
    
 
 
 
 
  
 24 to 35 drinks 
 
    
 
 
 
 
 
 18 to 23 drinks 
 
 
 
 
 
 
 
 12 to 17 drinks 
 
 
 
 
 
 
 
 8 to 11 drinks 
 
 
 
 
 
 
 
 5 to 7 drinks 
 
 
 
 
 
 
 
 4 drinks 
 
 
 
 
 
 
 
 3 drinks 
 
 
 
 
 
 
 
 2 drinks 
 
 
 
 
 
 
 
 1 drink 
 
STOP HERE, and proceed to Question #26. 
23b. So you have never had a drink containing alcohol in your entire life?  
 
 
 Yes, I never drank Skip to Question #26 
 
 
 No, I did drink.  Return to Question #23 
 
24. During the last 12 months, how many alcoholic drinks did you have on a typical day when 
you drank alcohol? Choose only one. 
 
 
 
 
 
 
 
 
 
 
 
 25 or more drinks 
 
 
 
 
 
 
 
 19 to 24 drinks 
 
 
 
 
 
 
 
 16 to 18 drinks 
 
 
 
 
 
 
 
 12 to 15 drinks 
 
 
 
 
 
 
 
 9 to 11 drinks 
 
 
 
 
 
 
 
 7 to 8 drinks 


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 5 to 6 drinks 
 
 
 
 
 
 
 
 3 to 4 drinks 
 
 
 
 
 
 
 
 2 drinks 
 
 
 
 
 
 
 
 1 drink 
 
25. During the last 12 months, how often did you have 4 or more drinks containing any kind of 
alcohol within a two-hour period? 
Choose only one.  (That would be equivalent of a least 4 12-
ounce cans or bottles of beer, 4 five ounce glasses of wine, 4 drinks each containing one shot of liquor or 
spirits.)  
 
 
 
 
 
 
 
 
 
 
 
 
 Everyday 
 
 
 
 
 
 
 
 5 to 6 days a week 
 
 
 
 
 
 
 
 3 to 4 days a week 
 
 
 
 
 
 
 
 2 days a week 
 
 
 
 
 
 
 
 one day a week 
 
 
 
 
 
 
 
 2 to 3 days a month 
 
 
 
 
 
 
 
 one day a month 
 
 
 
 
 
 
 
 3 to 11 days in the past year 
 
 
 
 
 
 
 
 1 or 2 days in the past year 
 
 
 
 
 
 
 
 0 days in the past year 
 
26. Are you exposed to pesticides on a regular basis? 
 Yes 
 No   
 
27. Have you been exposed to toxic chemicals? 
 
 Yes 
 No  Skip to Question #28 
 
27a. If yes, what types:  
___________________________________________________________ 
 
28. Are you exposed to radiation (x-rays) regularly?  
 Yes 
 No 
 


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29. Are you exposed to prolonged heat regularly?   
      (e.g. hot tubs, saunas)?  
 
 
 
 Yes 
 No 
 
 
30. Have you ever taken testosterone or anabolic steroids? 
 Yes 
 No  Skip to Question #31 
 
 
30a. Are you currently using steroids? 
 
 Yes 
 No  Skip to Question #31 
 
30b. Please list:  
________________________________________________________________ 
 
 
 
 
31. Have you ever created a pregnancy with anyone? 
 Yes 
 No 
 
32. Have you ever had any infertility treatment and/or surgery in the past?  
 
 
 
 
 
 
 
 
 
 
 Yes 
 No → Skip to Question #33 
32a.What type of treatment/surgery did you have?  
(check all that apply) 
 
 
 
 
 
 Varicocele Repair  
 
 
 
 
 
 
 
 Vasectomy Reversal 
 
 
 
 
 
 
 
 In Vitro Fertilization 
 In Vitro Fertilization with  
Intracytoplasmic 
Sperm Injection (IVF 
with ICSI) 
 
 
 Viagra/Cialis/Levitra 
 
 Intrauterine Insemination  
 
     (IUI) 
 
 
 
 
 
 
 
 
 
 Intrauterine Insemination  
 
 
 
 
 
 
 
 
 
     with ICSI (IUI with ICSI) 
 
 
 
 
 
 
 
 
 
 Inguinal hernia repair 
 Prostate Surgery 
 Other 
(specify):_________________ 
PATERNITY/FERTILITY HISTORY 


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33. During the time you have been trying to conceive, have you ever had a male genital 
examination?  
 
 
 
 
 
 Yes 
 No  Skip to Question #34 
 
33a. If yes, were you told that you have dilated scrotal veins?  (e.g. varicoceles) 
 
 
 
 
 
 
 
 
 
 Yes 
 No 
 
34. How long have you and your partner been trying to get pregnant?      
 
 
 
 
__ __ __  
 
 
 
 
months OR 
 Unknown 
 
35. Have you achieved pregnancy with your current partner? 
 Yes 
 No  Skip to Question #36 
 
35a. If yes, complete the table below: 
Pregnancy 
Date 
 #1 
__ __/__ __/__ __ __ __ 
Month    Day         Year 
 #2 
__ __/__ __/__ __ __ __ 
Month    Day         Year 
 #3 
__ __/__ __/__ __ __ __ 
Month    Day         Year 
 #4 
__ __/__ __/__ __ __ __ 
Month    Day         Year 
 #5 
__ __/__ __/__ __ __ __ 
Month    Day         Year 
        
36. Currently, what is your average frequency of intercourse with your partner? 
 
 
  
 
 
 
 
 
 
 
 <1 per month 
 
 
 
 
 
 
 
 
 
 
 1-2 times per month 
 
 
 
 
 
 
 
 
 
 
 1 time per week 
 
 
 
 
 
 
 
 
 
 
 2-3 times per week 
 
 
 
 
 
 
 
 
 
 
 Daily 


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37. Do you know how to time intercourse to your partner’s menstrual cycle? 
 
 
  
 
 
 
 
 
 
 Yes 
 No 
 
38. Do you use any lubrication during intercourse?  
 Yes 
 No 
 
 
 
39. Are you currently taking any medications? 
 
 Yes 
 No 
(include prescription medications and over the counter medications, do not include supplements here) 
 
If Yes, please list all medications on the Concomitant Medications CRF 
 
40. Are you taking any vitamins, multivitamins, or herbal supplements? 
 
 
 
  
 
 
 
 
 
 
 Yes 
 No 
If Yes, please speak with the study staff immediately 
 
41. Have you taken any vitamins, multivitamins, or herbal supplements over the past six 
months? 
 
 
 
 
 
 
 Yes 
 No 
 
 
 
42. What is your age? 
 
 
 
 
__ __ years old 
 
 
 
 
 
 
 
 
 
 
43. What is your marital status? (check only one) 
 
 Single 
 
 
 
 
 
 
 
 
 Married 
 
 
 
 
 
 
 
 
 Divorced 
 
 
 
 
 
 
 
 
 Separated 
 
 
 
 
 
 
 
 
 Widowed 
DEMOGRAPHICS 
MEDICATION INFORMATION 


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44. What is your highest level of education?  
 
 8th grade or less 
 
 
 
 
 
 
 
 
 Some high school 
 
 
 
 
 
 
 
 
 High school graduate 
 
 
 
 
 
 
 
 
 Some college 
 
 
 
 
 
 
 
 
 College graduate 
 
 
 
 
 
 
 
 
 Graduate degree 
 
45. What is your occupation? (check only one) 
 
 Management, Business &  
 
 
 
 
 
 
 
 
 Financial Occupations 
 
 
 
 
 
 
 
 
 Computer, Engineering &   
 
 
 
 
 
 
 
 
 Science Occupations 
 
 
 
 
 
 
 
 
 Education, Legal, Community  
 
 
 
 
 
 
 
 
 Service, Arts, & Media Occupations 
 
 
 
 
 
 
 
 
 Healthcare Practitioners and  
 
 
 
 
 
 
 
 
 Technical Occupations 
 
 
 
 
 
 
 
 
 Service Occupations 
 
 
 
 
 
 
 
 
 Sales and Related Occupations 
 
 
 
 
 
 
 
 
 Office & Administrative Support  
 
 
 
 
 
 
 
 
Occupations 
 
 
 
 
 
 
 
 
 Farming, Fishing, & Forestry  
 
 
 
 
 
 
 
 
Occupations 
 
 
 
 
 
 
 
 
 Construction & Extraction   
 
 
 
 
 
 
 
 
Occupations 
 
 
 
 
 
 
 
 
 Installation, Maintenance, &  
 
 
 
 
 
 
 
 
Repair Occupations 
 
 
 
 
 
 
 
 
 Production Occupations 
 
 
 
 
 
 
 
 
 Transportation & Material Moving 
 
 
 
 
 
 
 
 
 Occupations 
 
 
 
 
 
 
 
 
 Military Specific Occupations 
 
 
 
 
 
 
 
 
 Student 


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 Retired 
 
 
 
 
 
 
 
 
 Unemployed 
 
 
 
 
 
 
 
 
 Disabled 
46. What is your annual Household Income?  
 
(check only one) 
 
 
 
 
 <$25,000  
 
 
 
 
 
 
 
 
 $25,000 to $49,999 
   
 
 
 
 
 
 
 
 
 $50,000 to $74,999 
 
 
 
 
 
 
 
 
 
 $75,000 to $100,000 
 
 
 
 
 
 
 
 
 
 >$100,000  
 
 
 
 
 
 
 
 
 Wish to not answer 
 
47. What type(s) of Insurance coverage do you have? (check all that apply)  
 
 
 
 
 
 
 
 
 
 Managed Care Plan or HMO 
       
 
 
 
 
 
 
 
 
 Other Private Insurance 
 
 
 
 
 
 
 
 
 Medicaid 
 
 
 
 
 
 
 
 
 
 Medicare  
 
 
 
 
 
 
 
 
 Self-pay/Uninsured 
48. Are you currently participating in any other clinical trial? 
 
 
 
 
 
 
 
 
 
 
 
 
 Yes 
 No 
 
 
 
 Patient completed form 
 Study coordinator performed an interview of this questionnaire 
I have reviewed the data captured on this form and to the best of my knowledge it is correct. 
Signature: _______________________________________ 
Date: __ __/__ __/__ __ __  
 
 
 
 
 
 
 
 
 
        Month       Day       Year 
SIGNATURE 


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13 Appendix B: Female Medical History Questionnaire 
 
  
Medical History-Female Partner 
 
 
Source Document 
 
 
Reproductive Medicine Network 
 
 
Males, Antioxidants, and Infertility (MOXI) Trial 
 
 
 
Do you have a history of any of the following medical conditions or problems? 
 
Body System 
Response      
(If NO, skip to 
next question) 
 
Condition/Problem 
 
Currently 
Symptomatic 
 
Requires 
Medication
1. Problems with 
your head, ears, 
eyes, nose or 
throat?  
 Yes   
 No 
 Hearing loss 
 Blindness 
 Sinus  
 Surgery (specify):___________ 
 Other (specify):_____________ 
 Yes   
 
 
 
 
 Yes 
 
 
 
 
2. Problems with 
your brain, nervous 
system or any 
psychiatric 
conditions? 
 Yes   
 No 
 Stroke 
 Migraines 
 Seizures 
 CVA/TIA 
 Depression 
 Anxiety 
 Bipolar disorder 
 Schizophrenia/Psychosis  
 Yes   
 
 
 
 
 
 
 
 Yes 
 
 
 
 
 
 
 
MEDICAL HISTORY 


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 Obsessive-Compulsive Disorder 
 ADD/ADHD 
 Eating Disorder (anorexia, bulimia) 
 Post-Traumatic Stress 
 Acute Stress Disorder 
 Substance/Alcohol Abuse 
 PMS/PMDD 
 Phobia/Agoraphobia 
 Surgery (specify):___________ 
 Other (specify):_____________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. Problems with 
your respiratory 
system? 
 Yes   
 No 
 Asthma 
 Pneumonia 
 COPD 
 Emphysema 
 TB 
 Surgery (specify):____________ 
 Other (specify):______________ 
 Yes   
  
  
  
  
  
  
 
 Yes 
  
  
  
  
  
  
 


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4. Problems with 
your heart or 
cardiovascular 
system? 
 Yes   
 No 
 Previous heart attack 
 Congenital heart defect 
 Palpitations 
 Arrhythmias 
 Valve disease 
 Angina 
 CHF 
 Hypertension 
 Syncope 
 Blood clot in leg, lung, brain 
 Surgery (specify):____________ 
 Other (specify):______________ 
 Yes   
  
 
 
 
 
 
 
 
 
 
 Yes 
  
 
 
 
 
 
 
 
 
 
5. Problems with 
your muscles, joints, 
bones or 
musculoskeletal 
system? 
 Yes   
 No 
 Arthritis 
 Lupus 
 Osteoporosis 
 Gout 
 Disc disease 
 Surgery (specify):_____________ 
 Other (specify):_______________ 
 Yes   
  
 
 
 
 
 
 Yes   
  
 
 
 
 
 
6. Problems with 
your gastrointestinal 
system? 
 Yes   
 No 
 Irritable bowel 
 GI cancer 
 Liver disease 
 Peptic ulcer 
 GERD 
 Hepatitis 
 Pancreatitis 
 Yes   
  
 
 
 
 
 
 Yes   
  
 
 
 
 
 


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 Surgery (specify):_____________ 
 Other (specify):_______________ 
 
 
 
 
7. Problems with 
your blood and 
metabolic system? 
 Yes   
 
 No 
 Clotting 
 Anemia 
 Hyperlipidemia 
 Diabetes 
 Hyper/hypothyroidism 
 Surgery (specify):_____________ 
 Other (specify):_______________ 
 Yes   
 
  
  
  
  
   
 Yes   
  
 
 
 
 
 
 
8. Problems with 
the whole body? 
 Yes   
 No 
 Cancer 
(specify):_____________ 
 Alcoholism 
 Drug abuse 
 Allergies 
 Fatigue 
 Weakness 
 Adrenal or Ovarian androgen 
     secreting tumor 
 Cushing’s Syndrome 
 Surgery 
(specify):_____________ 
 Other 
(specify):_______________ 
 
 Yes   
  
 
 
 
 
 
 
 
 
 Yes   
  
 
 
 
 
 
 
 
 
If any of these conditions require medication treatment, record medications on the 
concomitant medication log 
 


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9. Have you ever used cigarettes? 
 
 
 
 Never  Skip to Question #10 
 
 
 
 
 
 
 
 
 Current 
 
 
 
 
 
 
 
 
 Former 
 
Current or former users, proceed to questions 9a through 9g 
 
9a. Are you currently smoking?  
 
 
 Yes 
 No 
 
9b. On average, how many cigarettes do/did you smoke per day? 
 
 
 
 
 
 
 
 
 
 
 
 1-10 
 21-40 
 
 
 
 
 
 
 
 
 11-20 
 >40 
 
9c. On days that you can/could smoke cigarettes freely, how soon after you wake do you 
smoke your first cigarette of the day? 
 
 
 minutes 
 hours 
 
9d. How many years have/had you smoked? 
 
 <1 year 
 6-10 years 
 
 
 
 
 
 
 
 
 1-5 years 
 >15 years 
 
9e. How many times have you tried to quit smoking (ever)? 
 
 times 
 
9f. How long ago did you quit smoking?  
 
 <1 year 
 11-15 years 
 
 
 
 
 
 
 
 
 1-5 years 
 >15 years 
 
 
 
 
 
 
 
 
 6-10 years  
 
 
 
 
 
 
 
 
 NA- currently smoking  
ENVIRONMENTAL EXPOSURES 


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9g. Do/did you use any other forms of tobacco?  
 Yes 
 No  Skip to Question #10 
 
9g1. If yes, please indicate other tobacco products:  
 Cigars 
 
 
 
 
 
 
 
 
 
 
 Pipes 
 
 
 
 
 
 
 
 
 
 Snus/snuff/dip 
 
 
 
 
 
 
 
 
 
 Electric Cigarettes 
 
 
 
 
 
 
 
 
 
 Dissolvables 
 
 
 
 
 
 
 
 
 
 Hookah/water pipe 
 
 
 
 
 
 
 
 
 
 Other  
 
 
 
 
 
 
 
 
 
(specify):________________ 
 
10. On a scale of 1 thru 7, are you around smokers much of the time? 
 
 
 
 
 
 
 
 
 
 
 
 
 1- Not at all true of me 
 
 
 
 
 
 
 
 
 
 2 
 
 
 
 
 
 
 
 
 
 3 
 
 
 
 
 
 
 
 
 
 4 
 
 
 
 
 
 
 
 
 
 5 
 
 
 
 
 
 
 
 
 
 6 
 
 
 
 
 
 
 
 
 
 7- Extremely true of me 
 
11. How many people who live in your household use tobacco? (Do not count yourself) 
 
 
 
 
__ __   
 
 
 
 
 
people 
 
12. Does your spouse or partner currently use tobacco? 
 Yes 
 No 
 
13. Have you used any recreational drugs or non-prescribed prescription medicines in the last 3 
months? 
 
 
 
 
 
 
 Yes 
 No  Skip to Question #14 
 
13a. If yes, indicate what type(s): (check all that apply) 
 
 Marijuana 


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 Cocaine 
 
 
 
 
 
 
 
 
 
 Methadone/Narcotics 
 
 
 
 
 
 
 
 
 
 Other  
 
 
 
 
 
 
 
 
 
 
 
(specify):_______________ 
14. During the last 12 months, how often did you usually have any kind of drink containing 
alcohol? Choose only one. 
(By a drink we mean half an ounce of absolute alcohol 
(e.g. a 12 
ounce can or glass of beer or cooler, a 5 ounce glass of wine, or a drink containing one shot of liquor). 
 
 
 
 
 
 
 
 
 
 
 Everyday 
 
 
 
 
 
 
 
 
 
 5 to 6 times a week 
     
 
 
 
 
 
 
 
 
 
 3 to 4 times a week 
 
 
 
 
 
 
 
 
 
 twice a week 
 
 
 
 
 
 
 
 
 
 once a week  
 
 
 
 
 
 
 
 
 
 
 2 to 3 times a month 
 
 
 
 
 
 
 
 
 
 once a month 
 
 
 
 
 
 
 
 
 
 3 to 11 times in the past  
 
 
 
 
 
 
 
 
 
     year 
 
 
 
 
 
 
 
 
 
 1 or 2 times in the past  
 
 
 
 
 
 
 
 
 
     year 
If any of the responses are checked above, proceed to Question #15. 
I did not drink any alcohol in the past year, but I did drink in the past 
  
 Skip to Question #14a. 
I never drank any alcohol in my life  
 
 
 
   
  
 Skip to Question #14b.  
 
14a. During your lifetime, what is the maximum number of drinks containing alcohol that you 
drank within a 24-hour period? 
  
 
 
 
 
 
 
 
 
 36 drinks or more 
 
    
 
 
 
 
 
 
 
 24 to 35 drinks 
 
    
 
 
 
 
 
 
 
 18 to 23 drinks 


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 12 to 17 drinks 
 
 
 
 
 
 
 
 
 
 8 to 11 drinks 
 
 
 
 
 
 
 
 
 
 5 to 7 drinks 
 
 
 
 
 
 
 
 
 
 4 drinks 
 
 
 
 
 
 
 
 
 
 3 drinks 
 
 
 
 
 
 
 
 
 
 2 drinks 
 
 
 
 
 
 
 
 
 
 1 drink 
STOP HERE, and proceed to Menstrual History Section. 
 
 
 
14b. So you have never had a drink containing alcohol in your entire life?  
 
 
 
 
 
 
 
 
 Yes, I never drank Skip to next section 
 
 
 
 
 
 
 
 No, I did drink.  Return to Question #14 
 
15. During the last 12 months, how many alcoholic drinks did you have on a typical day when 
you drank alcohol? Choose only one. 
 
 
 
 
 
 
 
 
 
 
 
 
 25 or more drinks 
 
 
 
 
 
 
 
 
 
 19 to 24 drinks 
 
 
 
 
 
 
 
 
 
 16 to 18 drinks 
 
 
 
 
 
 
 
 
 
 12 to 15 drinks 
 
 
 
 
 
 
 
 
 
 9 to 11 drinks 
 
 
 
 
 
 
 
 
 
 7 to 8 drinks 
 
 
 
 
 
 
 
 
 
 5 to 6 drinks 
 
 
 
 
 
 
 
 
 
 3 to 4 drinks 
 
 
 
 
 
 
 
 
 
 2 drinks 
 
 
 
 
 
 
 
 
 
 1 drink 
16. During the last 12 months, how often did you have 4 or more drinks containing any kind of 
alcohol within a two-hour period?  Choose only one.  (That would be equivalent of a least 4 12-


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ounce cans or bottles of beer, 4 five ounce glasses of wine, 4 drinks each containing one shot of liquor or 
spirits.)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Everyday 
 
 
 
 
 
 
 
 
 
 5 to 6 days a week 
 
 
 
 
 
 
 
 
 
 3 to 4 days a week 
 
 
 
 
 
 
 
 
 
 two days a week 
 
 
 
 
 
 
 
 
 
 one day a week 
 
 
 
 
 
 
 
 
 
 2 to 3 days a month 
 
 
 
 
 
 
 
 
 
 one day a month 
 
 
 
 
 
 
 
 
 
 3 to 11 days in the past  
 
 
 
 
 
 
 
 
 
     year 
 
 
 
 
 
 
 
 
 
 1 or 2 days in the past  
 
 
 
 
 
 
 
 
 
     year 
 
 
 
 
 
 
 
 
 
 0 days in the past year 
 
 
17. On average, how many periods do you have per year? __ __ periods OR 
 Unknown 
18. What is the average number of days between your period? 
    days OR 
 Unknown 
19. What is the number of days of bleeding per cycle? 
 
    days OR 
 Unknown 
20. Date of last menstrual period: 
 
 
 
__ _ /__ __/__ __ _  OR 
 Unknown 
 
 
 
 
 
 
 
        Month      Day      Year 
 
 
 
 
 
 
 
21. Have you ever used medication to regulate your period? 
 Yes 
 No  Skip to 
Question #22 
 
If yes, check below types of medications previously used: (check all that apply) 
MENSTRUAL HISTORY 
GYNECOLOGICAL HISTORY 


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Check if 
used 
Medication 
Duration (months) 
 
21a.Birth control pills 
__ __ __ 
 Unknown 
 
21b. Progesterone (e.g. Provera) 
__ __ __ 
 Unknown 
 
21c. Letrozole 
__ __ __ 
 Unknown 
 
21d. Anastrozole 
__ __ __ 
 Unknown 
 
21e. Cabergoline (Dostinex) 
__ __ __ 
 Unknown 
 
21f. GnRH agonist (e.g. any form- Lupron, 
Synnarel) 
__ __ __ 
 Unknown 
 
21g. Metformin (Glucophage) 
__ __ __ 
 Unknown 
 
21h. Rosiglitazone (Avandia) 
__ __ __ 
 Unknown 
 
21i. Other (specify):_____________________ 
__ __ __ 
 Unknown 
 
21j. Other (specify):_____________________ 
__ __ __ 
 Unknown 
 
21k. Other (specify):_____________________ 
__ __ __ 
 Unknown 
 
21l. Other (specify):______________________ 
__ __ __ 
 Unknown 
 
22. Have you ever had a pap smear? 
 
 
 
 Yes 
 No  Skip to 
Question #23 
22a. Date of last pap smear: 
 
 
 
 
__ __/__ __ /__ __ __ __ 
22b. Was the result of this pap smear abnormal? 
 
 Yes 
 No 
 
23. Have you ever been diagnosed with a sexually transmitted disease/infection?  
 
 
 
 
 
 
 
 
 
 
 Yes 
 No  Skip to 
Question #24 
  
23a. Type of STD/STI: (check all that apply) 
 
 
 Gonorrhea 
 
 
 
 
 
 
 
 
 
 Chlamydia 
 
 
 
 
 
 
 
 
 
 Syphillis 


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 Herpes Simplex Virus  
 
 
 
 
 
 
 
 
 
     (HSV) 
 
 
 
 
 
 
 
 
 
 Human Papillomavirus  
 
 
 
 
 
 
 
 
 
     (HPV) 
 
 
 
 
 
 
 
 
 
 Trichomoniasis (Trich) 
 
 
 
 
 
 
 
 
 
 Other  
 
 
 
 
 
 
 
 
 
 
(specify):_________________ 
23b. Did you receive treatment?  
 
 
 Yes 
 No 
 
24. Have you been diagnosed with Pelvic Inflammatory disease?  
 
 
 
 
 
 
 
 
 
 
 
 
 Yes 
 No  Skip to Question #25 
24a. Did you receive treatment?  
 
 
 Yes 
 No 
 
25. Have you ever been diagnosed with Fibroids?  
 Yes 
 No  Skip to Question #26 
25a. Did you receive treatment?  
 
 
 Yes 
 No 
 
26. Have you ever been diagnosed with Endometriosis? 
 Yes 
 No  Skip to Question #27 
26a. Did you receive treatment?  
 
 
 Yes 
 No 
 
27. Have you ever had any gynecological procedures or surgeries done with the past? 
 
 
 
 
 
 
 
 
 
 Yes 
 No  Skip to Question #28 
If yes, check below types of procedures or surgeries done: (check all that apply) 
Check if 
ever had 
 
Type of Procedure or Surgery 
Date  
(MM/YYYY) 
 
27a. Ultrasound (transvaginal or abdominal) 
 __ __/__ __ __ __ 
Unknown 
 
27b. Hysterosalpingogram (HSG) 
 __ __/__ __ __ __ 
Unknown 
 
27c. Sonohysterogram (SHG) 
 __ __/__ __ __ __ 
Unknown 


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27d. Hysteroscopy 
 __ __/__ __ __ __ 
Unknown 
 
27e. Colposcopy 
 __ __/__ __ __ __ 
Unknown 
 
27f. Salpingo-oophorectomy  
 __ __/__ __ __ __ 
Unknown 
 
27g. Tubal ligation 
 __ __/__ __ __ __ 
Unknown 
 
27h. Endometrial ablation 
 __ __/__ __ __ __ 
Unknown 
 
27i. Polypectomy 
 __ __/__ __ __ __ 
Unknown 
 
27j. Oophorectomy 
 __ __/__ __ __ __ 
Unknown 
 
27k. Uterine dilation & curettage 
 __ __/__ __ __ __ 
Unknown 
 
27l. Salpingectomy 
 __ __/__ __ __ __ 
Unknown 
 
27m. Ovarian surgery 
 __ __/__ __ __ __ 
Unknown 
 
27n. Hysterectomy  with or without 
oophorectomy 
 __ __/__ __ __ __ 
Unknown 
 
27o. Unilateral or bilateral oophorectomy 
 __ __/__ __ __ __ 
Unknown 
 
27p. Ovarian cyst removal 
 __ __/__ __ __ __ 
Unknown 
 
27q. Endometriosis  
 __ __/__ __ __ __ 
Unknown 
 
27r. Lysis of adhesions 
 __ __/__ __ __ __ 
Unknown 
 
27s. Myomectomy 
 __ __/__ __ __ __ 
Unknown 
 
27t. UAE (uterine artery embolization) 
 __ __/__ __ __ __ 
Unknown 
 
27u. Diagnostic laparoscopy 
 __ __/__ __ __ __ 
Unknown 
 
27v. IUD removal 
 __ __/__ __ __ __ 
Unknown 
 
27w. Caesarean section 
 __ __/__ __ __ __ 
Unknown 
 
27x. LEEP 
 __ __/__ __ __ __ 
Unknown 
 
27y. Other (specify):____________________ 
 __ __/__ __ __ __ 
Unknown 
 
27z. Other (specify):____________________ 
 __ __/__ __ __ __ 
Unknown 
 
 


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28. How long have you been trying to get pregnant? 
 
__ months  OR  
 Unknown 
 
29. Have you ever received a diagnosis from a physician for why you have trouble getting 
pregnant? 
 
 
 
 
 
 
 Yes 
 No  Skip to Question #30 
29a. What was your diagnosis? (Check all that apply) 
 Ovulatory dysfunction (e.g. PCOS) 
 
 
 
 
 
 
 
 
 Tubal factor (e.g. blocked tubes) 
  
 
 
 
 
 
 
 
 
 Endometriosis 
 
 
 
 
 
 
 
 
 Uterine factor (e.g. fibroids) 
 
 
 
 
 
 
 
 
 Male factor infertility 
 
 
 
 
 
 
 
 
 Unexplained 
 
 
 
 
 
 
 
 
 Intra-abdominal adhesions 
 
 
 
 
 
 
 
 
 Cervical factor 
 
30. Have you ever received therapy for infertility? 
 
 Yes 
 No  Skip to Question #31 
If yes, check below types of therapies previously used: (check all that apply) 
 
Check 
if ever 
used 
 
 
Name of Therapy 
Number 
of times 
received 
(enter 
“99” if 
unknown) 
 
 
Date  
(MM/YYYY) 
 
30a. Clomiphene Citrate (Clomid) 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30b. Clomid and Intrauterine Insemination (IUI) 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30c. Letrozole (Femara) 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30d. Letrozole and Intrauterine Insemination (IUI) 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30e. Intrauterine Insemination with no medication 
__ __ 
__ __ /__ __ __ __ 
 Unknown
INFERTILITY HISTORY 


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30f. Clomid/gonadatropins/IUI 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30g. Gonadatropins (infertility shots) 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30h. Gonadatropins with IUI 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30i. Lupron/gonadotropins/IUI 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30j. In Vitro Fertilization (IVF) 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30k. IVF with Intracytoplasmic Sperm Injection (ICSI) 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30l. Frozen Transfer 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30m. Donor sperm 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30n. Donor egg 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30o. Donor embryo 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30p. Other (specify):_______________ 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
30q. Other (specify):________________ 
__ __ 
__ __ /__ __ __ __ 
 Unknown
 
 
 
31. Are you allergic to any medications? 
 
 
 Yes 
 No  Skip to Question #32 
Please list these medications:  
____________________________________________________ 
 
32. Are you currently taking any medications on a daily basis? 
 Yes 
 No 
 
33. Are you currently taking any vitamins or supplements on a daily basis? 
 
 
 
 
 
 
 
 
 
 
 
 
 Yes 
 No 
 
If YES to Question #32 & #33, complete Concomitant Medication CRF 
 
CONCOMITANT MEDICATIONS  


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 Patient completed form 
 Study coordinator performed an interview of this questionnaire 
 
To the best of your knowledge the above information is correct. 
 
Signature of Patient: _________________________________ 
Date: __ __/__ __/__ __ __ _ 
 
 
 
 
 
 
 
 
 
         Month      Day       Year 
 
The above information has been verified with the patient and is complete. 
 
Signature: __________________________________________ 
Date: __ __/__ __/__ __ __  
 
 
 
 
 
 
 
 
 
        Month      Day       Year  
 
 
SIGNATURE  


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14 Appendix C: List of Prohibited Concomitant Medications 
Female 
 
Progestins (Oral or Cyclic)  
 
medroxyprogesterone acetate (Provera, Cycrin, Amen, Curretab)  
 
megestrol (Megase) norethindrone (Aygestin)  
 
progesterone gel (Crinone)  
 
Micronized progesterone (Prometrium)  
GnRH Agonists/Antagonists Leuprolide (Lupron)  
nafarelin (Synarel)  
buserelin gosarelin (Zoladex)  
ganarelix (Antagon) cetrorelix  
(Cetrotide) Gonadotropins  
Pergonal  
Repronex  
Follistim  
Gonal-F  
Fertinex  
Metrodin 
Injectable Contraceptives 
 
medroxyprogesterone acetate (Depo Provera)  
Oral Contraceptives Any Brand  
Continuous Progestins (Not including cyclic)  
 
Any Brand 
Contraceptive Implants  
 
Norplant (levonorgestrel implants) 
 
Implanon  
Clomiphene  
Letrozole (femara) 
Tamoxifen 
 
 


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Male 
 
Inflammatory bowel disease medications - Need 3 month washout 
Sulfasalazine 
           Azulfidine 
             Azulfidine EN 
 
Azathioprine 
Infliximab 
Antihypertensives - Need 3 month washout 
Calcium channel blockers 
 
Nifedipine 
 
Adalat 
 
Afeditab 
 
Nifediac 
 
Nifedical 
 
Procardia 
Spironolactone 
5 alpha reductase medications 
 
Finasteride (Propecia, Proscar) 
 
Alfatradiol (Ell-Cranell Alpha, Pantostin) 
 
Dutasteride (Avodart) 
 
Flutamide 
Cimetidine (Tagamet) - Need 3 month washout 
Immunosuppressive agents within the past 1 year 
Chemotherapeutic agents within the past 1 year 
Androgens  - Need 6 month washout 
 
DHEA or DHEAS, androstenedione 
 
OTC “testosterone boosting” herbals and supplements 
 
OTC workout enhancing supplements 
Synthetic testosterone or anabolic steroids - Need 6 month washout 
             Testred 
Android 
Axiron 


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Androgel 1% 
Androgel 1.62% 
Tesetim 
Fortesta 
Vogelxo 
Striant 
 
Androderm 
Natesto 
Aveed 
Testosterone cypionate 
Testosterone enanthate 
Testopel 
Testosterone modulating medications - Need 3 month washout 
Clomid 
Anastrazole 
HCG 
 
 
Profasi 
            
Ovidrel 
 
Lupron 
 
Zoladex 
 
Cannabis (Marijuana) - Need 3-month washout 
 
 


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15 Appendix D: Review of Antioxidant Formulations 
15.1 Commercially Available Formulations 
 
 
 


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15.2 Research Formulations  
 
 


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138 
 
16 Appendix E: Risk Factors for Genetic Disorders 
 
The following questions are designed to determine if you have an increased risk of 
having a baby with a genetic disorder. Sometimes genetic disorders occur even when 
there is no history of problems in your family. The following questions are related to you 
and your immediate family including mother, father, sister, brother, child, or grandparent. 
If you answer “yes” to any of the following questions and would like more information, 
please discuss this with your physician.  
 
Questions 
Yes 
No 
Unknown 
N/A 
1. If you conceive during this study, will you be 35 or older 
when your baby is due? 
 
 
 
 
2. If you are of Mediterranean or Asian descent, does 
anyone in your family have thalassemia?  
(a blood disorder that causes anemia) 
 
 
 
 
3. Is there a family history of neural tube defects? 
 
 
 
 
4. Have you had a child with a neural tube defect? 
 
 
 
 
5. Does anyone in your family have a history of congenital 
heart defects? (heart problems when they were born) 
 
 
 
 
6. Does anyone in your family have Down Syndrome? 
 
 
 
 
7. Have you ever had a child with Down Syndrome? 
 
 
 
 
8. If you are of Eastern European Jewish or French Canadian 
descent, does anyone in your family have a history of Tay-
Sachs disease? (a disorder of the central nervous system) 
 
 
 
 
9. If you are of Eastern European Jewish descent, does 
anyone in your family have a history of Canavan disease? 
(a disorder of the central nervous system that leads to blindness and 
muscle weakness) 
 
 
 
 
10. If you are of African American descent, is there any 
history of sickle cell trait? (a type of anemia) 
 
 
 
 


 
139 
 
11. If you are of African American descent, is there any 
history of sickle cell disease? (a type of anemia) 
 
 
 
 
12. Do you or anyone in your family have a history of 
hemophilia? (a disorder that causes bleeding) 
 
 
 
 
13. Do you or anyone in your family have a history of 
muscular dystrophy? (a neuromuscular disorder) 
 
 
 
 
14. Do you or anyone in your family have a history of cystic 
fibrosis? ( a disorder that causes thick mucous in the lungs and other 
organs) 
 
 
 
 
15. Do you or anyone in your family have a history of 
Huntington’s disease? (a degenerative brain disease) 
 
 
 
 
16. Do you or anyone in your family have a history of alpha-1 
antitrypsin deficiency? (lack of a liver protein) 
 
 
 
 
17. Do you or anyone in your family have a history of mental 
retardation? 
 
 
 
 
       17a. If yes to Question #17, was the person ever tested 
for fragile-x syndrome? ( a condition which can cause mild to severe 
mental retardation) 
 
 
 
 
18. Do you or anyone in your family have a history of any 
other genetic disease, chromosomal disorder or birth 
defect? 
 
 
 
 
19. Do you have any metabolic disorders such as diabetes or 
phenylketonuria (PKU)?  
(a disorder which prevents the normal use of protein foods) 
 
 
 
 
20. Have you ever had 3 or more miscarriages in a row? 
 
 
 
 
21. Have you ever had a baby that was stillborn? 
 
 
 
 
 
 
 


 
 
17 Appendix F: Female Sexual Function Index (FSFI) 
 


 
 
 


 
 
 
 


 
 
 


 
 
 
 
 


 
 
18 Appendix G: SF-12v2 Health Survey 
 


 
 
 
 


 
 
 
 
 


 
 
19 Appendix H: Patient Health Questionnaire (PHQ-9) 
 


 
 
 
 


 
 
20 Appendix I: FertiQoL 
 


 
 
21 Appendix J: Epworth Sleepiness Scale 
 
 
 


 
 
22 Appendix K: Stop Bang Questionnaire 
 


 
 
23 Appendix L: Female Sexual Distress Scale (FSDS- Revised 2005) 
 
INSTRUCTIONS 
Below is a list of feelings and problems that women sometimes have concerning their sexuality. Please read 
each item carefully, and circle the number that best describes HOW OFTEN THAT PROBLEM HAS 
BOTHERED YOU OR CAUSED YOU DISTRESS DURING THE PAST 7 DAYS INCLUDING TODAY. Circle 
only one number for each item, and take care not to skip any items. If you change your mind, erase your first 
circle carefully. Read the example before beginning, and if you have any questions please ask about them. 
Example: How often did you feel: Personal responsibility for your sexual problems. 
 
NEVER  
RARELY  
OCCASIONALLY  
FREQUENTLY  
ALWAYS 
     0   
    1  
 
           2  
 
 
3 
                  4 
 
HOW OFTEN DID YOU FEEL: 
1. Distressed about your sex life  
 
 
0  
1  
2  
3  
4 
2. Unhappy about your sexual relationship   
0  
1  
2  
3  
4 
3. Guilty about sexual difficulties  
 
 
0  
1  
2  
3  
4 
4. Frustrated by your sexual problems  
 
0  
1  
2  
3  
4 
5. Stressed about sex  
 
 
 
0  
1  
2  
3  
4 
6. Inferior because of sexual problems  
 
0  
1  
2  
3  
4 
7. Worried about sex   
 
 
 
0  
1  
2  
3  
4 
8. Sexually inadequate  
 
 
 
0  
1  
2  
3  
4 
9. Regrets about your sexuality  
 
 
0  
1  
2  
3  
4 
10. Embarrassed about sexual problems  
 
0  
1  
2  
3  
4 
11. Dissatisfied with your sex life  
 
 
0  
1  
2  
3  
4 
12. Angry about your sex life   
 
 
0  
1  
2  
3  
4 
13. Bothered by low sexual desire   
 
0  
1  
2  
3  
4 
Copyright 2000 by American Foundation for Urological Disease Inc. 
 


 
 
24 Appendix M:  International Index of Erectile Function (IIEF) 
(Write the number that best describes your erectile function for the past 4 weeks in the spaces 
provided.) 
 
Over the past four weeks: 
1. How often were you able to get an erection 
during sexual activity?     _______ 
 0 = No sexual activity 
1 = Almost never/never 
2 = A few times (much less than half the time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the time) 
5 = Almost always/always 
2. When you had erections with sexual 
stimulation, how often were your erections hard 
enough for penetration?     _______ 
 0 = No sexual activity 
1 = Almost never/never 
2 = A few times (much less than half the time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the time) 
5 = Almost always/always 
3. When you attempted sexual intercourse, how 
often were you able to penetrate (enter) your 
partner?     _______ 
 0 = Did not attempt intercourse 
1 = Almost never/never 
2 = A few times (much less than half the time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the time) 
5 = Almost always/always 
4. During intercourse, how often were you able 
to maintain your erection after you had 
penetrated (entered) your partner?     _______ 
 0 = Did not attempt intercourse 
1 = Almost never/never 
2 = A few times (much less than half the time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the time) 
5 = Almost always/always 
5. During sexual intercourse, how difficult was it 
to maintain your erection to completion of 
intercourse?     _______ 
 0 = Did not attempt intercourse 
1 = Extremely difficult 
2 = Very difficult 
3 = Difficult 
4 = Slightly difficult 
5 = Not difficult 
6. How many times have you attempted sexual 
intercourse?     _______ 
 0 = No attempts 
1 = One to two attempts 
2 = Three to four attempts 


 
 
3 = Five to six attempts 
4 = Seven to ten attempts 
5 = Eleven or more attempts 
7. When you attempted sexual intercourse, how 
often was it satisfactory for you?     _______ 
 0 = Did not attempt intercourse 
1 = Almost never/never 
2 = A few times (much less than half the time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the time) 
5 = Almost always/always 
8. How much have you enjoyed sexual 
intercourse?     _______ 
 0 = No intercourse 
1 = No enjoyment 
2 = Not very enjoyable 
3 = Fairly enjoyable 
4 = Highly enjoyable 
5 = Very highly enjoyable 
9. When you had sexual stimulation or 
intercourse, how often did you 
ejaculate?     _______ 
 0 = No sexual stimulation/intercourse 
1 = Almost never/never 
2 = A few times (much less than half the time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the time) 
5 = Almost always/always 
 
10. When you had sexual stimulation or 
intercourse, how often did you have the feeling 
of orgasm or climax?     _______ 
 0 = No sexual stimulation/intercourse 
1 = Almost never/never 
2 = A few times (much less than half the time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the time) 
5 = Almost always/always 
11. How often have you felt sexual 
desire?     _______ 
 1 = Almost never/never 
2 = A few times (much less than half the time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the time) 
5 = Almost always/always 
12. How would you rate your sexual 
desire?     _______ 
 1 = Very low/none at all 
2 = Low 
3 = Moderate 


 
 
4 = High 
5 = Very high 
13. How satisfied have you been with your 
overall sex life?     _______ 
 1 = Very dissatisfied 
2 = Moderately dissatisfied 
3 = About equally satisfied and dissatisfied 
4 = Moderately satisfied 
5 = Very satisfied 
 
14. How satisfied have you been with your 
sexual relationship with your 
partner?     _______ 
 1 = Very dissatisfied 
2 = Moderately dissatisfied 
3 = About equally satisfied and dissatisfied 
4 = Moderately satisfied 
5 = Very satisfied 
15. How would you rate your confidence that 
you could get and keep an erection?     _______ 
 1 = Very low 
2 = Low 
3 = Moderate 
4 = High 
5 = Very high 
*RC Rosen, A Riley, G Wagner et al. The international index of erectile dysfunction (IIEF): a 
multidimensional scale for assessment of erectile dysfunction. Urology 1997 49: 822-30. 
Copyright © 2004 Urology Specialists, S.C. All rights reserved. Last Updated: 18 May 2004 
 
 
 


 
 
25 Appendix N: Diet History Questionnaire II 
 
 


 
 
 


 
 
 


 
 
 


 
 
 


 
 
 


 
 
 


 
 
 


 
 
 


 
 
 


 
 
 


 
 
 


 
 
 
 
 


 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 


 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 


 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 


 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 


 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 


 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 


 
 
 
 
 


 
 
 
 
 


 
 
 
 
 


 
 
 
 


 
 
26 Appendix O: Automated Self-Administered 24-hour Recall (ASA24) 
 


 
 
 


 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 


 
 
27 Appendix P: qADAM Questionnaire 
 
The quantitative ADAM questionnaire.  Int J Impot Res. 2010 Jan; 22(1): 20–24.  
O Mohamed,1 R E Freundlich,1 H K Dakik,1 E D Grober,2 B Najari,3 L I Lipshultz,1 and M Khera1,* 
Published online 2009 Aug 6. doi:  10.1038/ijir.2009.35 
PMCID: PMC2834355 
 
 


 
 
28 Appendix Q: Psychosexual Daily Questionnaire 
 
 
A Simple Self-Report Diary for Assessing Psychosexual Function in Hypogonadal Men  
Ka Kui Lee1,2, Nancy Berman3, Gerianne M. Alexander4, Laura Hull1, Ronald S. Swerdloff1 and Christina 
Wang1,* 
Article first published online: 2 JAN 2013 
DOI: 10.1002/j.1939-4640.2003.tb02728.x 
 
 
 


 
 
29 Appendix R: Sun Exposure and Behaviour Inventory (SEBI v2) 
Subject ID: 
 
Survey Administration: 1st / 2nd 
Date:   
 
 
For each question listed, please check off the ONE answer that is the BEST response to the question. 
 
A sunburn is defined as skin redness or pain which lasts at least one day after sun exposure. 
 
1. Which of the following BEST describes your skin’s reaction to one hour of summer sun without 
sunscreen? 
 
Always burns, never gets darker /tans (Very light 
skin, Caucasian) 
 
Always burns at first, but sometimes gets darker/tans with continued sun exposure (Light skin, 
Caucasian) 
 
Sometimes burns first, but always gets darker/tans with continued sun exposure (Medium 
skin, usually Caucasian) 
 
Rarely burns, gets darker/tans easily with sun exposure (Olive skin, 
may be of many race/ethnic backgrounds) 
 
Never burns, skin gets darker with sun exposure 
(Brown to dark-brown skin, may be of many race/ethnic backgrounds) 
 
Never burns, no darkening of skin color with sun exposure (Black skin, 
African ancestry) 
 
2. How many times in your life have you had a SUNBURN? 
 
None 
 
1-10 
 
11-20 
 
More than 20 
 
3. How many times in your life have you had a SUNBURN that BLISTERED? 
 
None 
 
1-3 
 
4-10 
 
More than 10 
 
4. How many times in your life have you used a tanning bed/booth/sunlamp? 
 
None 
 
1-10 
 
11-50 
 
51-100 


 
 
 
101-500 
 
More than 500 
 
5. Have you lived in an area with a significantly sunnier climate than Boston for six months or more? 
 
Yes 
 
No 
 
IF yes, what city/state or country?   
 For how long? 
 
Less than 5 years 
 
6-10 years 
 
11-20 years 
 
More than 20 years 
 
6. Please rate your lifetime sun exposure 
 
Very low 
Low 
Moderate 
High 
Very high 
TOTAL sun exposure 
Exposure from OUTDOOR RECREATION 
Exposure from your JOB 
 
7. Which of the following BEST describes your NATURAL skin and hair color when you were a 
young adult (18-25)? 
 
Light skin, red or red-blonde hair 
 
Light skin, blonde or light brown hair 
 
Light skin, brown or black hair 
 
Medium-tone skin, brown or black hair 
 
Brown skin, dark brown or black hair 
 
Black skin, dark brown or black hair 
 
8. What is your eye color? 
 
Brown 
 
Blue, green, gray 
 
Hazel (brownish green) 
 
Now, think about your current lifestyle to answer the remaining questions. 
 
9. Think about what you do when you are outside during the summer on a warm sunny day. 
 
Never 
Rarely 
Sometimes 
Often 
Always 
How often do you wear SUNSCREEN? 


 
 
How often do you wear a SHIRT WITH 
SLEEVES that cover your shoulders? 
How often do you wear a HAT that shades 
your face, ears, and neck? 
How often do you stay in the SHADE or 
UNDER AN UMBRELLA? 
How often do you wear SUNGLASSES? 
 
10. What is the Sun Protection Factor (SPF) of the sunscreen that you use most often? 
 
Less than SPF 15 
 
SPF 15 or higher 
 
Don’t know 
 
I don’t use sunscreen 
 
11. Does your sunscreen have both UVA and UVB protection? 
 
Yes 
 
No 
 
Don’t know 
 
I don’t use sunscreen 
12. How often do you spend time in the sun or in a tanning bed/booth in order to get a tan or to feel 
good? 
 
Never 
 
Rarely 
 
Sometimes 
 
Often 
 
Always 
 
13. Have you been tan in the last 12 months? 
 
Yes 
 
No 
 
14. In the SUMMER (June, July, August), on average, how many hours per day are you outside 
between 10am and 4pm? 
 
Less than 1hour 
1hour 
2hours 
3hours 
4hours 
5hours 
6 hours 
On WEEKDAYS 
(Monday-Friday) 
On WEEKENDS 
(Saturday and Sunday) 
 
15. In NON-SUMMER months (September to May), on average, how many hours per day are you 
outside between 10am and 4pm? 


 
 
 
Less than 1hour 
1hour 
2hours 
3hours 
4hours 
5hours 
6 hours 
On WEEKDAYS 
(Monday-Friday) 
On WEEKENDS 
(Saturday and Sunday) 
 
 
 


 
 
30 Appendix S: Investigator Signature of Agreement 
 
Investigator Signature of Agreement 
The Eunice Kennedy Shriver National Institute of Child Health and Human Development 
Reproductive Medicine Network 
 
Title:  Males, Antioxidants, and Infertility (MOXI) Trial 
 
Version: 4.0 
 
Principal Investigator: 
 
I, [Insert PI’s name]                , the Principal Investigator for           [Insert Institute Name], hereby certify that I have read and 
agree to conduct this study in accordance with this protocol on behalf of all RMN Investigators and research staff from my 
site. 
I will conduct the clinical study as described and will adhere to the Code of Federal Regulations, Title 21 and Title 
25, Part 46, Good Clinical Practices (GCP), International Conference on Harmonisation (ICH), and the 
Declaration of Helsinki.  I have read and understood the contents of the Protocol. 
The signature of the investigator below indicates acceptance of the protocol and a complete understanding of the 
investigator commitments as outlined in Form FDA 1572, Statement of Investigator. 
 
______________________________________________________________________________ 
Principal Investigator’s Signature 
 
 
 
 
 
Date 
 
______________________________________________________________________________ 
Printed Name  
 
 
 
 
 
 
 
Date 
 
 
 


 
 
31 Appendix T: Data and Safety Monitoring Plan  
 
DATA AND SAFETY MONITORING BOARD (DSMB) CHARTER 
 
Males, Antioxidants, and Infertility (MOXI) Trial 
 
1. 
Purpose and Responsibilities of the DSMB 
The members of the Data and Safety Monitoring Board (DSMB) identified in this Charter for the MOXI study are 
responsible for safeguarding the interests of study participants, assessing the safety and efficacy of all study procedures, 
and shall monitor the overall conduct of the MOXI trial.  This Committee will serve as an independent advisory group to 
the Director of NICHD, and is required to provide recommendations about starting, continuing, and stopping the MOXI 
trial.   
This Committee is responsible for identifying mechanisms to complete various tasks that will impact the safety and efficacy 
of all study procedures, and overall conduct. The table below identifies the key areas where oversight is necessary and the 
ways in which the Committee for the MOXI trial will complete those tasks. 
Basic Responsibility of DSMB 
Method DSMB for MOXI will use to complete task 
Familiarize themselves with the study 
protocol  
⋅ Review study protocols and informed consent forms. 
Monitor adverse events 
⋅ Adverse Event: Review quarterly progress reports prepared 
by the DCC on behalf of RMN. 
⋅ Serious Adverse Events: Review report submitted by the 
DCC on behalf of RMN within one week of the event if life 
threatening or fatal, or within two weeks otherwise. The 
DSMB will submit a report of their review to the NICHD 
Committee Coordinator within 7 business days if the SAE 
is life threatening or fatal, or within two weeks otherwise. 
Monitor data quality 
⋅ Conduct interim evaluations of the data. 
Oversee participant recruitment and 
enrollment 
⋅ Review interim progress reports prepared by the DCC on 
behalf of RMN. 
Develop an understanding of the 
Study’s risks and benefits 
⋅ Review study protocols and related literatures. 
⋅ Review interim reports of subject accrual and outcome 
measures provided by the DCC. 
⋅ Assess the need to perform further in-depth evaluation of 
the benefits and risks of the study after reviewing each 
report.  
Ensure the proper reporting occurs 
⋅ Review and approve the meeting and reporting schedule 
listed in Section 5 of this DSMB charter. 


 
 
2. 
Contacts 
 
NICHD 
Louis DePaolo, PhD, Program Officer 
Charisee Lamar, PhD, MPH, RRT, Committee Coordinator 
Esther Eisenberg, MD, MPH, Project Scientist 
 
Data Coordination Center (DCC) 
Heping Zhang, PhD, DCC Principal Investigator 
Hao Huang, MD, DCC Data Manager 
 
The Data Manager at the DCC will prepare and review the DSMB reports prior to submission to the DSMB, and will not 
be blind to treatment condition. 
 
Lead Investigator 
Anne Z. Steiner, MD, MPH 
 
3. 
DSMB Members, Organizational Chart, & Communications 
 
Members 
The DSMB for the MOXI trial is comprised of the members listed in the table below.  In addition, their high level roles 
and responsibilities are identified in the table.  
Name of Member 
Role on DSMB 
High Level Responsibilities 
Frank Witter, MD 
Chair of DSMB 
Voting member 
⋅ Chair the DSMB discussion and prepare written recommendations 
to NICHD. 
⋅ Ensure the safety of study subjects, the integrity of the research 
data. 
⋅ Provide NICHD with advice on the ethical and safe progression of 
studies conducted in the RMN.  
⋅ Advises on research design issues, data quality and analysis, and 
research participant protection for each prospective and on-going 
study.  
Robert E. Brannigan, MD Voting member 
⋅ Ensure the safety of study subjects, the integrity of the research 
data. 
⋅ Provide NICHD with advice on the ethical and safe progression of 
studies conducted in the RMN.  
⋅ Advises on research design issues, data quality and analysis, and 
research participant protection for each prospective and on-going 
study.  
Rev. Phillip Cato, PhD 
Voting member 
PonJola Coney, MD 
Voting member 
Lurdes Y.T. Inoue, PhD 
Voting member 
Stacey A. Missmer, ScD 
Voting member 


 
 
Only Voting members for this DSMB may attend closed sessions for this Committee. In addition, only Voting members 
will have access to unblinded data points for this Committee.  
Organizational Chart  
The following diagram illustrates the relationship between the DSMB and other entities in the MOXI study.     
               
 
Communication 
Communication for members of this DSMB will be primarily through the NICHD Program Office and, where applicable, 
the Data Coordination Center (DCC). Investigators from the MOXI study will not communicate directly with DSMB 
members about the study, except when making presentations or responding to questions at DSMB meetings or during 
scheduled conference calls. 
 
4. 
Conflict of Interest and Compensation 
 
It is extremely important that all members of the DSMB state any real or apparent conflicts of interests at the onset of the 
study. Members of the DSMB shall read the NICHD Clinical Research Guidance Document regarding Conflict of Interest 
and provide their signed summary of any COI for the study, at its onset, to the NICHD Committee Coordinator, Dr. Charisee 
Lamar. A table summarizing any COI within the DSMB is provided in the Appendix.  
Prior to each meeting, all members of the RMN DSMB will have an opportunity to state whether they have developed any 
new conflicts of interest since the meeting. As a new COI is identified it must be documented in the table in the Appendix 
and a new signed summary of the COI should be provided to the NICHD Committee Coordinator. The Coordinator will 
forward the COI documentation to the DCC for record-keeping purposes. 
If a new conflict is reported, the Coordinator and staff will determine if the conflict limits the ability of the DSMB member 
to participate in the discussion. 
Study Site 
Study Site 
Study Site 
Data Coordinating 
Center 
Individual Institutional  
Review Boards  
NICHD Program 
Staff 
NICHD Director
DSMB 


 
 
All DSMB members will be compensated for their role in supporting the committee. Compensation will include an 
honorarium for meeting attendance and any travel costs. 
 
5. 
Meeting Schedule 
 
DSMB meetings will be conducted quarterly. However, the DSMB may hold a meeting at any time in accordance with their 
mission. The NICHD Committee Coordinator will notify the DCC of any change in schedule.  
 
6. 
Blinding 
 
All summaries for DSMB reports will be presented in a blinded fashion, unless specified by the DSMB Chair. 
 
7. 
Report Schedule and Content 
 
The type of reports (full or brief) is indicated below, followed by a description of the contents of each type. 
DSMB Report 
Report Submission Date 
Type of Report 
1. 
tbd 
Brief 
2. 
tbd 
Brief 
3. 
tbd 
Brief 
4. 
tbd 
Full 
5. 
tbd 
Brief 
6. 
tbd 
Full 
7. 
tbd 
Brief 
8. 
tbd 
Full 
9. 
tbd 
Brief 
10. 
tbd 
Full 
11. 
tbd 
Brief 
 
Brief DSMB reports will include the following summaries: 
• 
overall actual versus projected enrollment accrual 
• 
overall randomization update 
• 
overall study drop-out rate 
• 
serious adverse events 
• 
primary outcome measures update 
 
Full DSMB reports will include the following summaries: 
• 
recruitment update (number screened) overall and by site 


 
 
• 
enrollment update (enrolled defined as randomized to a treatment) overall and by site 
• 
accrual status including actual enrollment compared to projections overall and by site 
• 
randomization update (i.e., number assigned to each treatment arm) 
• 
study drop-out rate for enrolled patients (number, reason, time point) overall and by site) 
• 
pre-specified subset of baseline demographic data for enrolled patients 
• 
safety data, adverse events, and serious adverse events 
• 
number of case report forms expected 
• 
number/percentage of expected case report forms received – overall and by site 
• 
number of case report forms that are query clean 
• 
primary outcome measures update 
 
References 
NIH Policy for Data and Safety Monitoring  
http://grants.nih.gov/grants/guide/notice-files/NOT98-084.html  
Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-supported Multi-center Clinical Trials 
http://grants.nih.gov/grants/guide/notice-files/not99-107.html. 
 
 


 
 
Appendix: Summary of COI within the DSMB 
 
DSMB Member Name 
Date Submitted 
Signed COI  
Was a COI 
Identified? 
Will the Member Remain part 
of the Committee? 
Robert E. Brannigan, MD 
 
 
 
Rev. Phillip Cato, PhD 
 
 
 
PonJola Coney, MD 
 
 
 
Lurdes Y.T. Inoue, PhD 
 
 
 
Stacey A. Missmer, ScD 
 
 
 
Frank Witter, MD 
 
 
 
 
 
 


 
 
 
 
 
Reproductive Medicine Network 
Funded by Eunice Kennedy Shriver NICHD 
 
 
 
Conflict of Interest Statement 
 
Males, Antioxidants, and Infertility (MOXI) Trial 
 
 
I, ______________________, assuming the role of __________________________________________      
 
 
 
 
 
 
 
 
(insert role, for example: DSMB member)  
for the __________________________________________________________ 
 
 
 
 
(insert project or study name) 
agree to the following statements.   
□ I agree to: 
 
protect the interests and safety of study participants; 
 
uphold the integrity of the research process including data collection and analysis to be as free from bias and 
preconception as I am able; 
 
adhere to the highest scientific and ethical standards, to comply with all relevant regulations and to eliminate 
or disclose, during my involvement with the proposed clinical research project, any real or apparent conflicts 
of interest. 
 
In addition: 
□ I declare that I, my spouse or dependent children, or organization with which I am connected, do/does not have any 
financial interest in the ___________________ study, where financial interested is defined by the DHHS, as anything of 
monetary value, including but not limited to, salary or other payments for services (for example, consulting fees or 
honoraria); equity interests (for example, stocks, stock options or other ownership interests); and intellectual property 
rights (for example, patents, copyrights and royalties from such rights).   


 
 
The financial interest term does not include various items which can be found in The Federal regulation, PHS, DHHS Part 
50--Policies of General Applicability; Subpart F- Responsibility of Applicants for Promoting Objectivity in Research for 
Which PHS Funding Is Sought.  
For Federal employees, financial interests that are allowable and require disclosure are: 
Financial Interest Disclosure: Financial interest that require disclosure are stock holdings in pharmaceutical firms, medical 
device manufacturers, and biotechnology companies 
Allowable Financial Interests: In a company that produces a product that is being evaluated by a study, participants may 
hold up to $15,000 of stock: and up to an aggregate of $25,000 of the stock of that company and its competitors who 
produce that (or a similar) product. As an alternative to individual stock holdings, participants may hold up to an 
aggregate of $50,000 in sector mutual funds-including pharmaceutical/health care sectors. 
For holdings in excess of these de minimus levels, a conflict of interest analysis needs to be conducted by NIH regarding 
the holding, the company producing the product being evaluated under the study, and its competitors, and, if a conflict 
exists, could lead to the need to withdraw from the study. 
□ I agree to not withhold any data related to the _____________________ study or to interfere with the analysis or 
publication of the study’s results. 
□ I will not engage in activities that could be viewed as real or apparent COI, including but not limited to: 
□  having a part-time, full-time, paid, or unpaid employee status of any organizations that are: (a) involved in the 
study under review; (b) whose products will be used or tested in the study under review, or whose products or 
services would be directly and predictably affected in a major way by the outcome of the study; 
□  being an officer, member, owner, trustee, director, expert advisor, or consultant of such organizations;  
□  being a current collaborator or associate of the principal investigator (applicable to potential members of data 
safety and monitoring boards); 
□  having a scientific interest beyond that required for my role, where scientific interest is defined as having 
influence over the protocol, the study design, conducting the study analysis or any reporting related to the 
investigation (applicable to potential members of data safety and monitoring boards).