Clinical trial NCT03785366
Conditions: Women at Risk for Pregnancy
Sponsor: Sebela Women's Health Inc.
Start date: 2018-12-17; Completion date: 2024-08-01
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
to Assess the Pharmacokinetic Properties of VeraCept® Intrauterine Contraceptive vs ParaGard® in Healthy, Post- Menarcheal Women

Detailed description:

Arms: arm 1: VeraCept subjects will be inserted with VeraCept on Day 1. At Day 57 subjects will be informed that they received VeraCept and may continue in the study for up to 5 years arm 2: ParaGard subjects will be inserted with ParaGard on Day 1. At Day 57 subjects will be informed that they received ParaGard and may choose to have the ParaGard removed or continue use per standard of clinical care.
Interventions: intervention 1: VeraCept intervention 2: ParaGard
Intervention descriptions: intervention 1: VeraCept Intrauterine Device (IUD) intervention 2: ParaGard intrauterine copper contraceptive

Protocol documents:
Prot_000.pdf: 
NCT03785366 
STUDY PROTOCOL 
A Randomized, Single-Blind, Comparative Bioavailability Study to Assess the 
Pharmacokinetic Properties of VeraCept® Intrauterine Contraceptive vs ParaGard® in 
Healthy, Post-Menarcheal Women 
 
DOCUMENT DATE: 03 Jul 2019 




Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 2 of 49 
INVESTIGATOR PROTOCOL AGREEMENT 
I have received a copy of Protocol Number CMDOC-0045, A Randomized, Single-Blind, 
Comparative Bioavailability Study to Assess the Pharmacokinetic Properties of VeraCept® 
Intrauterine Contraceptive vs ParaGard® in Healthy, Post-Menarcheal Women, Version 2.0 
dated July 3, 2019 from Sebela. I agree to the conditions as set out in this protocol and fully 
accept that any change requires prior approval from Sebela. Additionally, I agree to carry out 
all terms of this protocol in accordance with International Conference on Harmonization 
(ICH) Guidelines, all applicable US Regulations (21 Code of Federal Regulations [CFR] 
parts 50, 54, 56 and 312) and Good Clinical Practice (GCP) Guidelines, as applicable. 
Finally, I will ensure that the investigational product will be used only as described in this 
protocol. 
The information contained in this protocol is provided to me in confidence, for review only 
by myself, the Independent Ethics Committee / Institutional Review Board authorized to 
review and approve the study at this study site, the designated research staff participating in 
this clinical study, and applicable regulatory agencies. 
I understand that the information/technology contained in this protocol is proprietary and 
may not be disclosed to any other party, in any form, without prior authorization from 
Sebela, except to the extent necessary to obtain informed consent and assent, if applicable, 
from potential study participants. 
 
 
 
  Investigator’s Name (print) 
 
 
 
Investigator’s Signature 
 
Date   (MM/DD/YYYY) 




Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 4 of 49 
SYNOPSIS 
Name of Sponsor Company: Sebela Pharmaceuticals, Inc. 
Name of Investigational Drug: VeraCept Intrauterine Contraceptive 
Name of Active Ingredient: Copper 
Title of Study 
A Randomized, Single-Blind, Comparative Bioavailability Study to 
Assess the Pharmacokinetic Properties of VeraCept® Intrauterine 
Contraceptive vs ParaGard® in Healthy, Post-Menarcheal Women 
Investigator(s) and 
Study Center(s) 
Jeffrey Jensen, MD, MPH 
Oregon Health and Science University 
Women’s Health Research Unit 
3181 SW Sam Jackson Park Rd. 
Mail code: UHN70 
Portland, OR 97239 
Robin Kroll, MD 
Seattle Women’s: Health, 
Research, Gynecology 
3216 NE 45th Place, Suite 100 
Seattle, WA 98105 
Phase of 
Development 
Phase 3 
Study Objectives 
The primary objective of this study is: 
• 
Assess the relative bioavailability of observed systemic 
copper from VeraCept versus ParaGard based on Cmax, 
Cmean, and AUC0-56 days   
The secondary objective of this study is: 
• 
To assess the relative bioavailability of baseline-corrected 
total serum copper from the VeraCept IUD versus ParaGard 
based on Cmax, Cmean, and AUC0-56 days.  
• 
To assess the total serum copper levels within each treatment 
relative to the normal range (49 to 184 µg/dL). 
• 
To assess the long-term stability of copper levels following 
insertion of the VeraCept IUD 
Study Design 
This randomized, single-blind study is designed to evaluate the 
comparative bioavailability of systemic copper exposure after insertion of 
VeraCept vs ParaGard in post-menarcheal women.  Up to 40 subjects from 
one or more sites will receive one of two treatments (A or B) as described 
below:  
• 
Treatment A (N=20): VeraCept IUD, test (referred to as 
VeraCept) 
• 
Treatment B (N=20): ParaGard IUD, reference (referred to as 
ParaGard)  
 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 5 of 49 
Treatment Comparison Phase 
 
Subjects will be screened within 60 days prior to the first insertion of study 
drug, and blood samples will be collected within 28 days from first 
insertion of study drug at two visits within this screening period  to 
establish baseline copper concentrations.  At least 24 hours should separate 
each baseline sample. On Day 1 of each treatment period, PK, safety and 
baseline assessments will be collected prior to IUD insertion. Subjects will 
return to the clinic at 48 hours post-IUD insertion (Day 3(±24 hours)) and 
on Days 8 (±1 day), 15 (±1 day), 22 (±1 day), 29 (±1 day) and 57 (±3 days) 
for blood collection for measurement of total serum copper concentrations.  
Extension Phase 
On Day 57, ParaGard subjects will exit the study and may continue 
ParaGard use per standard clinical care. VeraCept subjects will continue 
in the extension phase of the study intended to assess long-term stability 
of serum copper concentrations up to 5 years and monitor safety. During 
the first 3 years, subjects will return to the clinic every 6 months (±30 days) 
for clinical assessment and blood collection for measurement of total 
serum concentrations.  Following Year 3, subjects will return annually for 
up to Year 5. A schedule of the study procedures and assessments to be 
conducted for each subject is provided in the Time and Events Table 
(Appendix 1). 
Study Rationale 
In order to maximize the ability to detect a difference in copper exposure 
following insertion of VeraCept and ParaGard, this study has been 
designed to sample total serum copper concentrations for the first 60 days 
post-insertion. Copper release rates from copper IUDs have been shown to 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 6 of 49 
decrease over time with the predominant decrease in release rate occurring 
in the first 60 days [1].  The initial release rate of copper (the burst release) 
appears to be correlated with the exposed surface area of copper in the 
device.  However, as the release rates decrease over time, the release rate 
of copper plateaus and appears to be less dependent on the exposed surface 
area of the device (Figure 1-1).   
Ion release testing (CTM-20141110-1) comparing VeraCept with Optima 
TCu380S, a commercial copper IUD with twice the exposed copper 
surface area, demonstrated that insertion of a copper IUD results in an 
initial burst of copper release followed by a steady decline in copper 
release rate which stabilizes by approximately 21 days of immersion 
(Figure 1-2). The highest average daily release rate was observed on day 1 
at 1,600 ppb/day (~45 µg/day).  From 21 to 60 days, the copper release 
rate remained relatively low and continued to decrease slightly from 278 
ppb/day (~7.8 µg/day) on day 21 to 149 ppb/day (~4.2 µg/day) on day 60.  
According to Chantler et al. (1977) [1], the highest copper release rate for 
an IUD with a similar surface area to that of the marketed ParaGard IUD 
is approximately 3.2 µmol/day (~200 µg/day) while the corresponding 
value for VeraCept is approximately 1.2 µmol/day (~75 µg/day).  By 60 
days, the release rate for IUDs with exposed copper surface areas similar 
to that of ParaGard and VeraCept decreased to below 0.5 µmol/day or 
approximately 30 µg/day.  Long-term studies of other copper IUDs have 
reported similar and even lower copper release rates [2, 3]. 
Average daily dietary intake of copper has been reported to be 
approximately 1.0 to 1.6 mg/day [4-6].  Based on the data described above, 
by 60 days following insertion, the copper released from these IUDs would 
represent less than 3% of daily dietary intake of copper.  Given the small 
amount of copper released by the IUDs relative to the total daily intake of 
copper, it would be difficult to attribute serum copper concentrations to the 
IUD beyond this initial release period.  Therefore, in order to maximize 
the potential to capture a difference in copper exposure following insertion 
of the IUD, the sampling schedule will focus on the first 60 days post-
insertion (i.e. 48 hours post-insertion through Day 57). 
An extension phase following Day 57 for the VeraCept subjects will assess 
the long-term stability of copper levels following insertion of the VeraCept 
IUD up to 5 years. 
Number of planned 
subjects  
40 post-menarcheal women will be randomized (20 subjects per 
treatment), to obtain data from at least 12 evaluable subjects per treatment 
group.  An evaluable subject is a subject who has pre-insertion copper 
concentrations within the normal range (49 to 184 µg/dL) [7], had an IUD 
placed successfully, and completes all scheduled PK sample collections 
without a protocol deviation or AEs that significantly impact the planned 
PK analyses to Day 57 and for VeraCept subjects continuing in the 
extension phase.  Replacement subjects may be enrolled, as needed, to 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 7 of 49 
ensure that at least 24 evaluable subjects (12 subjects per treatment) 
complete the study.   
Inclusion/Exclusion 
Criteria 
Inclusion Criteria 
A subject will be eligible for inclusion in this study if they meet all of the 
following criteria:  
1. Post-menarcheal, pre-menopausal females up to 45 years of age at the 
time of informed consent/assent and in good general health; 
2. History of regular menstrual cycles defined as occurring every 21-35 
days when not using hormones or prior to recent pregnancy or 
spontaneous or induced abortion; 
3. Sexually active with a male partner who has not had a vasectomy; 
4. Reasonably expect to have coitus at least once monthly during the 
study period; 
5. In a mutually monogamous relationship of at least 3 months duration; 
6. Seeking to avoid pregnancy for the duration of the study; 
7. Willing to use the study drug as the sole form of contraception; 
8. Willing to accept a risk of pregnancy;   
9. Subjects must be in compliance with cervical cancer screening 
guidelines per the American Society for Colposcopy and Cervical 
Pathology (ASCCP) guidelines without evidence of disease. Subjects 
who are age 21-24 y/o, at time of informed consent, must have a 
normal papanicolaou test (Pap), atypical squamous cells of 
undetermined significance (ASC-US), or low-grade squamous 
intraepithelial lesion (LSIL). Subjects who are 25 or older at the time 
of informed consent with ASC-US results, must also have a negative 
high risk human papilloma virus (HPV) test result within the 
appropriate screen timeframe per American Society for Colposcopy 
and Cervical Pathology (ASCCP) guidelines, and prior to the study 
IUD insertion. Alternatively, the subject must have had a colposcopy 
performed within the appropriate screen timeframe, and prior to the 
study IUD insertion that showed no evidence of dysplasia requiring 
treatment per ASCCP guidelines, or treatment was performed and 
follow-up at least 6 months after the treatment showed no evidence of 
disease by clinical evaluation; 
10. Able and willing to comply with all study tests, procedures, 
assessment tools and follow-up;  
11. Able and willing to provide and document informed consent and 
Authorization for Release of Protected Health Information (PHI). 
Unemancipated subjects under 18 years old must provide assent and 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 8 of 49 
have written parental consent documented on the consent form 
consistent with local legal requirements; 
12. Plan to reside within a reasonable driving distance of a research site 
for the duration of the study. 
13. Subject agrees not to self-remove VeraCept 
 
Exclusion Criteria 
A subject will be excluded from participating in the study if any of the 
following conditions apply:  
1. Known or suspected pregnancy; or at risk for pregnancy from 
unprotected intercourse earlier in current cycle; 
2. A previously inserted intrauterine device (IUD) that has not been 
removed by the time the study IUD is placed; 
3. History of previous IUD complications, such as perforation, 
expulsion, or pregnancy with IUD in place; 
4. Pain with current IUD; 
5. Injection of hormonal contraceptive (e.g., Depo-Provera) within the 
last 10 months and has not had 2 normal menstrual cycles since the 
last injection; 
6. Use of ParaGard IUD within the past 3 months 
7. Planned use of any non-contraceptive estrogen, progesterone or 
testosterone any time during the 60 months of study participation; 
8. Exclusively breastfeeding before return of menses; lactating women 
will be excluded unless they have had 2 normal menstrual periods 
prior to enrollment; 
9. Unexplained abnormal uterine bleeding (suspicious for a serious 
condition), including bleeding 4 weeks post-septic abortion or 
puerperal sepsis; 
10. Severely heavy or painful menstrual bleeding; 
11. Suspected or known cervical, uterine or ovarian cancer, or unresolved 
clinically significant abnormal Pap smear requiring evaluation or 
treatment; 
12. Any history of gestational trophoblastic disease with or without 
detectable elevated ß-human chorionic gonadotropin (ß-hCG) levels, 
or related malignant disease;  
13. Any congenital or acquired uterine anomaly that may complicate 
study drug placement, such as: 
● 
Submucosal uterine leiomyoma 
● 
Asherman’s syndromes 
● 
Pedunculated polyps 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 9 of 49 
● 
Bicornuate uterus 
● 
Didelphus or uterine septa 
14. Any distortions of the uterine cavity (e.g. fibroids), that, in the 
opinion of the investigator, are likely to cause issues during insertion, 
retention or removal of the IUD;  
15. Known anatomical abnormalities of the cervix such as severe cervical 
stenosis, prior trachelectomy or extensive conization that, in the 
opinion of the investigator would prevent cervical dilation and study 
drug placement;  
16. Untreated or unresolved acute cervicitis or vaginitis; 
17. Known or suspected human immunodeficiency virus (HIV) infection 
or clinical AIDS; 
18. Subjects who have an established immunodeficiency; 
19. Known intolerance or allergy to any components of VeraCept or 
ParaGard including intolerance or allergy to nickel, titanium, or 
copper, and including Wilson’s Disease; 
20. Currently participating or planning future participation in a research 
study of an investigational drug or device during the course of this 
investigational study.  Subject must have waited at least 30 days from 
exiting their last study prior to informed consent in this study; 
21. Subject has been enrolled in a previous VeraCept or LevoCept study; 
22. Known or suspected alcohol or drug abuse within 12 months prior to 
the screening visit; 
23. Any general health, mental health or behavioral condition that, in the 
opinion of the investigator, could represent an increased risk for the 
subject or would render the subject less likely to provide the needed 
study information; 
24. Study staff or a member of the immediate family of study staff. 
25. Concurrent use of corticosteroids  
26. Subject is <4 weeks post-pregnancy (postpartum, spontaneous or 
induced abortion) 
 
Note: VeraCept can be inserted on any day of the menstrual cycle using 
the first three criteria for the Centers for Disease Control and Prevention 
(CDC) U.S. Selected Practice Recommendations for Contraceptive Use, 
2016[10] guidance to avoid an undetected pregnancy (see the revised 
Box 2 below and a copy is located in the study reference manual 
provided to the site). If a subject has a previously inserted IUD and has 
pain from that IUD upon removal, then the insertion of VeraCept should 
not occur until the pain has resolved. 
 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 10 of 49 
Post Pregnancy Guidelines 
Subjects who were recently pregnant must have a urine pregnancy test 
performed no sooner than 4 weeks post-pregnancy. If a subject has not 
had 2 normal menses since the end of a pregnancy, the study IUD may be 
placed if her hCG is negative and she has been on a reliable method of 
contraception (e.g. pills, patch, ring) that was started within 2 weeks 
post-pregnancy or has been on this reliable method for 4 weeks. If the 
urine hCG is still positive, investigators can obtain two quantitative hCG 
tests that must demonstrate declining hCG values at least 1 day apart. 
 
BOX 2. How to be reasonably certain that a woman is not 
pregnant[10] 
A health care provider can be reasonably certain that a woman is not 
pregnant if she has no symptoms or signs of pregnancy and meets any 
one of the following criteria: 
 is ≤7 days after the start of normal menses 
 has not had sexual intercourse since the start of last normal menses 
 has been correctly and consistently using a reliable method of 
contraception* 
* If condoms are being used, a double barrier method must be used (e.g. condoms + 
spermicide). 
 
Investigational 
Products, Dose, and 
Mode of 
Administration 
VeraCept IUD (Test) 
ParaGard IUD (Reference) 
 
Duration of 
treatment 
The total duration of each subject’s participation in this study will be 
approximately 57 days for the ParaGard subjects and up to 5 years for the 
VeraCept subjects. 
Endpoints 
The primary endpoint is:  
• 
Mean total serum copper concentration, Cmax, and AUC0-56 
days for observed copper for each treatment   
The secondary endpoints are: 
• 
Mean total serum copper concentration, Cmax, and AUC0-56 
days for baseline-corrected copper for each treatment 
• 
Total serum copper concentrations within each treatment for 
each assessment day for 56 days. 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 11 of 49 
• 
Mean total serum copper concentration for observed and 
baseline-adjusted copper for each treatment over 5 years 
(Treatment A, VeraCept IUD only) 
Criteria for 
Evaluation 
Pharmacokinetics 
Both baseline-corrected and observed total serum copper concentrations 
will be used for calculation of relevant serum PK parameters (e.g., Cmax, 
Cmean, AUC0-56 days) using standard non-compartmental methods and 
actual sampling times utilizing a PK data analysis program (e.g., Phoenix 
WinNonlin® or equivalent).  Baseline correction will utilize the mean 
value of the three baseline copper concentrations.  A linear up/log down 
method using the trapezoidal rule will be used to estimate the area under 
the curve.  If a negative serum concentration value results after baseline 
correction, the value will be set to zero for the calculation of baseline-
corrected PK parameters.  All relevant parameters will be summarized 
using descriptive statistics. 
Statistical Analyses 
For the primary analysis, an ANCOVA model with fixed effects for 
treatment and Day 1 pre-insertion concentration as a continuous effect will 
be used to analyze the uncorrected PK parameters Cmax, Cmean, and 
AUC0-56.  As such, a point estimate of the difference between treatments 
and 90% CIs of the difference will be provided.   
For the secondary analysis, an ANCOVA model with fixed effects for 
treatment and natural ln transformed Day 1 pre-insertion concentration as 
a continuous effect will be used to analyze the natural-log transformed 
corrected PK parameters Cmax, Cmean, and AUC0-56. For each treatment 
comparison, a point estimate and 90% CIs will be provided for the 
geometric least squares mean ratio upon back-transformation.  
In addition, for each PK assessment day, the number and percentage of PK 
assessments within the total serum copper normal range (49 to 184 µg/dL) 
will be assessed for each treatment.  In addition, a shift table will also be 
provided for each of the PK days post Day 1 relative to the normal range. 
Following Day 57 (Extension Phase), serum copper concentrations will 
only be collected for the VeraCept treatment group.  These data will be 
summarized in a Listing and additional statistical analysis or data 
presentations may be performed as appropriate.  
Sample Size 
Determination 
The assumption is that there is no additional systemic exposure of copper 
when using VeraCept vs ParaGard IUD.  For the analysis using mean 
copper concentrations and Cmax, no formal hypothesis testing is being 
done. As such, a precision approach will be taken with boundaries chosen 
to reflect typical BE boundaries in the ln scale (plus or minus 22%).  
Assuming a normal range of 49 to 184 µg/dL, an estimate of the normal 
(mean) value could be close to 110-120. A comparable boundary would be 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 12 of 49 
plus or minus 22.  This estimated mean with the added half-width still falls 
well within the normal range. 
For the analysis using AUC0-56 days, no formal hypothesis testing is 
being done. As such, a precision approach will be taken with boundaries 
chosen to reflect typical BE boundaries in the ln scale (plus or minus 22%).  
AUC values will be ln transformed. 
For a two-sided 90% confidence interval for a two-sample normal mean 
difference, assuming a common standard deviation of 25, a sample size of 
12 per group is required to obtain a half-width of at most 22 µg/dL with a 
conditional probability of at least 0.90 given that the interval contains the 
true mean difference.  The actual probability is 0.95.  
Assuming a maximum unevaluable rate of 40%, up to 20 subjects will be 
enrolled in each group. Replacement subjects may be enrolled, as needed, 
to ensure that at least 24 evaluable subjects complete the study. 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 13 of 49 
Table of Contents 
Inclusion Criteria ................................................................................................................7 
Exclusion Criteria ...............................................................................................................8 
LIST OF ABBREVIATIONS ...............................................................................................17 
1. 
INTRODUCTION ..........................................................................................................18 
1.1.  Background .............................................................................................................18 
1.2.  Study Rationale .......................................................................................................18 
2. 
STUDY OBJECTIVES ..................................................................................................21 
2.1.  Primary Objective ...................................................................................................21 
2.2.  Secondary Objectives ..............................................................................................21 
3. 
INVESTIGATIONAL PLAN ........................................................................................21 
3.1.  Overall Study Design and Plan ...............................................................................21 
3.2.  Primary and Secondary Endpoints ..........................................................................22 
3.2.1.  Primary Endpoint ........................................................................................22 
3.2.2.  Secondary Endpoints ...................................................................................22 
4. 
SELECTION OF STUDY POPULATION ..................................................................23 
4.1.  Inclusion Criteria .....................................................................................................23 
4.2.  Exclusion Criteria....................................................................................................24 
Post Pregnancy Guidelines ......................................................................................25 
4.3.  Screen and Baseline Failures ..................................................................................26 
4.4.  Removal of Subjects from Therapy/Premature Discontinuation ............................26 
5. 
TREATMENTS ..............................................................................................................26 
5.1.  Method of Assigning Subjects to Treatment Groups ..............................................26 
5.2.  Treatments Administered ........................................................................................26 
5.3.  Identity of Investigational Products(s) ....................................................................27 
5.3.1.  VeraCept (Test treatment) ...........................................................................27 
5.3.2.  ParaGard (Reference treatment) ..................................................................27 
5.3.3.  Labeling ......................................................................................................27 
5.3.4.  Storage and Handling ..................................................................................27 
5.4.  Selection of Doses in the Study ..............................................................................28 
5.5.  Prior and Concomitant Therapy ..............................................................................28 
5.5.1.  Prior Therapy ..............................................................................................28 
5.5.2.  Concomitant Therapy ..................................................................................28 
5.5.3.  Prohibited Medications and Devices ...........................................................28 
5.5.4.  Dietary Restrictions .....................................................................................28 
5.6.  Treatment Compliance ............................................................................................30 
5.6.1.  Study Drug Accountability .........................................................................30 
5.6.2.  Treatment After the End of the Study .........................................................30 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
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6. 
STUDY PROCEDURES ................................................................................................30 
6.1.  Study Phases and Procedures ..................................................................................30 
6.1.1.  Screening Window (Day -60 through Day 1) .............................................31 
6.1.2.  Device Insertion, Day 1...............................................................................31 
6.1.3.  Day 3 (48 hours (±24 hours) post-insertion) ...............................................32 
6.1.4.  Days 8, 15, 22, 29 (±1 day) and 57 (±3 days) .............................................32 
6.1.5.  Months 6, 12, 18, 24, 30, 36, and 48 (±30 days).........................................33 
6.1.6.  Month 60 (±30 days) or Exit Visit ..............................................................33 
6.1.7.  Early Discontinuation Visit .........................................................................34 
6.2.  Study Measurements and Assessments ...................................................................34 
6.2.1.  Pharmacokinetic Sample Collection and Processing ..................................34 
6.2.2.  Allergic Reaction or Hypersensitivity to Components of VeraCept ...........34 
7. 
ADVERSE EVENTS ......................................................................................................34 
7.1.  Definition of a Serious Adverse Event....................................................................35 
7.2.  Definition of an Adverse Event...............................................................................35 
7.3.  Adverse Events of Specific Interest ........................................................................35 
7.4.  Causality: Serious Adverse Event and Adverse Event Relationship to Study 
Treatment ................................................................................................................36 
7.4.1.  Clarification of Adverse Events Related to Study Procedures....................36 
7.5.  Serious Adverse Event and Adverse Event Severity ..............................................37 
7.6.  Adverse Event Outcome .........................................................................................37 
7.7.  Prompt Reporting of SAEs to Sponsor ...................................................................38 
7.8.  Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events and Serious Adverse Events .........................................................38 
7.9.  Documenting Adverse Events .................................................................................39 
7.10.  Follow-up of Adverse Events and Serious Adverse Events....................................39 
7.11.  Clarification in Reporting of Deaths .......................................................................39 
7.12.  Post-Study Treatment Reporting Requirements .....................................................39 
7.13.  IUD or Introducer Malfunction ...............................................................................39 
8. 
PROTOCOL VIOLATIONS AND DEVIATIONS .....................................................40 
9. 
SUBJECT CONFIDENTIALITY .................................................................................40 
10.  ON-TREATMENT PREGNANCY DETERMINATION AND FOLLOW UP ........41 
11.  STATISTICAL CONSIDERATIONS ..........................................................................41 
11.1.  Determination of Sample Size ................................................................................41 
11.2.  Randomization ........................................................................................................42 
11.3.  Analysis Populations ...............................................................................................42 
11.4.  Pharmacokinetic Analyses ......................................................................................42 
11.4.1. Pharmacokinetic Methods ...........................................................................42 
11.5.  Statistical Analyses .................................................................................................43 
11.6.  Safety Analyses .......................................................................................................43 


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CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
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12.  STUDY ADMINISTRATION .......................................................................................44 
12.1.  Data Monitoring and Quality Control .....................................................................44 
12.1.1. Data Collection and Tracking .....................................................................44 
12.2.  Study Responsibilities .............................................................................................44 
12.2.1. Investigator Responsibility .........................................................................44 
12.2.2. Data Transmittal and Sample/Record Retention .........................................44 
12.2.3. Audit/Inspections ........................................................................................45 
12.3.  Pharmacokinetic Sample Handling & Shipping .....................................................45 
13.  ETHICAL AND LEGAL CONSIDERATIONS ..........................................................45 
14.  REFERENCES ...............................................................................................................47 
 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 16 of 49 
LIST OF IN-TEXT TABLES, FIGURES, APPENDICES 
Figure 1-1.  
Release Rate of Copper from Different Sizes of Copper IUDs at Five 
Intervals (Modified from Chantler et al, 1977)[1] ...........................................20 
Figure 1-2.   
Comparison of In Vitro Copper Elution Rates between a Commercial 
Plastic-Cu IUD (CuT380) and Nitinol-Cu Sebela Devices with 
Different Galvanic Characteristics (from CTM-20141110-1) .........................20 
Figure 3-1.  
Study Design Schemata – Treatment Comparison Phase ................................21 
Figure 3-2.  
Study Design Schemata – Extension Phase .....................................................22 
 
Table 5-1.  
Maximum Recommended Consumption Guidelines for Copper Rich 
Foods ................................................................................................................30 
Table 2: 
Adverse Event Relationship to Drug ...............................................................36 
 
Appendix 1.   Time and Events Schedule ...............................................................................48 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AUC0-56 days 
Area under the concentration-time curve from study time 0 (study Day 
1) to day 56 (study Day 57) 
BE 
Bioequivalence 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CI 
Confidence interval   
Cmax 
Maximum observed serum concentration 
Cmean 
Mean copper concentration of samples collected after Day 1 (Days 2-56) 
CRU 
Clinical research unit  
IUD 
Intrauterine Device 
CV% 
Coefficient of variation 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional review board 
PE 
Physical examination  
PK 
Pharmacokinetic 
SD 
Standard deviation 
SOP 
Standard operating procedure 
US 
United States 
oz 
Ounce 
c 
Cup 


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1. 
INTRODUCTION 
1.1. 
Background 
Sebela has developed VeraCept to provide a long-acting reversible method of contraception 
for non-pregnant, parous and nulliparous women of child-bearing age.  VeraCept’s design 
utilizes a shape memory nitinol spring frame with the same active chemical entity as the 
marketed reference product, ParaGard (99.99% pure copper), yet containing less than half of 
the exposed copper surface area (175mm2). VeraCept is delivered preloaded in an introducer, 
which is narrower than the ParaGard inserter, to simplify clinician insertions and facilitate 
correct, easy placement in the uterus. Correct placement and a shape memory frame optimize 
VeraCept’s long-term efficacy by decreasing expulsions and increasing its tolerability, 
thereby improving end-user continuation rates. In contrast to the passive plastic “T” utilized 
in ParaGard, VeraCept has been designed to mitigate the side effects associated with 
ParaGard without compromising contraceptive effectiveness. 
The primary mechanism of action of the Cu-IUD is the prevention of fertilization through a 
cytotoxic inflammatory reaction that is spermicidal [8]. The copper concentration in cervical 
mucus also leads to an inhibition of sperm motility [9]. The primary mechanism in which the 
Cu-IUD provides contraception lies within the significant changes within the endometrial 
cavity, sperm quality and migration of the copper ions [10]. There is also evidence 
suggesting that the Cu-IUD impairs implantation [9, 11].  Copper IUDs have a first-year 
pregnancy-prevention success rate ranging from 97.8 to 99.9%. ParaGard, the single copper 
IUD approved for use in the US, can be used for up to 10 years. 
The mechanism of action of a typical copper IUD is essentially a predictable electrochemical 
process of corrosion, driven by the IUD’s immersion in the uterine fluid. Over time, the 
copper elements (wires, beads, tubes, etc.) corrode and release ions. Typically, the release 
rate is governed by the surface area and volume of copper, the chemistry (especially pH) of 
the uterine fluid, and the specific composition and surface properties of the copper elements. 
The release rate of the copper from a copper IUD is highest during the first month after IUD 
placement but does not result in significant changes to serum copper levels [12].  
1.2. 
Study Rationale 
The current study will assess systemic copper exposure after insertion of VeraCept as 
compared to ParaGard in enrolled subjects.  The study will characterize the pharmacokinetics 
and comparative bioavailability of observed and baseline-corrected total serum copper 
exposure in patients after receiving either VeraCept or ParaGard.  
In order to maximize the ability to detect a difference in copper exposure following insertion 
of VeraCept and ParaGard, this study has been designed to sample total serum copper 
concentrations for the first 60 days post-insertion. Copper release rates from copper IUDs 
have been shown to decrease over time with the predominant decrease in release rate 
occurring in the first 60 days [1].  The initial release rate of copper (the burst release) appears 
to be correlated with the exposed surface area of copper in the device.  However, as the 
release rates decrease over time, the release rate of copper plateaus and appears to be less 
dependent on the exposed surface area of the device (Figure 1-1).   


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Ion release testing (CTM-20141110-1) comparing VeraCept with Optima TCu380S, a 
commercial copper IUD with twice the exposed copper surface area, demonstrated that 
insertion of a copper IUD results in an initial burst of copper release followed by a steady 
decline in copper release rate which stabilizes by approximately 21 days of immersion 
(Figure 1-2). The highest average daily release rate was observed on day 1 at 1,600 ppb/day 
(~45 µg/day).  From 21 to 60 days, the copper release rate remained relatively low and 
continued to decrease slightly from 278 ppb/day (~7.8 µg/day) on day 21 to 149 ppb/day 
(~4.2 µg/day) on day 60.   
According to Chantler et al. (1977) [1], the highest copper release rate for an IUD with a 
similar surface area to that of the marketed ParaGard IUD is approximately 3.2 µmol/day 
(~200 µg/day) while the corresponding value for VeraCept is approximately 1.2 µmol/day 
(~75 µg/day).  By 60 days, the release rate for IUDs with exposed copper surface areas 
similar to that of ParaGard and VeraCept decreased to below 0.5 µmol/day or approximately 
30 µg/day.  Long-term studies of other copper IUDs have reported similar and even lower 
copper release rates [2, 3]. 
Average daily dietary intake of copper has been reported to be approximately 1.0 to 1.6 
mg/day [4-6].  Based on the data described above, by 60 days following insertion, the copper 
released from these IUDs would represent less than 3% of daily dietary intake of copper.  
Given the small amount of copper released by the IUDs relative to the total daily intake of 
copper, it would be difficult to attribute total serum copper concentrations to the IUD beyond 
this initial release period.  Therefore, in order to maximize the potential to capture a 
difference in copper exposure following insertion of the IUD, the sampling schedule will 
focus on the first 60 days post-insertion (i.e. 48 hours post-insertion through Day 57).   


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Figure 1-1.  
Release Rate of Copper from Different Sizes of Copper IUDs at Five 
Intervals (Modified from Chantler et al, 1977)[1] 
 
Figure 1-2.   Comparison of In Vitro Copper Elution Rates between a Commercial 
Plastic-Cu IUD (CuT380) and Nitinol-Cu Sebela Devices with Different 
Galvanic Characteristics (from CTM-20141110-1) 
 
 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of this study is: 
 To assess the relative bioavailability of observed systemic copper from the VeraCept 
IUD versus ParaGard based on Cmax, Cmean, and AUC0-56 days.  
2.2. 
Secondary Objectives 
The secondary objectives of this study are: 
 To assess the relative bioavailability of baseline-corrected total serum copper from 
the VeraCept IUD versus ParaGard based on Cmax, Cmean, and AUC0-56 days.  
 To assess the total serum copper levels within each treatment relative to the normal 
range (49 to 184 µg/dL) [7]. 
 To assess the long-term stability of copper levels following insertion of the VeraCept 
IUD 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This parallel, open-label study is designed to evaluate the comparative bioavailability of 
systemic copper exposure after insertion of VeraCept intrauterine contraceptive (IUD) vs 
ParaGard in post-menarcheal women.  Up to 40 subjects will receive one of two treatments 
(A or B) as described below:  
 
Treatment A (N=20):  VeraCept® IUD, test (referred to as VeraCept) 
 
Treatment B (N=20): ParaGard® IUD, reference (referred to as ParaGard) 
Figure 3-1.  
Study Design Schemata – Treatment Comparison Phase 
 
 
Subjects will be screened within 60 days prior to the first insertion of study drug, and  blood 
samples will be collected within 28 days from first insertion of study drug at two visits within 
this screening period to establish baseline copper concentrations.  At least 24 hours should 
separate each baseline sample. On Day 1 of each treatment period, PK, safety and baseline 


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assessments will be collected prior to IUD insertion.  Subjects will return to the clinic at 48 
hours post-IUD insertion (Day 3 (+24 hours)) and on Days 8 (±1 day), 15 (±1 day), 22 (±1 
day), 29 (±1 day) and 57 (±3 days) for blood collection for measurement of total serum 
copper concentrations.  
 
Figure 3-2.  
Study Design Schemata – Extension Phase
On Day 57, ParaGard subjects will exit the study and may continue ParaGard use per 
standard clinical care.  VeraCept subjects will continue in the extension phase of the study 
intended to assess long-term stability of serum copper concentrations up to 5 years and 
monitor safety.   During the first 3 years, subjects will return to the clinic every 6 months for 
clinical assessments and blood collection for measurement of total serum concentrations.  
Following Year 3, subjects will return annually up to Year 5.  During the extension phase, 
PK collections may occur anytime within 30 days of the planned collection time.  Subjects 
prematurely discontinuing the study should follow the procedures specified in Section 6.1.7 
Early Discontinuation Visit.  Additional follow-up visits may be scheduled, as needed, if a 
subject has an ongoing significant adverse event (AE) and/or a clinically significant 
laboratory abnormality.  A schedule of the study procedures and assessments to be conducted 
for each subject is provided in the Time and Events Table (Appendix 1). 
3.2. 
Primary and Secondary Endpoints 
3.2.1. 
Primary Endpoint 
The primary endpoint is: 
 
Mean total serum copper concentration, Cmax, and AUC0-56 days for observed copper 
for each treatment. 
3.2.2. 
Secondary Endpoints 
The secondary endpoints are: 
 
Mean total serum copper concentration, Cmax, and AUC0-56 days for baseline-corrected 
copper for each treatment 
 
Total serum copper concentrations within each treatment for each assessment day for 56 
days. 
 
Mean total serum copper concentration for observed and baseline-adjusted copper for 
each treatment over 5 years (Treatment A, VeraCept IUD only) 


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4. 
SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria 
A subject will be eligible for inclusion in this study if they meet all of the following criteria:  
1. Post-menarcheal, pre-menopausal females up to 45 years of age at the time of informed 
consent/assent and in good general health; 
2. History of regular menstrual cycles defined as occurring every 21-35 days when not 
using hormones or prior to recent pregnancy or spontaneous or induced abortion; 
3. Sexually active with a male partner who has not had a vasectomy; 
4. Reasonably expect to have coitus at least once monthly during the study period; 
5. In a mutually monogamous relationship of at least 3 months duration; 
6. Seeking to avoid pregnancy for the duration of the study; 
7. Willing to use the study drug as the sole form of contraception; 
8. Willing to accept a risk of pregnancy;   
9. Subjects must be in compliance with cervical cancer screening guidelines per the 
American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines without 
evidence of disease. Subjects who are age 21-24 y/o, at time of informed consent, must 
have a normal papanicolaou test (Pap), atypical squamous cells of undetermined 
significance (ASC-US), or low-grade squamous intraepithelial lesion (LSIL). Subjects 
who are 25 or older at the time of informed consent with ASC-US results, must also have 
a negative high risk human papilloma virus (HPV) test result within the appropriate 
screen timeframe per American Society for Colposcopy and Cervical Pathology 
(ASCCP) guidelines, and prior to the study IUD insertion. Alternatively, the subject must 
have had a colposcopy performed within the appropriate screen timeframe, and prior to 
the study IUD insertion that showed no evidence of dysplasia requiring treatment per 
ASCCP guidelines, or treatment was performed and follow-up at least 6 months after the 
treatment showed no evidence of disease by clinical evaluation; 
10. Able and willing to comply with all study tests, procedures, assessment tools and follow-
up;  
11. Able and willing to provide and document informed consent and Authorization for 
Release of Protected Health Information (PHI). Unemancipated subjects under 18 years 
old must provide assent and have written parental consent documented on the consent 
form consistent with local legal requirements; 
12. Plan to reside within a reasonable driving distance of a research site for the duration of 
the study. 
13. Subject agrees not to self-remove VeraCept. 
 


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4.2. 
Exclusion Criteria 
A subject will be excluded from participating in the study if any of the following conditions 
apply:  
1. Known or suspected pregnancy; or at risk for pregnancy from unprotected intercourse 
earlier in current cycle; 
2. A previously inserted intrauterine device (IUD) that has not been removed by the time the 
study IUD is placed; 
3. History of previous IUD complications, such as perforation, expulsion, or pregnancy with 
IUD in place; 
4. Pain with current IUD; 
5. Injection of hormonal contraceptive (e.g., Depo-Provera) within the last 10 months and 
has not had 2 normal menstrual cycles since the last injection; 
6. Use of ParaGard IUD within the past 3 months 
7. Planned use of any non-contraceptive estrogen, progesterone or testosterone any time 
during the 60 months of study participation; 
8. Exclusively breastfeeding before return of menses; lactating women will be excluded 
unless they have had 2 normal menstrual periods prior to enrollment; 
9. Unexplained abnormal uterine bleeding (suspicious for a serious condition), including 
bleeding 4 weeks post-septic abortion or puerperal sepsis; 
10. Severely heavy or painful menstrual bleeding; 
11. Suspected or known cervical, uterine or ovarian cancer, or unresolved clinically 
significant abnormal Pap smear requiring evaluation or treatment; 
12. Any history of gestational trophoblastic disease with or without detectable elevated ß-
human chorionic gonadotropin (ß-hCG) levels, or related malignant disease;  
13. Any congenital or acquired uterine anomaly that may complicate study drug placement, 
such as: 
● 
Submucosal uterine leiomyoma 
● 
Asherman’s syndromes 
● 
Pedunculated polyps 
● 
Bicornuate uterus 
● 
Didelphus or uterine septa 
14. Any distortions of the uterine cavity (e.g. fibroids), that, in the opinion of the 
investigator, are likely to cause issues during insertion, retention or removal of the IUD;  
15. Known anatomical abnormalities of the cervix such as severe cervical stenosis, prior 
trachelectomy or extensive conization that, in the opinion of the investigator would 
prevent cervical dilation and study drug placement;  
16. Untreated or unresolved acute cervicitis or vaginitis; 
17. Known or suspected human immunodeficiency virus (HIV) infection or clinical AIDS; 
18. Subjects who have an established immunodeficiency; 
19. Known intolerance or allergy to any components of VeraCept or ParaGard including 
intolerance or allergy to nickel, titanium, or copper, and including Wilson’s Disease; 


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20. Currently participating or planning future participation in a research study of an 
investigational drug or device during the course of this investigational study.  Subject 
must have waited at least 30 days from exiting their last study prior to informed consent 
in this study; 
21. Subject has been enrolled in a previous VeraCept or LevoCept study; 
22. Known or suspected alcohol or drug abuse within 12 months prior to the screening visit; 
23. Any general health, mental health or behavioral condition that, in the opinion of the 
investigator, could represent an increased risk for the subject or would render the subject 
less likely to provide the needed study information; 
24. Study staff or a member of the immediate family of study staff. 
25. Concurrent use of corticosteroids  
26. Subject is <4 weeks post-pregnancy (postpartum, spontaneous or induced abortion) 
 
Note: VeraCept can be inserted on any day of the menstrual cycle using the first three criteria 
for the Centers for Disease Control and Prevention (CDC) U.S. Selected Practice 
Recommendations for Contraceptive Use, 2016[10] guidance to avoid an undetected 
pregnancy (see the revised Box 2 below and a copy is located in the study reference manual 
provided to the site). If a subject has a previously inserted IUD and has pain from that IUD 
upon removal, then the insertion of VeraCept should not occur until the pain has resolved. 
 
Post Pregnancy Guidelines 
Subjects who were recently pregnant must have a urine pregnancy test performed no sooner 
than 4 weeks post-pregnancy. If a subject has not had 2 normal menses since the end of a 
pregnancy, the study IUD may be placed if her hCG is negative and she has been on a 
reliable method of contraception (e.g. pills, patch, ring) that was started within 2 weeks post-
pregnancy or has been on this reliable method for 4 weeks. If the urine hCG is still positive, 
investigators can obtain two quantitative hCG tests that must demonstrate declining hCG 
values at least 1 day apart. 
 
BOX 2. How to be reasonably certain that a woman is not pregnant[10] 
A health care provider can be reasonably certain that a woman is not pregnant if she has no 
symptoms or signs of pregnancy and meets any one of the following criteria: 
 is ≤7 days after the start of normal menses 
 has not had sexual intercourse since the start of last normal menses 
 has been correctly and consistently using a reliable method of contraception* 
* If condoms are being used, a double barrier method must be used (e.g. condoms + spermicide). 


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4.3. 
Screen and Baseline Failures  
Data for screen and baseline failures will be collected in source documentation at the site. 
4.4. 
Removal of Subjects from Therapy/Premature Discontinuation 
Subjects will be encouraged to complete the study and all assessments.  A subject will be 
discontinued from the study for the following medical or administrative reasons: 
 
Occurrence of a treatment-emergent AE that represents an unacceptable risk to the 
subject and continued participation in the investigational study is not warranted per 
judgment of the Investigator.  The Investigator must follow the subject until the AE 
resolves or satisfactorily stabilizes; 
 
Pregnancy;  
 
Sponsor decision;  
 
Subject request; and/or  
 
Non-compliance with the protocol. 
The Investigator may discontinue individual subjects from the study at any time.  Subjects 
may voluntarily withdraw at any time.  The reason(s) for subject not completing the study 
will be recorded.  Where subjects are “lost to follow-up”, the site should make every attempt 
to contact the subject (3 telephone calls and if necessary, a certified letter to the subject’s 
mailing address) so that they can be appropriately withdrawn from the study. 
For subjects that fail to attend a required visit, the site should attempt to contact the subject 
and re-schedule the missed visit as soon as possible. If a subject fails to attend 2 or more 
visits as scheduled, the subject may be discontinued per agreement between the Sponsor and 
the Principal Investigator. 
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects (and assigned to the same treatment) at the discretion of the Sponsor in 
consultation with the Investigator. 
5. 
TREATMENTS 
5.1. 
Method of Assigning Subjects to Treatment Groups 
After assessment of the Day 1 procedures, the subjects who qualify for enrollment will be 
randomly assigned to one of the following treatments in a 1:1 fashion per the randomization 
scheme described in Section 11.2: 
 
Treatment A: VeraCept, test 
 
Treatment B: ParaGard, reference 
5.2. 
Treatments Administered  
Insertions may only be performed by inserters that have been approved by Sebela. VeraCept 
can be inserted on any day of the menstrual cycle using the first three criteria for the Centers 
for Disease Control and Prevention (CDC) U.S. Selected Practice Recommendations for 
Contraceptive Use, 2016[10] guidance to avoid an undetected pregnancy (see the revised 
Box 2 above). If a subject has a current IUD and pain is present from removal of the IUD, 
insertion of VeraCept or ParaGard should not occur until the pain has resolved.   


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ParaGard should be used according to the ParaGard package insert which includes a 
description of ParaGard design and layout and instructions for use (ParaGard® T380 
Prescribing Information. Trumbull, CT; Cooper Surgical, Inc; 2018). 
 
5.3. 
Identity of Investigational Products(s) 
5.3.1. 
VeraCept (Test treatment) 
The VeraCept IUD is a low-dose copper-releasing IUD. The VeraCept IUD has 175mm2 of 
exposed copper surface area on a shape memory nitinol frame. VeraCept is inserted using a 
simple two-step introducer and is provided preloaded in the introducer. The smaller diameter 
introducer is narrower than the ParaGard inserter. 
5.3.2. 
ParaGard (Reference treatment) 
The ParaGard IUD is a T-shaped intrauterine device with 380 ± 23 mm total exposed copper 
surface area. ParaGard measures 32 mm horizontally and 36 mm vertically, with a 3 mm 
diameter bulb at the tip of the vertical stem. A monofilament polyethylene thread is tied 
through the tip, resulting in two white threads, each at least 10.5 cm in length, to aid in 
detection and removal of the device. The T-frame is made of polyethylene with barium 
sulfate to aid in detecting the device under x-ray with approximately 176 mg of wire coiled 
along the vertical stem and a 68.7 mg collar on each side of the horizontal arm. One 
ParaGard weighs less than one (1) gram. No component of ParaGard or its packaging 
contains latex. 
ParaGard is packaged together with an insertion tube and solid white rod in a Tyvek 
polyethylene pouch that is then sterilized. A moveable flange on the insertion tube aids in 
gauging the depth of insertion through the cervical canal and into the uterine cavity. 
 
ParaGard should be used according to the ParaGard package insert which includes a 
description of ParaGard design and layout and instructions for use (ParaGard® T380 
Prescribing Information. Trumbull, CT; Cooper Surgical, Inc; 2018). 
5.3.3. 
Labeling 
VeraCept will bear a label that meets applicable laws for an investigational drug, which 
includes, but is not limited to, the following information: 
 
Federal law statement 
 
Protocol number 
 
Lot number/ Manufacture date or expiration date 
 
Dosing instructions 
 
Storage information 
5.3.4. 
Storage and Handling 
All study products will be kept in a locked area with limited access.  
Storage conditions for all study drugs are provided in the Study Reference Manual. 


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5.4. 
Selection of Doses in the Study 
A single IUD (VeraCept or ParaGard) will be placed in a subject for the study.  No study 
drug will be replaced if an expulsion or removal occurs. 
5.5. 
Prior and Concomitant Therapy  
5.5.1. 
Prior Therapy 
All medications taken within 30 days of the screening visit will be documented in source 
documents and CRF (based on subject report and/or medical records).  
5.5.2. 
Concomitant Therapy 
All prescription and non-prescription medications (including herbal therapies) taken from the 
time of informed consent/assent until Study Exit must be documented in the source 
documents and CRF (brand and/or generic name, dose, dosing frequency, start and stop 
dates).    
5.5.3. 
Prohibited Medications and Devices 
Consumption of substances that are known to affect total serum copper levels are not 
permitted during this study.   
The following medications and devices are prohibited: 
 Known copper chelators, such as d-Penicillamine or Tetraethylenetetraamine 
 Oral contraceptives containing estrogen and/or progestogens 
 Treatment with corticosteroids 
 Menstrual Cups 
o Subjects should be instructed to abstain from using menstrual cups to avoid 
accidental IUD removal during menstrual cup removal. Menstrual cup use 
may dramatically increase the likelihood of unintentional IUD expulsion and 
should not be used. If a subject cannot be discouraged from using a menstrual 
cup, ensure the subject is familiar with the menstrual cup instructions for use 
for proper insertion and removal. It is recommended that placement be low in 
the vagina and not in contact with the cervix. Should a menstrual cup user 
notice that the cup is in contact with the cervix the recommendation is to 
break the seal of the cup by pinching the edge of the cup first and then 
removing the cup.  
The subject may be discontinued from the study at the discretion of the Investigator or the 
medical monitor if additional medications are required after the first dose of study drug 
through any follow-up assessments.  Please contact the medical monitor or Sponsor 
representative if a subject requires a concomitant therapy, unless the concomitant therapy is 
needed immediately for subject safety. 
5.5.4. 
Dietary Restrictions 
Copper is an important nutrient and patients are not recommended to avoid foods or 
supplements containing copper.  The Recommended Dietary Allowance (RDA) of copper for 
adult woman is 0.9 mg/day, the median intake of copper from food in the United States is 
approximately 1.0 to 1.6 mg/day, and the Tolerable Upper Intake Level (UL) for adults of 10 
mg/day [13].   


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Patients are advised to adhere to their normal dietary patterns, but should try to avoid 
consuming excessive amounts of foods rich in copper, such as the foods listed in Table 5-1 
below [14]. Daily or monthly serving sizes are listed for each food item, and patients should 
not exceed the amounts listed.   
Subjects who begin to consume excessive amounts of foods rich in copper may require 
discontinuation from the study.  The Medical Monitor should be contacted to discuss possible 
discontinuation of these subjects. 
 
 


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Table 5-1.  
Maximum Recommended Consumption Guidelines for Copper Rich 
Foods 
Food Item 
mg/serving 
serving size 
Don't exceed: 
beef/calf liver 
5.27 
3 oz (85g) 
3 oz/month 
pecans 
0.302 
1oz (28 g) 
3 oz/day 
canned chili con carne 
0.365 
1 c (225 g) 
2 cups/day 
pork and beans 
0.236 
1/2 c 
2 c/day 
fried shrimp 
0.181 
3 oz (85g) 
15 oz/day  
spaghetti with meat sauce 
0.258 
1 c (248 g) 
4 c/day 
homemade lasagne 
0.214 
7 oz entrée (198 g) 
28 oz/day 
Beans (navy, pinto, red, lima, blackeye 
peas) 
0.243 
1/2 c 
2 c/day 
canned mushrooms 
0.176 
1/2 c (82g) 
2.5 c/day 
sweet potato 
0.206 
1 potato (114 g) 
4/day 
raisin bran cereal 
0.286 
1 c (56 g) 
3 c/day 
granola with raisins 
0.216 
1/2 c 
2c/day 
shredded wheat 
0.211 
2 biscuits (47g) 
8 biscuits/day 
oatmeal 
0.194 
1 c cooked, 234 g 
5 c/day 
chocolate milk/shake 
0.226 
10 oz (283 g) 
40 oz/day 
chocolate cake/chocolate icing 
0.142 
2 oz slice 
14 oz/day 
 
5.6. 
Treatment Compliance 
The date and time of the IUD insertion, and of each PK sample collection should be 
recorded.   
5.6.1. 
Study Drug Accountability 
IUDs will be distributed in accordance with the procedures of this protocol.  Only authorized 
site personnel may supply or administer the devices and only subjects enrolled in the study 
may receive a device, in accordance with applicable regulatory requirements.  
Device accountability information will be maintained. 
5.6.2. 
Treatment After the End of the Study 
Upon completion of the procedures described within this protocol, ParaGard subjects may 
continue ParaGard use per standard clinical care.  Subjects will not receive any additional 
treatment from the Sponsor.  The Investigator is responsible for ensuring that consideration 
has been given to the post-study care for each subject. 
6. 
STUDY PROCEDURES 
6.1. 
Study Phases and Procedures 
A Time and Events Schedule is provided in Appendix 1.  Protocol deviations are not allowed 
with the exception of immediate safety concerns.  The IRB will be informed of any safety 
issues that require changes to the safety monitoring or to the Informed Consent Form. 


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The window for screening is between Day -60 and Day 1, and two blood samples will be 
collected within 28 days from Day 1, and at least 24 hours apart within this screening period 
(can be performed on Screening and Day 1 visits prior to IUD insertion).  IUD will be 
inserted on Day 1.  The assessment period for this study is from Day 1 through Day 57.  
6.1.1. 
Screening Window (Day -60 through Day 1) 
Subjects will be screened within 60 days prior to device insertion, and two blood samples 
will be collected within 28 days from Day 1, and at least 24 hours apart within this screening 
period (can be performed on Screening and Day 1 visits prior to IUD insertion).  The 
following procedures will be performed at Screening:   
 
Assess eligibility including inclusion/exclusion criteria 
 
Distribution of subject materials 
 
Informed consent and assent, if applicable, PHI and Bill of Rights forms, where 
applicable 
 
Demographics and baseline characteristics 
 
Medical/surgical, gynecological, and menstrual history 
 
Vital signs, height and weight 
 
General physical exam 
 
Pelvic exam 
 
Cervical cytology 
 
Cervical infection tests 
 
Screening for cervical infection tests are to be done at screening unless these tests 
have been previously completed within 3 months of the screening visit and were 
negative. If a subject tests positive prior to IUD insertion, the subject should be 
treated prior to IUD placement. The subject may be inserted 7 days post-
treatment. A cervical infection retest should be done 3-months post-IUD insertion 
to assure there is not a case of re-infection. 
 
Insertion can occur without receipt of test results if there is no clinical evidence of 
infection. If, after IUD insertion, the screening cervical infection test results are 
positive, the subject should be treated. 
 
Pregnancy test-urine 
 
Prior and concurrent medication 
 
Subject education 
 
Baseline serum copper sample  
Two baseline blood samples will be collected within 28 days from Day 1, and at 
least 24 hours apart within this screening period (can be performed on Screening 
and Day 1 visits prior to IUD insertion) 
6.1.2. 
Device Insertion, Day 1 
Prior to IUD placement, the following evaluations will be completed: 
 Assessment of Eligibility 
 Vital signs and weight 


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 Pelvic Exam  
 Transvaginal ultrasound (if clinically indicated) 
 Pregnancy test (urine) 
 Prior and concurrent medications  
 Pre-insertion PK sample (final baseline sample) 
 Adverse events and assess for any changes to health status  
 IUD placement 
 If placement is unsuccessful, a second attempt may be made on the same day 
or within 1 week following the first attempt.  If a second attempt is also 
unsuccessful, the subject will be discontinued early from the study.   
Post IUD placement, the following evaluations will be completed: 
 Pelvic exam to confirm IUD placement/string check 
 Transvaginal ultrasound, if clinically indicated to confirm adequate IUD placement 
 Concomitant medications 
 Adverse events 
 Subject education including: 
 Concomitant contraception - if there are concerns that the IUD is not properly 
placed, counsel the subject on the need for additional contraception 
 
6.1.3. 
Day 3 (48 hours (±24 hours) post-insertion) 
 
Vital signs and weight 
 
48-hour (±24 hours) post IUD insertion PK sample collection 
 
Prior and concurrent medication  
 
Adverse events  
 
Subject education including: 
 
Concomitant contraception - if there are concerns that the IUD is not properly placed, 
counsel the subject on the need for additional contraception 
 
6.1.4. 
Days 8, 15, 22, 29 (±1 day) and 57 (±3 days) 
 
Vital signs and weight 
 
PK sample collection (at approximately the same time of day as collection of the Day 3, 
48-hr PK collection) 
 
Pelvic exam to confirm IUD placement/string check 
 
Transvaginal ultrasound, if clinically indicated to confirm adequate IUD placement 
 
Prior and concurrent medication  
 
Adverse events 
 
Subject education including: 


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 
Concomitant contraception - if there are concerns that the IUD is not properly placed, 
counsel the subject on the need for additional contraception 
 
ParaGard Subjects: Day 57 (+3 days) 
 
Exit Visit procedures should be completed as described in Section 6.1.6. 
 
6.1.5. 
Months 6, 12, 18, 24, 30, 36, and 48 (±30 days) 
 
Vital signs and weight 
 
PK sample collection  
 
Pelvic exam to confirm IUD placement/string check 
 
Transvaginal ultrasound, if clinically indicated to confirm adequate IUD placement 
 
Prior and concurrent medication  
 
Adverse events 
 
Subject education including: 
 
Concomitant contraception - if there are concerns that the IUD is not properly placed, 
counsel the subject on the need for additional contraception 
 
6.1.6. 
Month 60 (±30 days) or Exit Visit 
 
Vital signs and weight 
 
Pregnancy test (urine) 
 
PK sample collection  
 
Pelvic exam to confirm IUD placement/string check 
 
Transvaginal ultrasound, if clinically indicated to confirm adequate IUD placement 
 
VeraCept removal 
 
The subject's preferred method of contraception will be provided 
 
If the subject elects a non-hormonal method of contraception, a 14-day supply 
will be provided by the site 
 
If the subject elects to use hormonal contraceptive pills, a one-month supply of 
hormonal contraceptive pills will be provided to the subject by the site for the first 
2 weeks following VeraCept removal 
 
The subject will also be provided with condoms to take with her as an extra 
precaution if the subject fails to acquire the contraception noted above 
 
Subjects should be reminded to avoid conception within 7 days after VeraCept 
removal 
 
ParaGard Subjects 
 
Subjects may continue ParaGard use per standard clinical care or have the device 
removed 


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 
If ParaGard is removed, subject’s preferred method of contraception will be 
provided as outlined above 
 
Prior and concurrent medication  
 
Adverse events 
6.1.7. 
Early Discontinuation Visit 
All subjects who request removal of VeraCept before 5 years or ParaGard before Day 57 
should follow the procedures of the Exit Visit as described in Section 6.1.6. 
6.2. 
Study Measurements and Assessments 
All study measurements and assessments to be conducted in this PK study are described 
below. 
6.2.1. 
Pharmacokinetic Sample Collection and Processing 
Blood samples for pharmacokinetic analysis will be collected twice during Screening at least 
24 hours apart, on Day 1 prior to insertion, Day 3, approximately 48 hours after insertion, 
and on Days 8, 15, 22, 29 and 57 at approximately the same time of day as the prior PK 
collections.  Approximately 3-5 mL of whole blood will be collected for each blood draw.  
The total volume collected from each subject for all pharmacokinetic samples will be 
approximately 20 mL.  
Blood samples will be collected in containers appropriate for serum collection, such as a “red 
topped” tube, that does not contain an anticoagulant. 
Blood samples will be processed for serum as described in the PK Laboratory Manual.  The 
yield of serum will be subdivided into 2 samples (~1 mL each).  One of these samples will be 
shipped as soon as possible to the analytical lab for analysis of total serum copper and the 
other will be stored at -20ºC at the site until completion of the study (or until directed by 
Sebela or designee) and then sent to the analytical lab in one group. 
6.2.2. 
Allergic Reaction or Hypersensitivity to Components of VeraCept 
If a subject experiences allergy-related symptoms or a hypersensitivity reaction (e.g. 
urticarial allergic skin reaction, rash) while VeraCept is placed, she should be assessed for a 
possible allergy to the components of VeraCept (nickel, titanium and copper). A clinician 
will determine the historical relationship between symptoms and IUD use to inform a 
determination of causality. As needed, a nickel, titanium, and/or copper patch test will be 
performed and/or an assessment by a specialist for VeraCept users. If the IUD is determined 
to be the cause or highly suspected of causing the allergic reaction or hypersensitivity, the 
IUD should be removed, and the AE(s) must be followed until resolution, the condition 
stabilizes, 30 days post study drug removal, or the subject dies or is lost to follow up 
(including withdrawal of consent/assent), whichever occurs first. 
7. 
ADVERSE EVENTS 
During the study, the investigator or study site personnel will be responsible for querying and 
recording adverse events (AEs) and serious adverse events (SAEs), as detailed below. For the 
sponsor to fulfill safety assessment obligations, the investigator must report all SAEs to the 


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study sponsor, whether or not they result from study participation, within 24 hours of 
learning of the event. 
7.1. 
Definition of a Serious Adverse Event  
A serious adverse event (SAE) is any adverse event occurring within the timelines specified 
in the protocol that results in any of the following outcomes: 
● 
Death; 
● 
Life-threatening situation (subject is at immediate risk of death); 
● 
Inpatient hospitalization or prolongation of existing hospitalization; 
● 
Persistent or significant disability/incapacity; 
● 
Congenital anomaly/birth defect in the offspring of a subject who received study 
drug; or 
● 
Important medical events that may not result in death, be immediately life-
threatening, or require hospitalization, may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
serious adverse events include but are not limited to: intensive treatment in an emergency 
room, hospitalization for any reason, and extensive treatment at home for an adverse event.  
An ectopic pregnancy is considered a serious adverse event. 
7.2. 
Definition of an Adverse Event  
An adverse event is any untoward medical occurrence in a clinical investigation subject 
administered an investigational product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can, therefore, be any unfavorable and unintended 
sign (that could include a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
Any AE (i.e., a new event or an exacerbation of a pre-existing condition) with an onset from 
the day of informed consent/assent through Study Exit should be recorded as an AE on the 
eCRF. All AEs must be recorded regardless of the severity or relationship to study drug. It is 
important that investigators also report all AEs that result in expulsion or removal of the 
investigational product being studied, whether serious or non-serious. 
Pregnancy is an outcome, and not an AE in this study. 
7.3. 
Adverse Events of Specific Interest 
Adverse events of particular clinical importance, other than SAEs will be classified as 
adverse events of specific interest (AESIs). For this study, AESIs refer to reports of pain 
during insertion, pelvic infection (PID or endometritis), expulsion and uterine perforation. 
AESIs will be identified and assessed by the Medical Monitor during the ongoing monitoring 
of safety data during the trial, during DMSB meetings and for the Clinical Study Report. For 
each AESI, a narrative may be written and included in the Clinical Study Report. 


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7.4. 
Causality: Serious Adverse Event and Adverse Event Relationship to 
Study Treatment 
An Investigator who is qualified in medicine must make the determination of relationship to 
the drug for each AE.  The relationship of an AE to the drug should be assessed using the 
guidelines presented in Table 3.  An AE for which there has been no causal relationship 
reported initially will require follow-up to determine causality.  Of the definitions in Table 3, 
“possibly”, “probably” and “related” to an investigational medical product are considered 
adverse reactions. “Unlikely” and “not related” do not qualify as a causal relationship.  
Table 2: 
Adverse Event Relationship to Drug  
Relationship to 
Drug 
Description 
Related 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected 
response pattern to the suspected drug; that is confirmed by stopping or reducing the 
dosage of the drug; and that is not explained by any other reasonable hypothesis 
Probably related 
The adverse event: 
 
Follows a reasonable temporal sequence from the time of study drug 
administration; and/or 
 
Follows a known response pattern to the study drug; and 
 
Was unlikely to have been produced by other factors such as the subject’s 
clinical state, therapeutic intervention, or concomitant therapy 
Possibly related 
The adverse event: 
 
Follows a reasonable temporal sequence from the time of study drug 
administration; and/or 
 
Follows a known response pattern to the study drug; but 
 
Could have been produced by other factors such as the subject’s clinical 
state, therapeutic intervention, or concomitant therapy 
Unlikely related 
The adverse event: 
 
Does not follow a reasonable temporal sequence from the time of study 
drug administration; and 
 
Was likely produced by other factors such as the subject’s clinical state, 
therapeutic intervention, or concomitant therapy but for which relationship 
cannot be definitely ruled out 
Not related 
The adverse event can be determined with certainty to have no relationship to the 
study drug 
7.4.1. 
Clarification of Adverse Events Related to Study Procedures  
Any untoward event that occurs from the time of informed consent/assent, including the 
study drug placement procedure until completion of placement, or from the beginning of the 
removal procedure until the completion of removal, will be reported as an AE. The AE 
should be recorded on the AE eCRF with a causality assessment of “related to study drug 
placement procedure.” If the AE also meets the criteria for an SAE, an SAE report should be 
completed and submitted to the sponsor. 


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7.5. 
Serious Adverse Event and Adverse Event Severity 
The investigator will assess the severity of the AE using the following general guidelines: 
Mild: An AE that is usually transient, requiring no special treatment, and does not interfere 
with the subject’s daily activities. 
Moderate: An AE that introduces a low level of inconvenience or concern to the subject and 
may interfere with daily activities but is usually ameliorated by simple therapeutic measures. 
Severe: An AE that interrupts a subject’s usually daily activity and typically requires 
systemic drug therapy or other treatment (a severe AE may not necessarily qualify as an 
SAE). 
Life-threatening: An AE that put the subject at immediate risk of death from the event as it 
occurred. This does not include an event that might have led to death if it had occurred with 
greater severity. 
Fatal: An AE that was the cause of the subject’s death. 
7.6. 
Adverse Event Outcome 
The investigator will categorize the outcome of each SAE and AE according to the 
definitions below: 
Resolved: The subject recovered from the SAE or AE. 
Resolved with sequelae: a condition whereby the consequences of a disease or injury 
include lingering effects. 
Not Recovered/Not Resolved: At the time of the last assessment, the event is 
ongoing, with an undetermined outcome. Note: Ongoing SAEs and AEs are not 
considered resolved as a result of death and no SAE or AE stop date should be 
recorded for an AE that is ongoing at the time of death. 
Fatal: Adverse Event directly caused death. The sponsor may request that the 
investigator perform or arrange for the conduct of supplemental measurements and/or 
evaluations. If a subject dies during participation in the study or during a recognized 
follow-up period, the sponsor should be provided with a copy of any post-mortem 
findings, including histopathology.  Note: Death is an outcome of an adverse event 
and not an adverse event in itself. All reports of subject death should include an 
adverse event term (other than “Death”) for the cause of the death. 
Since reporting of an SAE is required within 24 hours of discovery, Death can be reported as 
an initial event term and updated to the final diagnosis in a follow-up report. If an adverse 
event term is not provided, the investigator will be queried to obtain the cause of death. Only 
in the rare occurrence that no verbatim description of an adverse event can be obtained from 
the investigative site will “Death – Unknown Cause” be used as the event term. 
The investigator should attempt to establish a diagnosis of the event based on the signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE (and SAE if serious) and not the individual signs/symptoms. 
In the case of abnormal labs or diagnostic tests judged to be clinically significant by the 
investigator a diagnosis, if known, or clinical signs or symptoms if the diagnosis is unknown, 


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rather than the clinically significant laboratory finding or abnormal assessment, should be 
used to complete the AE or SAE report. If no diagnosis is known and clinical signs or 
symptoms are not present, then the abnormal finding should be recorded on the AE or SAE 
report. If an SAE report is completed, pertinent laboratory data should be recorded on the 
SAE report, preferably with baseline values and copies of laboratory reports. 
7.7. 
Prompt Reporting of SAEs to Sponsor 
The sponsor has requirements for reporting serious adverse events to regulatory agencies for 
a drug under clinical investigation. The sponsor must be notified within 24 hours of 
discovery if the investigator determines that an adverse event meets the protocol definition of 
an SAE. 
All SAEs occurring from the time of IUD insertion through study exit require immediate 
reporting to the sponsor. Investigators should not wait to receive additional information to 
fully document the event prior to notifying the sponsor but should provide as much relevant 
information as immediately available. Further details of the event can be provided as they 
become available. The procedures for reporting SAEs are as follows: 
● 
Complete the “Serious Adverse Event Report” form; 
● 
Submit the completed form to sponsor; 
● 
For fatal or life-threatening events, also submit copies of hospital case reports, 
autopsy reports, and other documents when requested and applicable; 
● 
The sponsor may request additional information from the investigator to ensure the 
timely completion of accurate safety reports; 
● 
Any fatal or life-threatening events should also be reported immediately by telephone 
to sponsor; 
● 
The SAE report should be completed as thoroughly as possible and signed by the 
investigator before transmittal to sponsor. It is very important that the Investigator 
provides an assessment of the causal relationship between the event and the study 
drug at the time of the initial report; and 
● 
The investigator, or responsible person according to local requirements, must comply 
with the applicable local regulatory requirements concerning the reporting of SAEs to 
regulatory authorities and the IRB. 
7.8. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events and Serious Adverse Events  
Abnormal laboratory findings (e.g., clinical chemistry, hematology) or other abnormal 
assessments (e.g., electrocardiogram, X-rays, vital signs) per se are not reported as AEs. 
However, abnormal findings that are deemed clinically significant (i.e., associated with signs 
and/or symptoms or requiring therapeutic intervention) must be recorded as AEs if they meet 
the definition of an adverse event (and recorded as an SAE if they meet the criteria of being 
serious) as described previously. Clinically significant abnormal laboratory or other 
abnormal findings that are detected after study drug placement or that are present at baseline 
and worsen following placement of IUD are included as AEs (or SAEs if serious). 


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The investigator should exercise his or her medical judgment in deciding whether an 
abnormal laboratory finding, or other abnormal assessment is clinically significant. A 
clinically significant laboratory abnormality in the absence of clinical symptoms may also 
jeopardize the subject and may require intervention to prevent immediate consequences (e.g., 
a markedly high serum potassium concentration may not be accompanied by arrhythmia, yet 
be of a magnitude to require potassium-binding resin administration to prevent such 
sequelae). Subjects should undergo repeat testing of clinically significant abnormal 
laboratory findings as soon as they are recognized. 
7.9. 
Documenting Adverse Events 
Any AE occurring from the time of informed consent/assent through Study Exit must be 
documented in the subject’s study records and on the AE eCRF. SAEs that occur during the 
study must be documented in the subject’s study record, on the AE eCRF and on the SAE 
report as appropriate. 
The investigator’s assessment of causality, severity and status of the adverse event must be 
documented. When a causality assessment is provided for a serious adverse event, it is 
important to include a rationale for the assessment so that a better understanding of the 
reported event can be compiled. The rationale should be accompanied by all available 
supporting evidence, including relevant laboratory tests, histopathology evaluations and the 
results of other diagnostic procedures. The investigator’s rationale with supporting evidence 
is valuable when sponsor performs a cumulative analysis of similar events. 
7.10. 
Follow-up of Adverse Events and Serious Adverse Events 
All AEs and SAEs must be followed until resolution, the condition stabilizes, 30 days post 
study drug removal, or the subject dies or is lost to follow-up (including withdrawal of 
consent/assent), whichever occurs first. The investigator is responsible to ensure that follow-
up includes any supplemental investigations as may be indicated to elucidate as completely 
as practical the nature and/or causality of the AE/SAE. This may include additional 
laboratory tests or investigations, histopathologic examinations, or consultation with other 
health care professionals. Follow-up information should be submitted to the sponsor in a 
timely many as the information is obtained. 
7.11. 
Clarification in Reporting of Deaths 
All subject deaths (regardless of relationship to study drug) should be reported that occur 
from the beginning of study drug placement through Study Exit. The information should be 
recorded on the Subject Death form and the SAE report. 
7.12. 
Post-Study Treatment Reporting Requirements 
For all enrolled subjects, all AEs and SAEs, regardless of cause or relationship, that occur 
from the beginning of study drug placement through Study Exit require reporting to the 
sponsor.  In addition, if the investigator learns of any SAE at any time after a subject has had 
the study drug removed, and such event seems reasonably related to study drug, the 
investigator should immediately notify the sponsor. 
7.13. 
IUD or Introducer Malfunction 
Should the VeraCept IUD or its introducer not perform mechanically as expected, the 
sponsor should be informed. Details of the malfunction will be collected, and the sponsor 


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will determine if the IUD and/or introducer should be returned to the study sponsor for 
assessment.  
Should ParaGard IUD or its introducer not perform mechanically as expected, the sponsor 
should be informed. Details of the malfunction will be collected. 
8. 
PROTOCOL VIOLATIONS AND DEVIATIONS 
Except in the event of a medical emergency or where it is necessary to protect the safety, 
rights or welfare of the study subject, any changes to the protocol will require written 
approval of Sebela or designee.  Violations or deviations from the Clinical Investigational 
Plan to protect the health and safety of the subject will be reported to the IRB and as required 
by local regulations. All protocol violations or deviations will be recorded, tracked and 
reviewed periodically by Sebela and its designee, according to the process established prior 
to first patient enrolled. A protocol violation or deviation may be requested in advance of 
implementation and will be reviewed for approval by Sebela or its designee, or a 
violation/deviation may be identified after the fact, by the investigator, Sebela, or the 
monitoring staff.  Investigators should ensure all scheduled PK samples are collected without 
protocol deviations. Investigators will be asked to provide an explanation for the all 
violations and deviations identified. Sebela, or designee, will be responsible for analyzing 
deviations and may implement corrective actions as necessary.   
9. 
SUBJECT CONFIDENTIALITY 
At all times throughout this study, all parties shall strictly observe the confidentiality of 
subject’s health information.  All data shall be secured against unauthorized access.  Each 
subject participating in this study will have consented/assented to allow access to her data, as 
described during the informed consent process and documented in the signed informed 
consent/assent form.  Each subject will also sign an Authorization for Release of Protected 
Health Information (PHI) form granting Sebela and its designees access to her medical 
records, should she receive medical care from non-study sites where she gets care (e.g., 
emergency room, urgent care, etc.). Each subject will be assigned a unique identifier.  All 
eCRFs will be tracked, evaluated, and stored using only this unique identifier.  HIPAA 
guidelines and regulations will be followed.  
The investigator will maintain a confidential study subject list identifying all enrolled 
subjects. This list will contain the assigned study subject’s unique identifier and name.  The 
investigator bears responsibility for keeping this list confidential.  This list will not be 
provided to the study sponsor and is only to be used at the study center. 
Monitors and auditors will have access to the study subject list and other personally 
identifying information of study subjects to ensure that data reported in the eCRFs 
corresponds to the person who signed the consent/assent form and the information contained 
in the original source documents.  Such personal identifying information may include, but 
not limited to, the subject’s name, address, date of birth, gender, race and medical record 
number. 
In an effort to protect subject confidentiality, any source documents copied for monitoring 
purposes by the sponsor or designee will be identified using the subject’s assigned unique 
identifier and personal identifying data will be obscured. 


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10. 
ON-TREATMENT PREGNANCY DETERMINATION AND FOLLOW UP 
On-treatment suspected pregnancy will be confirmed with both a urine and serum pregnancy 
test.   Pregnancies will be promptly confirmed and dated by ultrasound evaluation and 
medical assessment as needed. Presence or absence of the study drug will also be determined 
by ultrasound.  Removal of the study drug, if in place, will be performed as deemed 
appropriate by the study physician and upon obtaining subject consent/assent (note: removal 
itself may be performed by another clinician, such as a nurse practitioner).  Consideration of 
study drug removal should include the following standard of care criteria: If the subject has 
an intrauterine pregnancy in the first trimester and the study drug is seen to be in the uterine 
cavity or cervix on ultrasound, remove the study drug if the retrieval threads are visible. If 
the retrieval threads are not accessible, the IUD should remain in the uterus until delivery 
(abortion or term).  
Subjects will be counseled and followed for at least 6-weeks post-delivery, and the clinical 
outcome will be recorded.  Any infant abnormalities should be reported. 
11. 
STATISTICAL CONSIDERATIONS 
The statistical analysis will be conducted following the principles as specified in 
International Conference on Harmonisation (ICH) Topic E9 (CPMP/ICH/363/96). 
All statistical and pharmacokinetic analyses will be described in a separate statistical analysis 
plan.  
This study is designed to test the comparative bioavailability of copper as released from 
VeraCept vs ParaGard.   
11.1. 
Determination of Sample Size 
The assumption is that there is no additional systemic exposure of copper when using the 
IUD.  The primary analysis will use uncorrected total serum copper parameters (Cmax, 
Cmean, AUC0-56 days).  A secondary analysis will be conducted using baseline-corrected 
total serum copper parameters (Cmax, Cmean, AUC0-56 days). 
For the analysis using Cmax and Cmean, no formal hypothesis testing is being done. As 
such, a precision approach will be taken with boundaries chosen to reflect typical BE 
boundaries in the ln scale (plus or minus 22%).  Assuming a normal range of 49 to 184 
µg/dL, an estimate of the normal (mean) value could be close to 110-120 µg/dL. A 
comparable boundary would be plus or minus 22.  This estimated mean with the added half-
width still falls well within the normal range. 
For the analysis using AUC0-56 days, no formal hypothesis testing is being done. As such, a 
precision approach will be taken with boundaries chosen to reflect typical BE boundaries in 
the ln scale (plus or minus 22%).  AUC values will be ln transformed.  
For a two-sided 90% confidence interval for a two-sample normal mean difference, assuming 
a common standard deviation of 25, a sample size of 12 per group is required to obtain a 
half-width of at most 22 µg/dL with a conditional probability of at least 0.90 given that the 
interval contains the true mean difference.  The actual probability is 0.95.  


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CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 42 of 49 
Assuming a maximum unevaluable rate of 40%, up to 20 subjects will be enrolled in each 
group.  Replacement subjects may be enrolled, as needed, to ensure that at least 24 evaluable 
subjects complete the study 
11.2. 
Randomization 
Subjects will be randomized to a treatment group (VeraCept or ParaGard). The study will be 
conducted at one or two study sites. Participants will be randomly allocated in a 1:1 ratio 
either to VeraCept or ParaGard. The randomization will be stratified by site, if needed, but 
centrally managed until 40 subjects have been randomized.  
Once the screening assessments are performed, data have been reviewed by an investigator 
and the subject is considered to be eligible, the investigator or site designee will enroll the 
subject, assign the subject’s enrollment number and determine the treatment group. The 
subject’s number and treatment group will be determined by the sponsor provided 
randomization schedule. The site will assign the next consecutive subject number and 
corresponding treatment group.  The randomization will occur on the day of first drug 
placement attempt. If a subject has failed two drug placement attempts, she will be 
withdrawn from study.  Subjects will be blinded to the treatment they receive. 
Subjects who drop out of the study may be replaced as agreed by the Principal Investigator 
and the Sponsor. 
11.3. 
Analysis Populations 
The PK study population will include all randomized subjects whose pre-insertion total 
serum copper concentrations were within the normal range (49 to 185 µg/dL) [7], had an 
IUD placed successfully, and completes all scheduled PK sample collections without a 
protocol deviation or AEs that significantly impact the planned PK analyses. 
11.4. 
Pharmacokinetic Analyses  
11.4.1. 
Pharmacokinetic Methods 
Pharmacokinetic blood samples will be analyzed for total serum copper concentrations using 
validated bioanalytical methods. The mean of the 2 screening baseline values and the Day 1 
pre-dose concentration will be used for baseline-correction. 
Baseline-corrected serum concentrations that are less than zero will be treated as zero in the 
computation of mean baseline-corrected serum concentration values and derivation of 
individual subject computed parameters.  Descriptive statistics (number of subjects, mean, 
standard deviation [SD], CV%, median, minimum, and maximum) will be used to summarize 
observed and baseline-corrected serum concentrations. 
Both baseline corrected and observed post-dose copper concentrations will be used for 
calculation of relevant serum PK parameters (e.g., Cmax, Cmean, AUC0-56 days) using 
standard non-compartmental methods and actual sampling times utilizing a PK data analysis 
program (e.g., Phoenix WinNonlin® or equivalent).  A linear trapezoidal method will be used 
to estimate the area under the curve.  All relevant parameters will be summarized using 
descriptive statistics (number of subjects, mean, standard deviation [SD], CV%, median, 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 43 of 49 
minimum, maximum, geometric mean, geometric CV%).  Parameters that are less than or 
equal to zero will be treated as “missing”. 
PK Parameters to be calculated will include: 
Cmax 
Maximum observed concentration 
Tmax 
Time of maximum observed concentration 
Cmean 
Mean total serum copper concentration of samples collected after Day 
1 (Days 3-57) 
AUC0-56 days 
The area under the concentration time curve, from time 0 (study Day 1) 
to the last measurable non-zero concentration up to 56 days (study Day 
57), calculated by the linear trapezoidal method. 
Total serum copper concentration and pharmacokinetic data will be listed and presented in 
graphical form and will be summarized descriptively by treatment group. 
11.5. 
Statistical Analyses 
For the primary analysis, an ANCOVA model with fixed effects for treatment and Day 1 pre-
insertion concentration as a continuous effect will be used to analyze the uncorrected PK 
parameters Cmax, Cmean, and AUC0-56.  As such, a point estimate of the difference 
between treatments and a 90% CIs of the difference will be provided.  
For the secondary analysis, an ANCOVA model with fixed effects for treatment and natural 
ln transformed Day 1 pre-insertion concentration as a continuous effect will be used to 
analyze the natural-log transformed corrected PK parameters Cmax, Cmean, and AUC0-56.  
For each treatment comparison, a point estimate and 90% CIs will be provided for the 
geometric least squares mean ratio upon back-transformation. 
In addition, for each PK assessment day, the number and percentage of PK assessments within 
the total serum copper normal range (49 to 184 µg/dL) will be assessed for each treatment.  In 
addition, a shift table will also be provided for each of the PK days post Day 1 relative to the 
normal range. 
Following day 56 (Extension Phase), serum copper concentrations will only be collected for 
the VeraCept treatment group.  These data will be summarized in a Listing and additional 
statistical analysis or data presentations may be performed as appropriate.   
11.6. 
Safety Analyses 
In addition, for each PK assessment day, the number and percentage of PK assessments 
within the total serum copper normal range (49 to 184 µg/dL) [7] will be assessed for each 
treatment.  In addition, a shift table will also be provided for each of the PK days post Day 1 
relative to the normal range. 
Other safety analyses will be recorded and analyzed for the ParaGard subjects up to Day 57 
and up to 5 years for the VeraCept subjects.    


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 44 of 49 
12. 
STUDY ADMINISTRATION 
12.1. 
Data Monitoring and Quality Control 
Sebela or its designee will perform the quality assurance and quality control activities of this 
study; however, responsibility for the accuracy, completeness, and reliability of the study 
data presented to the Sponsor lies with the Principal Investigator generating the data. 
Prior to study initiation, the Sponsor or designee will explain the protocol, Investigator’s 
Brochure, and eCRFs to Investigators. Additionally, the monitor will explain all applicable 
regulations and will answer any questions regarding the conduct of the study. 
The Sponsor may conduct audits (at its discretion) as part of the implementation of quality 
assurance to ensure that the study is being conducted in compliance with the ICH harmonized 
tripartite guideline E6(R1): Good Clinical Practice (GCP), the protocol, standard operating 
procedures (SOPs), and all applicable regulatory requirements. Audits will be independent of 
and separate from the routine monitoring and quality control functions. The clinic may also 
be compelled to undergo an inspection by a regulatory authority. 
12.1.1. 
Data Collection and Tracking 
For this study, all subject data will be entered into the electronic case report form (eCRF), 
transmitted electronically to the Sponsor and combined with data provided from other 
sources in a validated data system. 
The full details of procedures for data handling will be documented in the Data Management 
Plan. Adverse events, medical history, and concurrent conditions will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA, current version). 
12.2. 
Study Responsibilities 
The Investigator must provide the Sponsor with complete test results and all data collected by 
the Investigator from the study. During the study, only the Sponsor may make study 
information available to other study Investigators or to regulatory agencies, except as 
required by law or regulation.  
12.2.1. 
Investigator Responsibility 
The following administrative responsibilities are meant to guide the Investigator in the 
conduction of the study but may be subject to change based on industry and government 
SOPs or working practice documents or guidelines. Changes will be reported but will not 
result in protocol amendments. 
The Investigator will permit study-related monitoring, audit(s), IRB review(s), and regulatory 
inspection(s), and will facilitate direct access to all the required source documents and 
associated records.  
12.2.2. 
Data Transmittal and Sample/Record Retention 
All data that are a result of the original observations and activities of the study and that are 
necessary for the reconstruction and evaluation of any study report will be retained in a 
secure archive at the study site for a period not less than 2 years after the last approval of a 
marketing application in an ICH region, and until there are no pending or contemplated 
marketing applications in an ICH region, or until at least 2 years have lapsed since the formal 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 45 of 49 
discontinuation of the clinical development of the investigational product.  Reserve samples 
of both the test article and the reference standard (5-times quantity) should be retained at the 
study site or an independent third party for a period of at least 5 years following the date of 
completion of the bioavailability study in which the sample from which the reserve sample 
was obtained. 
The site will maintain a clinical study document binder, which will be maintained at the 
study site. In this binder, there will be sections for study documents including but not limited 
to the following: study personnel identification and signature list, subject screening records, 
subject roster (names omitted), protocol and amendments or administrative changes, study 
staff Curricula Vitae, study staff financial disclosures, IEC documentation, an approved 
sample ICF, drug accountability records, correspondence, site monitoring follow up letters, 
lab accreditations and normal values, significant correspondence. The site must keep this 
binder current and available for review by the Sponsor and/or regulatory authorities. 
12.2.3. 
Audit/Inspections 
Authorized representatives of Sebela, a regulatory authority, or an Independent Ethics 
Committee (IEC) may visit the site to perform audits or inspections, including source data 
verification.  The purpose of a Sebela audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported 
according to the study protocol, GCP guidelines of the International Conference on 
Harmonization (ICH), and any applicable regulatory requirements.  The Investigator should 
contact Sebela immediately if contacted by a regulatory agency about an inspection. 
12.3. 
Pharmacokinetic Sample Handling & Shipping 
The procedure for pharmacokinetic sample collection, storage and shipping and the required 
supplies are provided in the study’s Sample Collection Manual. Serum samples collected in 
the study will be shipped to the analytical lab for analysis per the procedures outlined in the 
Sample Collection Manual. 
13. 
ETHICAL AND LEGAL CONSIDERATIONS 
Study information from this protocol will be posted according to regulatory guidelines before 
enrollment of subjects begins. 
The final study protocol, including the final version of the ICF, must be approved in writing 
by an IEC.  The Investigator must submit written approval to Sebela before he or she can 
enroll any patient/subject into the study. 
The Principal Investigator is responsible for informing the IEC of any amendment(s) to the 
protocol in accordance with local requirements.  In addition, the IEC must approve all 
advertising used to recruit patients for the study.  The protocol must be re-approved by the 
IEC upon receipt of any amendments and annually, according to local regulations. 
The Principal Investigator is also responsible for providing the IEC with reports of any 
reportable SAEs from any other study conducted with the investigational product.  Sebela 
will provide this information to the Principal Investigator. 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 46 of 49 
Progress reports and notifications of SAEs will be provided to the IEC according to local 
regulations and guidelines. 
The Principal Investigator(s) at each center will ensure that the patient is given full and 
adequate oral and written information about the nature, purpose, possible risk and benefit of 
the study.  Patients must also be notified that they are free to discontinue from the study at 
any time.  The patient should be given the opportunity to ask questions and allowed time to 
consider the information provided. 
The patient’s signed and dated ICF must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed ICF.  A copy of the signed 
ICF must be given to the patient. 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 47 of 49 
14. 
REFERENCES 
1. 
Chantler, E., F. Critoph, and M. Elstein, Release of copper from copper-bearing 
intrauterine contraceptive devices. Br Med J, 1977. 2(6082): p. 288-91. 
2. 
Drost, R.H., M. Thiery, and R.A. Maes, Long-term release of copper from two 
multiload IUD models: MLCu250 and MLCu375. Adv Contracept, 1987. 3(4): p. 
315-8. 
3. 
Zhang, S., et al., In vitro release of cupric ion from intrauterine devices: influence of 
frame, shape, copper surface area and indomethacin. Biomed Microdevices, 2015. 
17(1): p. 19. 
4. 
Bost, M., et al., Dietary copper and human health: Current evidence and unresolved 
issues. J Trace Elem Med Biol, 2016. 35: p. 107-15. 
5. 
Ghayour-Mobarhan, M., et al., Determinants of serum copper, zinc and selenium in 
healthy subjects. Ann Clin Biochem, 2005. 42(Pt 5): p. 364-75. 
6. 
Johnson, P.E., D.B. Milne, and G.I. Lykken, Effects of age and sex on copper 
absorption, biological half-life, and status in humans. Am J Clin Nutr, 1992. 56(5): p. 
917-25. 
7. 
Salwen, M.J., Vitamins and Trace Elements 23 ed. Henry's Clinical Diagnosis and 
Management by Laboratory Methods, 23rd Edition. 2017, St. Louis, Missouri: 
Elsevier Health Sciences. 1700. 
8. 
Holland, M.K. and I.G. White, Heavy metals and human spermatozoa. III. The 
toxicity of copper ions for spermatozoa. Contraception, 1988. 38(6): p. 685-95. 
9. 
Stanford, J.B. and R.T. Mikolajczyk, Mechanisms of action of intrauterine devices: 
update and estimation of postfertilization effects. Am J Obstet Gynecol, 2002. 187(6): 
p. 1699-708. 
10. 
Mishell, D.R., Jr., Intrauterine devices: mechanisms of action, safety, and efficacy. 
Contraception, 1998. 58(3 Suppl): p. 45S-53S; quiz 70S. 
11. 
Segal, S.J., et al., Absence of chorionic gonadotropin in sera of women who use 
intrauterine devices. Fertil Steril, 1985. 44(2): p. 214-8. 
12. 
Prema, K., B.A. Lakshmi, and S. Babu, Serum copper in long-term users of copper 
intrauterine devices. Fertil Steril, 1980. 34(1): p. 32-5. 
13. 
Medicine, I.o., Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, 
Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, 
Vanadium, and Zinc. 2001, Washington, DC: The National Academies Press. 800. 
14. 
Pennington, J.A.T., et al., Composition of Core Foods of the U.S. Food Supply, 1982-
1991: III. Copper, Manganese, Selenium, and Iodine. Journal of Food Composition 
and Analysis, 1995. 8(2): p. 171-217. 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 48 of 49 
Appendix 1.  Time and Events Schedule   
Visit 
Screening 
Enrollment/IUD 
Placement 
Clinic PK Visits 
 
Clinic PK Visits 
(VeraCept 
Subjects ONLY) 
Month 60 
OR  
Exit Visit 
Day 
Day -28 to 1 
Day 1 
Day 3 
(±24 hrs) 
Days 8, 15, 
22, 29 (±1 
day) 
Day 576  
(±3 days) 
Months 6, 12, 18, 
24, 30, 36 and 48 
(±30 days) 
Month 60  
(±30 days) 
OR 
Exit Visit 
Assessment of Eligibility 
X 
X 
  
  
 
 
Distribution of subject materials (if applicable) 
X 
  
  
  
 
 
Informed Consent/Assent/PHI and Bill of Rights   
X 
  
  
  
 
 
Demographics and baseline characteristics 
X 
  
  
  
 
 
Medical/surgical, gynecologic and menstrual history 
X 
  
  
  
 
 
Vital signs and weight 
X 
X 
 X 
 X 
X 
X 
Height 
X 
 
  
  
 
 
General physical exam 
X 
  
  
  
 
 
Pelvic exam (string check if post IUD insertion) 
X 
X1  
  
X  
X 
X 
Cervical cytology 
X 
  
  
  
 
 
Cervical infection tests 
X2,3 
  
  
  
 
 
Transvaginal ultrasound, only if clinically indicated 
  
X 
  
 X 
X 
X 
Pregnancy test – urine 
X 
X 
  
  
 
X 
Prior and concurrent medication 
X 
X 
 X 
 X 
X 
X 
Adverse events 
X 
X 
 X 
 X 
X 
X 
IUD placement 
  
X 
 
 
 
 
IUD removal 
  
  
  
  
 
X7 
Concomitant contraception 
 
X 
 
 
 
X 
Subject education – need for contraception 
X 
X 
X 
X 
X 
X 
Blood draw for PK analysis (serum copper sample) 
X4 
X5 
X5 
X5 
X5 
X5 
1. 
Pelvic exam for IUD string check by palpation or visualization. 
2. 
Screening for cervical infection tests are to be done at screening unless these tests have been previously completed within 3 months of the screening visit and were negative. 
If a subject tests positive prior to IUD insertion, the subject should be treated prior to IUD placement. The subject may be inserted 7 days post-treatment. A cervical infection 
retest should be done 3-months post-IUD insertion to assure there is not a case of re-infection. 
3. 
Insertion can occur without receipt of test results if there is no clinical evidence of infection. If, after IUD insertion, the screening cervical infection test results are positive, 
the subject should be treated. A cervical infection retest should be done 3 months post-treatment. 
4. 
Subjects will be screened within 60 days prior to the first insertion of study drug, , and two blood samples will be collected within 28 days from Day 1, and at least 24 hours 
apart within this screening period (can be performed on Screening and Day 1 visit prior to IUD insertion).  to establish baseline copper concentrations.  
5. 
On Day 1, collect blood samples for pharmacokinetic analysis prior to intrauterine insertion.  On Day 3, collect samples 48 hours ±24 hours after IUD insertion.  PK samples 
on Day 8, 15, 22, and 29 should be collected within 1 day of the planned collection day while Day 57 should be collected within 3 days of planned collection day, at 


Sebela Pharmaceuticals, Inc. 
CMDOC-0045 PK Study 
VeraCept Intrauterine Contraceptive 
Clinical Bioavailability Protocol 
CMDOC-0045 Version 2.0 / 03 Jul 2019 
CONFIDENTIAL 
Page 49 of 49 
approximately the same time as the Day 3, 48-hr ±1 day PK sample collection.  Following the PK collections on Day 57, the PK samples should be collected within 30 days 
of the planned collection day 
6. 
Paragard subjects will have Exit Visit procedures completed on Day 57 
7. 
ParaGard subjects may continue ParaGard use per standard clinical care or have the device removed.  

SAP_001.pdf: 
NCT03785366 
Statistical Analysis Plans 
A Randomized, Single-Blind, Comparative Bioavailability Study to Assess the 
Pharmacokinetic Properties of VeraCept® Intrauterine Contraceptive vs ParaGard® in 
Healthy, Post-Menarcheal Women 
 
DOCUMENT DATES: 21 November 2021 and 20 September 2024 


Sebela Pharmaceuticals, Inc. 
Amended Pharmacokinetic Analysis Plan 
Study CMDOC-0045 
Analysis Plan Prepared By 
 
CONFIDENTIAL 
Page 1 of 25 
 
 
 
Amended Pharmacokinetic Analysis Plan 
 
A Randomized, Single-Blind, Comparative 
Bioavailability Study to Assess the Pharmacokinetic 
Properties of VeraCept® Intrauterine Contraceptive vs. 
ParaGard® in Healthy, Post-Menarcheal Women 
 
Name of Investigational Drug: 
VeraCept Intrauterine Contraceptive 
Study Number: 
CMDOC-0045 
Sponsor: 
Sebela Pharmaceuticals, Inc. 
645 Hembree Parkway, Suite I  
Roswell, GA 30076   
Pharmacokinetic Analysis Site: 
Nuventra, LLC 
2525 Meridian Parkway, Suite 200 
Durham, NC 27713  
Phase: 
3 
Version:  
Amendment 2 Final 
Date of Report:  
05 November 2021 
 


Sebela Pharmaceuticals, Inc. 
 Amended Pharmacokinetic Analysis Plan 
 Study CMDOC-0045 
CONFIDENTIAL 
Page 2 of 25 
SUMMARY OF CHANGES 
Amendment/Date 
Location 
Description of Changes 
Amendment 2 
5 November 2021 
 
 
Header 
Updated “PK Analysis Plan” to “Amended 
Pharmacokinetic Analysis Plan” 
Title Page 
Updated “Pharmacokinetic Analysis Plan” to 
“Amended Pharmacokinetic Analysis Plan” added 
Pharmacokinetic Analysis Site; updated version to 
Amendment 2; updated date from 02 October 2019 
to 5 November 2021  
Summary of 
Changes 
Updated to reflect changes made in PK Analysis 
Plan Amendment 2  
Approval Page 
Updated Nuventra signatory from “Author” to 
“Project Lead”; updated “Nuventra, Inc.” to 
“Nuventra, LLC”; removed address from all 
signature lines 
Table of Contents 
Updated to reflect new sections and page numbers; 
added List of Tables and List of Figures 
Abbreviations 
Updated to include additional abbreviations 
Section 1 
Updated to include information about the 3-part 
analysis plan and the planned summary and 
reporting of safety data 
Section 3 
Added Study Endpoints 
Section 5 
Added information about PK blood collection 
during the Extension Phase 
Section 6 
Included Changes to Protocol-Specified Population 
Section 8 
Updated heading to emphasize NCA and statistical 
analyses focus on Treatment Comparison Phase, 
clarified use of actual dosing and sampling times for 
the final NCA; removed information about the 
Extension Phase from Statistical Analyses; added 
Changes to Protocol-Defined Analysis, Imputation 
of Missing Data, and Data Exclusions 
Section 9 
Added Part C – Pharmacokinetic and Statistical 
Analyses During Extension Phase 
Section 10 
Added Safety Data Summary and Reporting During 
Treatment Comparison Phase and Treatment 
Extension Phase 
Section 11 
Updated to address the planned Tables, Figures, 
Listings, and Appendices for the PK data collected 
during the Extension Phase; added information 


Sebela Pharmaceuticals, Inc. 
 Amended Pharmacokinetic Analysis Plan 
 Study CMDOC-0045 
CONFIDENTIAL 
Page 3 of 25 
about list of planned safety data summary tables and 
listings for the safety data 
Global 
Added clarifying language to delineate analysis and 
reporting of pharmacokinetic and safety data; minor 
updates to reflect updates in Nuventra’s PK analysis 
plan template and formatting 
Amendment 1 
02 October 2019 
 
 
Title Page 
Updated to match Nuventra’s updated PK analysis 
plan template and formatting 
Updated to match the protocol title in protocol 
version 2.0 
Document Approval 
Page 
Updated Nuventra signatory name and address 
Table of Contents 
Added to this version 
Abbreviations 
Added to this version 
Section 1 
Updated to include planned interim analysis 
Section 3 
Updated to match protocol version 2.0 
Section 4 
Updated to match protocol version 2.0 
Section 6 
Updated to include planned interim analysis 
Section 10 
Updated to specify deliverables associated with 
interim and final analyses 
Header 
Updated to include change in sponsor name 
Footer 
Updated to match Nuventra’s updated PK analysis 
plan template and formatting 
Throughout 
Edits to correct headings, heading numbering, 
typographical errors, formatting, and clarify 
language 
 
 
 




Sebela Pharmaceuticals, Inc. 
 Amended Pharmacokinetic Analysis Plan 
 Study CMDOC-0045 
CONFIDENTIAL 
Page 5 of 25 
TABLE OF CONTENTS 
SUMMARY OF CHANGES ...................................................................................................2 
APPROVAL PAGE .................................................................................................................4 
TABLE OF CONTENTS ........................................................................................................5 
LIST OF TABLES ...................................................................................................................6 
LIST OF FIGURES .................................................................................................................6 
ABBREVIATIONS ..................................................................................................................7 
1. 
INTRODUCTION ............................................................................................................8 
2. 
PHARMACOKINETIC OBJECTIVES .........................................................................8 
2.1 
Primary Objective .....................................................................................................8 
2.2 
Secondary Objectives ................................................................................................8 
3. 
STUDY ENDPOINTS ......................................................................................................9 
3.1 
Primary Endpoint ......................................................................................................9 
3.2 
Secondary Endpoints .................................................................................................9 
4. 
INVESTIGATIONAL PLAN ..........................................................................................9 
4.1 
Overall Study Design ................................................................................................9 
5. 
PHARMACOKINETIC SAMPLE COLLECTION ...................................................11 
5.1 
Blood Collection and Sample Processing ...............................................................11 
5.2 
Bioanalytical Methods for Pharmacokinetic Samples ............................................11 
6. 
PHARMACOKINETIC POPULATION .....................................................................11 
6.1 
Pharmacokinetic Population ...................................................................................11 
6.2 
Changes to Protocol-Specified Population..............................................................11 
7. 
PART A – INTERIM PHARMACOKINETIC AND STATISTICAL ANALYSES 
DURING TREATMENT COMPARISON PHASE ....................................................12 
7.1 
Noncompartmental Pharmacokinetic Analysis and Descriptive Statistics .............12 
8. 
PART B – FINAL PHARMACOKINETIC AND STATISTICAL ANALYSES 
DURING TREATMENT COMPARISON PHASE ....................................................12 
8.1 
Noncompartmental Pharmacokinetic Analysis and Descriptive Statistics .............12 
8.2 
Statistical Analyses .................................................................................................14 
8.3 
Changes to Protocol-Defined Analysis ...................................................................14 
8.4 
Imputation of BLQ Values ......................................................................................14 
8.5 
Imputation of Missing Data ....................................................................................15 
8.6 
Data Exclusions .......................................................................................................15 
8.7 
Significant Figures ..................................................................................................15 
9. 
PART C – PHARMACOKINETIC AND STATISTICAL ANALYSES DURING 
EXTENSION PHASE ....................................................................................................15 
9.1 
Noncompartmental Pharmacokinetic Analysis and Descriptive Statistics .............15 
9.2 
Statistical Analyses .................................................................................................16 


Sebela Pharmaceuticals, Inc. 
 Amended Pharmacokinetic Analysis Plan 
 Study CMDOC-0045 
CONFIDENTIAL 
Page 6 of 25 
10. SAFETY DATA SUMMARY AND REPORTING DURING TREATMENT 
COMPARISON PHASE AND TREATMENT EXTENSION PHASE .....................16 
10.1 Definition of an Adverse Event...............................................................................16 
10.2 Definition of a Serious Adverse Event....................................................................16 
10.3 Adverse Events of Specific Interest ........................................................................17 
10.4 Safety Analyses .......................................................................................................17 
11. TABLES, FIGURES, LISTINGS, AND APPENDICES .............................................18 
11.1 List of Tables...........................................................................................................18 
11.1.1 In-text Tables ..............................................................................................18 
11.1.2 Post-text Tables ...........................................................................................20 
11.2 List of Figures .........................................................................................................21 
11.2.1 In-text Figures .............................................................................................21 
11.2.2 Post-text Figures .........................................................................................22 
11.3 Listings ....................................................................................................................24 
11.4 Appendix Figures ....................................................................................................25 
 
LIST OF TABLES 
Table 8-1.  
Software List ....................................................................................................13 
Table 8-2.  
Pharmacokinetic Parameters ............................................................................13 
Table 9-2.  
Pharmacokinetic Parameters ............................................................................16 
 
LIST OF FIGURES 
Figure 1 
Study Design Schemata — Treatment Comparison Phase ..............................10 
Figure 2 
Study Design Schemata — Extension Phase ...................................................10 
 
 
 
 


Sebela Pharmaceuticals, Inc. 
 Amended Pharmacokinetic Analysis Plan 
 Study CMDOC-0045 
CONFIDENTIAL 
Page 7 of 25 
ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse Events of Specific Interest  
ANCOVA 
Analysis of Covariance 
BLQ 
Below the Limit of Quantification  
CI 
Confidence Interval  
CV% 
Coefficient of Variation (given as a percentage) 
IUD 
Intrauterine Contraceptive Device 
NCA 
Noncompartmental Analysis 
PK 
Pharmacokinetic 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOP 
Standard Operating Procedures 
PK parameter abbreviations can be found in Table 8-2 and Table 9-2 
 
 
 


Sebela Pharmaceuticals, Inc. 
 Amended Pharmacokinetic Analysis Plan 
 Study CMDOC-0045 
CONFIDENTIAL 
Page 8 of 25 
1. INTRODUCTION 
This pharmacokinetic analysis plan describes the analysis and reporting of the pharmacokinetic 
(PK) results for study CMDOC-0045, in which the bioavailability of systemic copper exposure 
after insertion of Sebela’s investigational VeraCept intrauterine contraceptive device (IUD) is 
compared to the marketed ParaGard IUD in healthy, post-menarcheal women.  
Sebela has developed VeraCept to provide a long-acting, reversible method of contraception for 
non-pregnant, parous, and nulliparous women of child-bearing age. VeraCept’s design utilizes a 
shape memory nitinol spring frame with the same active chemical entity as the marketed 
reference product, ParaGard (99.99% pure copper), yet containing less than half of the exposed 
copper surface area (175 mm2). VeraCept is delivered preloaded in an introducer, which is 
narrower than the ParaGard inserter, to simplify clinician insertions and facilitate correct, easy 
placement in the uterus. Correct placement and a shape memory frame optimize VeraCept’s 
long-term efficacy by decreasing expulsions and increasing its tolerability, thereby improving 
end-user continuation rates. In contrast to the passive plastic “T” utilized in ParaGard, VeraCept 
has been designed to mitigate the side effects associated with ParaGard without compromising 
contraceptive effectiveness. 
The current study will assess systemic copper exposure after insertion of VeraCept as compared 
to ParaGard in enrolled subjects. The study will characterize the PK and comparative 
bioavailability of observed and baseline-corrected total serum copper exposure in patients after 
receiving either VeraCept or ParaGard.  
This is a 3-part analysis plan with Part A addressing the planned interim PK analysis, Part B 
addressing the noncompartmental analysis (NCA) and statistical analysis of the PK data for the 
Treatment Comparison Phase and resulting final PK report, and Part C addressing the analyses 
on PK data collected during the Extension Phase.  
In addition to PK analysis and reporting, the study will also monitor the safety of VeraCept and 
ParaGard in enrolled subjects. The safety sections of this PK analysis plan address the planned 
summary and reporting of the safety data for this study but detailed information, including the 
list of planned safety data summary tables and listings, can be found in the safety analysis plan 
authored by Synteract. The safety data summary tables and listings and the resulting safety 
conclusions will be generated by Synteract and will be included in the final PK report.    
2. PHARMACOKINETIC OBJECTIVES 
This analysis plan is based on the information provided in Protocol Version 2.0 (03 Jul 2019).  
2.1 
Primary Objective 
The primary objective of the study related to the PK analysis is: 
• To assess the relative bioavailability of observed systemic copper from VeraCept versus 
ParaGard based on Cmax, Cmean, and AUC0-56 days.  
2.2 
Secondary Objectives 
The secondary objectives of the study related to the PK analysis are: 


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• To assess the relative bioavailability of baseline-corrected total serum copper from 
VeraCept versus ParaGard based on Cmax, Cmean, and AUC0-56 days. 
• To assess the total serum copper levels within each treatment relative to the normal range 
(49 to 184 µg/dL). 
• To assess the long-term stability of copper levels following insertion of VeraCept. 
3. STUDY ENDPOINTS 
3.1 
Primary Endpoint 
The primary endpoint related to the PK analysis is: 
• Mean total serum copper concentration (Cmean), Cmax, and AUC0-56 days for observed 
copper for each treatment. 
3.2 
Secondary Endpoints 
The secondary endpoints related to the PK analysis are: 
• Mean total serum copper concentration (Cmean), Cmax, and AUC0-56 days for 
baseline-corrected copper for each treatment. 
• Total serum copper concentrations within each treatment for each assessment day for 
56 days. 
• Mean total serum copper concentration for observed and baseline-adjusted copper for 
each treatment over 5 years (Treatment A, VeraCept IUD only). 
4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This parallel, open-label study is designed to evaluate the comparative bioavailability of 
systemic copper exposure after insertion of VeraCept versus ParaGard in post-menarcheal 
women. Up to 40 subjects will receive one of two treatments (A or B) as described below:  
• Treatment A (N=20): VeraCept® IUD, test (referred to as VeraCept) 
• Treatment B (N=20): ParaGard® IUD, reference (referred to as ParaGard) 
Figure 1 and Figure 2 display the study design schematic for the Treatment Comparison Phase 
and Extension Phase, respectively. 


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Figure 1 
Study Design Schemata — Treatment Comparison Phase 
 
Subjects will be screened within 60 days prior to the first insertion of study drug, and blood 
samples will be collected within 28 days from first insertion of study drug at two visits within 
this screening period to establish baseline copper concentrations. At least 24 hours should 
separate each baseline sample. On Day 1 of each treatment period, PK, safety, and baseline 
assessments will be collected prior to IUD insertion. Subjects will return to the clinic at 48 hours 
post-IUD insertion (Day 3(±24 hours)), and on Days 8 (±1 day), 15 (±1 day), 22 (±1 day), 
29 (±1 day), and 57 (±3 days) for blood collection for measurement of total serum copper 
concentrations.  
Figure 2 
Study Design Schemata — Extension Phase 
 
On Day 57, ParaGard subjects will exit the study and may continue ParaGard use per standard of 
clinical care. VeraCept subjects will continue in the extension phase of the study, intended to 
assess long-term stability of serum copper concentrations up to 5 years and monitor safety. 
During the first 3 years, subjects will return to the clinic every 6 months (±30 days) for clinical 
assessments and blood collection for measurement of total serum concentrations. Following Year 
3, subjects will return annually, up to Year 5. During the extension phase, PK collections may 
occur anytime within 30 days of the planned collection time. Subjects prematurely discontinuing 
the study should follow the Early Discontinuation procedures specified in the protocol. 
Additional follow-up visits may be scheduled, as needed, if a subject has an ongoing significant 
adverse event (AE) and/or a clinically significant laboratory abnormality. A schedule of the 
study procedures and assessments to be conducted for each subject is provided in the Time and 
Events Table in the protocol. 


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Subjects will be randomized to a treatment group (VeraCept or ParaGard). The study will be 
conducted at one or more study sites. Participants will be randomly allocated in a 1:1 ratio, either 
to VeraCept or ParaGard. The randomization will be stratified by site, if needed, but centrally 
managed until 40 subjects have been randomized.   
5. PHARMACOKINETIC SAMPLE COLLECTION 
5.1 
Blood Collection and Sample Processing 
Two blood samples for PK analysis will be collected within 28 days from Day 1, and at least 
24 hours apart within this screening period (can be performed on Screening and Day 1 visits 
prior to IUD insertion) to establish baseline copper concentrations, on Day 1 prior to IUD 
insertion, on Day 3, approximately 48 hours after insertion, and on Days 8, 15, 22, 29, and 57 at 
approximately the same time of day as the prior PK collections. Following the PK collections on 
Day 57, the PK samples for Months 6, 12, 18, 24, 30, 36, and 48 will be collected within 30 days 
of the planned collection day. Approximately 3-5 mL of whole blood will be collected for each 
blood draw. The total volume collected from each subject for all PK samples will be 
approximately 20 mL.  
Blood samples will be collected in containers appropriate for serum collection, such as a “red 
topped” tube, which does not contain an anticoagulant. 
5.2 
Bioanalytical Methods for Pharmacokinetic Samples 
Blood samples will be processed for serum as described in the PK laboratory manual. The yield 
of serum will be subdivided into 2 samples (~1 mL each). One of these samples will be shipped 
as soon as possible to the analytical lab for analysis of total serum copper, and the other will be 
stored at -20ºC at the site until completion of the study (or until directed by Sebela or designee), 
and then sent to the analytical lab in one group.   
6. PHARMACOKINETIC POPULATION 
6.1 
Pharmacokinetic Population  
The PK study population is defined as all randomized subjects for which all pre-insertion total 
serum copper concentrations were within the normal range (49 to 184 µg/dL), had an IUD placed 
successfully, and completed all scheduled PK sample collections without a protocol deviation or 
AEs that significantly impact the planned PK analyses. 
6.2 
Changes to Protocol-Specified Population  
The protocol defines the overall PK study population but not the PK concentration and PK 
parameter populations.  
The PK concentration population is defined as all randomized subjects that have an IUD placed 
successfully and have at least one quantifiable total serum copper concentration post-insertion. 
Concentration data from this population will be presented in the tables and used in the 
calculation of summary statistics for plotting purposes. 


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The PK parameter population is defined as subjects in the PK concentration population with 
sufficient data to calculate PK parameters (at least 4 quantifiable total serum copper 
concentrations and no protocol deviations that have a material impact on the PK). This 
population will be included in the NCA and individual copper concentration versus time figures. 
Any other changes to protocol-specified population due to protocol deviations or other factors 
that may impact PK will be detailed in the final PK report. 
7. PART A – INTERIM PHARMACOKINETIC AND STATISTICAL ANALYSES 
DURING TREATMENT COMPARISON PHASE 
7.1 
Noncompartmental Pharmacokinetic Analysis and Descriptive Statistics 
An interim analysis for the Treatment Comparison Phase will be performed once approximately 
20 subjects have completed the visit on Day 57. All interim PK analysis and reporting will be 
performed according to applicable Nuventra standard operating procedures and protocol 
specifications. PK parameters will be calculated by Nuventra using Phoenix® WinNonlin® 8.1 or 
later (Certara, Princeton, NJ, USA) using nominal doses and sampling times. 
For these analyses, all relevant PK parameters from Section 8.1 and Tables, Listings, and Figures 
from Section 11 will be generated using Phoenix® WinNonlin®. 
The mean of the two screening baseline values and the Day 1 pre-dose concentration will be used 
for baseline correction. Descriptive statistics (number of subjects [N], mean, standard deviation 
[SD], percent coefficient of variation [CV%], median, minimum, and maximum) will be used to 
summarize observed and baseline-corrected serum concentrations. All relevant parameters will 
be summarized using descriptive statistics (N, mean, SD, CV%, median, minimum, maximum, 
geometric mean, and geometric CV%). Parameters that are equal to zero will be reported as 
“missing”.  
No statistical analyses are planned for interim analyses.  
8. PART B – FINAL PHARMACOKINETIC AND STATISTICAL ANALYSES 
DURING TREATMENT COMPARISON PHASE 
8.1 
Noncompartmental Pharmacokinetic Analysis and Descriptive Statistics 
All final PK analysis and reporting for the Treatment Comparison and Extension Phases will be 
performed according to applicable Nuventra standard operating procedures and protocol 
specifications. PK parameters will be calculated using NCA implemented within a validated 
installation of Phoenix® WinNonlin® using actual dosing and sampling times. Programming of 
tables, figures, and listings will be performed using verified templated R code run in validated R 
Software and RStudio environments. Additional information on the software to be utilized in this 
study can be found in Table 8-1. The actual version of the software will be included in the final 
PK report. Additional software may be used, if necessary. All software used will be documented 
in the final PK report.  


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Table 8-1.  
Software List  
Software 
Use 
Version 
Company 
Phoenix 
WinNonlin 
NCA 
V 8.1 or later (Validated as per 
VAL.001.04) 
Certara (Princeton, NJ) 
R Software 
Input file 
generation 
V 3.4.0 or later 
(custom code) 
R Foundation for 
Statistical Computing 
(Vienna, Austria) 
TLFs 
V 3.4.0 or later (Validated as per 
VAL.002.07) 
RStudio 
TLFs 
V 1.0.143 or later (Validated as per 
VAL.002.07) 
RStudio (Boston, MA) 
SAS 
Biostatistics SAS 9.4 or later 
SAS Institute, Inc. (Cary, 
NC) 
PK blood samples will be analyzed for total serum copper concentrations using validated 
bioanalytical methods. The mean of the two screening baseline values and the Day 1 pre-dose 
concentration will be used for baseline correction. 
Descriptive statistics to summarize observed and baseline-corrected serum concentrations 
include: N (number of non-missing data), Mean (arithmetic mean), standard deviation (SD), 
arithmetic percent coefficient of variation (CV%), minimum, median, and maximum. 
Summaries of plasma concentration data will include data for all subjects in the PK 
concentration population (see Section 6.2).  
PK parameters for uncorrected and baseline-corrected serum copper will be calculated as 
described in Table 8-2. 
Table 8-2.  
Pharmacokinetic Parameters 
Parameter 
Description 
Data from Treatment Comparison Phase  
Cmax 
Maximum observed concentration, observed by inspection of individual study 
participant serum concentration-time plots 
Tmax 
Time of maximum observed concentration, obtained directly from the observed 
concentration-time data 
Cmean 
Mean total serum copper concentration of samples collected after Day 1 (Days 3-
57) 
AUC0-56 days 
Area under the concentration time curve, from time 0 (study Day 1) to the last 
measurable non-zero concentration up to 56 days (study Day 57), calculated by the 
linear trapezoidal method 
Note that the abbreviations and definitions listed above may differ slightly from the protocol in the phrasing; 
however, the equations and methods used to generate these parameters do not differ from the protocol. 
Additional PK parameters may be calculated, as necessary, to fully characterize the PK profiles 
of uncorrected and baseline-corrected serum copper and will be defined in the final PK report. 


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No PK parameters will be calculated for subjects with fewer than 4 quantifiable total serum 
copper (uncorrected) concentrations following imputation of concentrations below the limit of 
quantification (BLQ) (see Section 8.4). Baseline-corrected copper PK parameters will be 
calculated for all subjects regardless of the number of non-zero concentrations.  
All subjects in the PK parameter population (see Section 6.2) will be included in the descriptive 
statistics for the PK parameters. PK parameters will be listed for each subject by treatment, and 
the following descriptive statistics will be provided: N (number of subjects with non-missing 
data), arithmetic mean, SD, CV%, median, minimum, and maximum. Geometric mean and 
geometric CV% will be calculated for continuous PK parameters. Tmax will be presented as N, 
median, minimum, and maximum. Parameters that are equal to zero will be reported as 
“missing”. 
8.2 
Statistical Analyses 
For the primary analysis, an analysis of covariance (ANCOVA) model with fixed effects for 
treatment and Day 1 pre-insertion concentration as a continuous effect will be used to analyze 
the uncorrected PK parameters Cmax, Cmean, and AUC0-56 days. As such, a point estimate of 
the difference between treatments and a 90% confidence interval (CI) of the difference will be 
provided.  
For the secondary analysis, an ANCOVA model with fixed effects for treatment and natural log 
(ln) transformed Day 1 pre-insertion concentration as a continuous effect will be used to analyze 
the ln transformed corrected PK parameters Cmax, Cmean, and AUC0-56 days. For each 
treatment comparison, a point estimate and 90% CIs will be provided for the geometric least 
squares mean ratio upon back-transformation. 
In addition, for each PK assessment day, the number and percentage of PK assessments within 
the total serum copper normal range (49 to 184 µg/dL) will be assessed for each treatment. A 
shift table will also be provided for each of the PK days post Day 1 relative to the normal range.  
8.3 
Changes to Protocol-Defined Analysis  
No changes to the protocol-defined analysis are planned at this time. Any changes will be 
detailed in the final PK report.  
8.4 
Imputation of BLQ Values 
For the calculation of mean concentrations and generation of mean concentration versus time 
profiles, all BLQ values will be set to zero, except when an individual BLQ falls between two 
quantifiable values, in which case it will be treated as missing data.   
For the PK analysis and individual concentration versus time plots, a concentration that is BLQ 
is assigned a value of zero if it occurs in a profile before the first measurable concentration. If a 
BLQ value occurs after a measurable concentration in a profile and is followed by a value above 
the lower limit of quantification, then the BLQ is treated as missing data. If a BLQ value occurs 
at the end of the collection interval (after the last quantifiable concentration), it is treated as 
missing data. If 2 BLQ values occur in succession after Cmax, the profile is deemed to have 
terminated at the first BLQ value, and any subsequent concentrations are omitted from PK 
calculations.  


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In circumstances where alternative approaches to handling BLQ data are necessary, the relevant 
modifications will be appropriately documented in the clinical study report or final PK report.  
Baseline-corrected serum copper concentrations that are less than or equal to zero will be treated 
as zero for the calculation of summary statistics and in the noncompartmental analysis. 
8.5 
Imputation of Missing Data 
No imputation of missing data is planned at this time. Any missing data imputations will be 
detailed in the final PK report.  
8.6 
Data Exclusions 
No data exclusions are planned at this time. Any exclusions will be detailed in the final PK 
report.  
8.7 
Significant Figures 
Concentration data and PK parameters will be generally reported to 3 significant figures. All 
associated summary statistics for these parameters will also be reported to 3 significant figures, 
except for N which will be reported as an integer. Discrete time parameters (such as Tmax) and 
associated summary statistics will be reported to 2 decimal places. 
9. PART C – PHARMACOKINETIC AND STATISTICAL ANALYSES DURING 
EXTENSION PHASE 
9.1 
Noncompartmental Pharmacokinetic Analysis and Descriptive Statistics 
All final PK analysis and reporting for the VeraCept data for the combined Treatment 
Comparison and Extension Phases will be performed according to applicable Nuventra standard 
operating procedures and protocol specifications as outlined in Section 8. Analyses of Extension 
Phase data will be conducted at sponsor-directed intervals (e.g., after a 2-year data cut) as well as 
at the end of the 5-year study.   
PK parameters for uncorrected and baseline-corrected serum copper will be calculated as 
described in Table 9-2. 


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Table 9-1.  
Pharmacokinetic Parameters 
Parameter 
Description 
Combined Data from Treatment Comparison and Extension Phases (Treatment A, VeraCept 
IUD only) 
Cmax 
Maximum observed concentration, observed by inspection of individual study 
participant serum concentration-time plots 
Tmax 
Time of maximum observed concentration, obtained directly from the observed 
concentration-time data 
Cmean 
Mean total serum copper concentration of samples collected after Day 1 
Note that the abbreviations and definitions listed above may differ slightly from the protocol in the phrasing; 
however, the equations and methods used to generate these parameters do not differ from the protocol. 
9.2 
Statistical Analyses 
Following Day 56 (study Day 57/Extension Phase), serum copper concentrations will only be 
collected for the VeraCept treatment group. These data will be listed, and additional statistical 
analyses or data presentations may be performed as appropriate.   
10. SAFETY DATA SUMMARY AND REPORTING DURING TREATMENT 
COMPARISON PHASE AND TREATMENT EXTENSION PHASE 
During the study, the investigator or study site personnel will be responsible for querying and 
recording AEs and serious adverse events (SAEs), as detailed below. For the sponsor to fulfill 
safety assessment obligations, the investigator will have to report all SAEs to the study sponsor, 
whether or not they result from study participation, within 24 hours of learning of the event. 
10.1 Definition of an Adverse Event 
The protocol defines an AE as any untoward medical occurrence in a clinical investigation 
subject administered an investigational product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can, therefore, be any unfavorable and unintended 
sign (that could include a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
Any AE (i.e., a new event or an exacerbation of a pre-existing condition) with an onset from the 
day of informed consent/assent through Study Exit will be recorded as an AE on the electronic 
Case Report Form. All AEs will have to be recorded regardless of the severity or relationship to 
study drug. Investigators will also report all AEs that result in expulsion or removal of the 
investigational product being studied, whether serious or non-serious.  
Pregnancy is an outcome, and not an AE in this study. 
10.2 Definition of a Serious Adverse Event 
The protocol defines an SAE as any AE occurring within the timelines specified in the protocol 
that results in any of the following outcomes: 


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• Death; 
• Life-threatening situation (subject is at immediate risk of death); 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• Persistent or significant disability/incapacity; 
• Congenital anomaly/birth defect in the offspring of a subject who received study drug; or 
• Important medical events that may not result in death, be immediately life threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  
Examples of SAEs include but are not limited to: intensive treatment in an emergency room, 
hospitalization for any reason, and extensive treatment at home for an AE. An ectopic pregnancy 
is considered an SAE. 
10.3 Adverse Events of Specific Interest 
AEs of particular clinical importance, other than SAEs will be classified as adverse events of 
specific interest (AESIs). For this study, AESIs will refer to reports of pain during insertion, 
pelvic infection (pelvic inflammatory disease or endometritis), expulsion and uterine perforation. 
AESIs will be identified and assessed by the Medical Monitor during the ongoing monitoring of 
safety data during the trial, during Data and Safety Monitoring Board meetings and for the 
Clinical Study Report. For each AESI, a narrative will be written and included in the Clinical 
Study Report. 
10.4 Safety Analyses 
Safety analyses will be recorded and analyzed for the ParaGard subjects up to Day 57 and up to 5 
years for the VeraCept subjects. Further information about safety analyses can be found in the 
safety analysis plan authored by Synteract.  
 


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11. TABLES, FIGURES, LISTINGS, AND APPENDICES 
The following is a proposed listing of tables, figures, listings, and appendices to be generated 
with the interim and final PK analyses and included in the final PK report. Additional tables, 
figures, listings, and appendices may be generated, as necessary, to fully characterize and 
explore the available PK data, and captions/titles may be modified to accurately reflect the 
contents. Only those tables, figures, listings, and appendices supported by sufficient PK data will 
be generated. 
The list of planned safety data summary tables and listings for the safety data can be found in the 
safety analysis plan authored by Synteract. The safety data summary tables and listings and the 
resulting safety conclusions will be generated by Synteract and will be included in the final PK 
report. 
11.1 List of Tables 
11.1.1 In-text Tables 
Caption 
Comments 
Notes for  
Programming  
Subject Demographics by Phase 
and Treatment Group 
Separate columns for Treatment 
Comparison and Extension Phases, 
with the former presenting data for 
VeraCept, ParaGard, and Overall 
Extension Phase column will 
present data for VeraCept subjects 
from the Treatment Comparison 
Phase who will continue in the 
Extension Phase  
Shortcut: DT 
Previous Shortcut: 
DT1 
S.VAR: Phase + 
Treatment Group 
Update previous Day 
57 table “Subject 
Demographics by 
Treatment Group” 
Summary of Noncompartmental 
Pharmacokinetic Parameters for 
Serum Copper by Treatment for 
the Treatment Comparison 
Phase 
Include Cmax, Tmax, Cmean, 
AUC0-56 
Treatment Comparison Phase only 
Shortcut: PSf 
Previous Shortcut: 
PS2 
S.VAR: Treatment  
Summary of Noncompartmental 
Pharmacokinetic Parameters for 
Serum Copper for the 
Combined Treatment 
Comparison Phase and 
Extension Phase 
Include Cmean, Cmax, and Tmax 
Combined data from Treatment 
Comparison and Extension Phases, 
VeraCept data only 
Shortcut: PSf 
Previous Shortcut: 
PS2 
S.VAR: Treatment 
Summary of Noncompartmental 
Pharmacokinetic Parameters for 
Include Cmax, Tmax, Cmean, 
AUC0-56 
Shortcut: PSf 


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Caption 
Comments 
Notes for  
Programming  
Baseline-Corrected Serum 
Copper by Treatment for the 
Treatment Comparison Phase 
Treatment Comparison Phase only 
Previous Shortcut: 
PS2 
S.VAR: Treatment 
Summary of Noncompartmental 
Pharmacokinetic Parameters for 
Baseline-Corrected Serum 
Copper for the Combined 
Treatment Comparison Phase 
and Extension Phase 
Include Cmean, Cmax, and Tmax 
Combined data from Treatment 
Comparison and Extension Phases, 
VeraCept data only 
Shortcut: PSf 
Previous Shortcut: 
PS2 
S.VAR: Treatment 
Results from Statistical 
Assessment of Relative 
Bioavailability Based on Serum 
Copper Pharmacokinetic 
Parameters for the Treatment 
Comparison Phase 
Cmax, Cmean, and AUC0-56 to be 
assessed 
Treatment Comparison Phase only 
Shortcut: LT 
Previous Shortcut: 
LT1 
S.VAR: None 
Results from Statistical 
Assessment of Relative 
Bioavailability Based on 
Baseline-Corrected Serum 
Copper Pharmacokinetic 
Parameters for the Treatment 
Comparison Phase 
Cmax, Cmean, and AUC0-56 to be 
assessed 
Treatment Comparison Phase only 
Shortcut: LT 
Previous Shortcut: 
LT1 
S.VAR: None 
Summary of Shifts from 
Baseline in Serum Copper 
Concentrations by Phase and 
Treatment Group 
Separate columns for Treatment 
Comparison and Extension Phases, 
with the former presenting data for 
VeraCept, ParaGard, and Overall 
Extension Phase column will 
present data for VeraCept subjects 
from the Treatment Comparison 
Phase who will continue in the 
Extension Phase 
Shortcut: Custom 
Previous Shortcut: 
Custom 
S.VAR: Phase + 
Treatment Group 
Update previous Day 
57 table “Summary 
of Shifts from 
Baseline in Serum 
Copper 
Concentrations by 
Treatment Group and 
Overall” 
 


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11.1.2 Post-text Tables 
Caption 
Comments 
Notes for  
Programming  
Summary of Subject 
Disposition by Phase and 
Treatment Group 
Separate columns for Treatment 
Comparison and Extension Phases, 
with the former presenting data for 
VeraCept, ParaGard, and Overall 
Extension Phase column will 
present data for VeraCept subjects 
from the Treatment Comparison 
Phase who will continue in the 
Extension Phase 
Shortcut: Custom 
Previous Shortcut: 
Custom 
S.VAR: Phase + 
Treatment Group 
Update previous Day 
57 table “Summary of 
Subject Disposition” 
Subject Accountability Table 
for the Treatment Comparison 
Phase 
Treatment Comparison Phase only 
Shortcut: AC 
Previous Shortcut: 
AC1 
S.VAR: Treatment 
Serum Copper Concentrations 
(ng/mL) and Summary 
Statistics by Sample Collection 
Time and Treatment for the 
Treatment Comparison Phase 
Treatment Comparison Phase only 
Shortcut: CT 
Previous Shortcut: 
CT1 
S.VAR: Treatment 
Baseline-Corrected Serum 
Copper Concentrations (ng/mL) 
and Summary Statistics by 
Sample Collection Time and 
Treatment for the Treatment 
Comparison Phase 
Treatment Comparison Phase only 
Shortcut: CT 
Previous Shortcut: 
CT1 
S.VAR: Treatment 
Noncompartmental 
Pharmacokinetic Parameters for 
Serum Copper and Summary 
Statistics by Treatment for the 
Treatment Comparison Phase 
Treatment Comparison Phase only 
Shortcut: PT 
Previous Shortcut: 
PT1 
S.VAR: Treatment 
Noncompartmental 
Pharmacokinetic Parameters for 
Baseline-Corrected Serum 
Copper and Summary Statistics 
by Treatment for the Treatment 
Comparison Phase 
Treatment Comparison Phase only 
Shortcut: PT 
Previous Shortcut: 
PT1 
S.VAR: Treatment 


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Subject Accountability Table 
for the Extension Phase 
Include Treatment column to 
indicate all data belongs to 
VeraCept Treatment Group 
Shortcut: AC 
Previous Shortcut: 
AC1 
S.VAR: Treatment 
Serum Copper Concentrations 
(ng/mL) and Summary 
Statistics by Sample Collection 
Time for the Extension Phase 
Include Treatment column to 
indicate all concentrations belong 
to VeraCept Treatment Group 
Shortcut: CT 
Previous Shortcut: 
CT1 
S.VAR: Treatment 
Baseline-Corrected Serum 
Copper Concentrations (ng/mL) 
and Summary Statistics by 
Sample Collection Time for the 
Extension Phase 
Include Treatment column to 
indicate all concentrations belong 
to VeraCept Treatment Group 
Shortcut: CT 
Previous Shortcut: 
CT1 
S.VAR: Treatment 
Noncompartmental 
Pharmacokinetic Parameters for 
Serum Copper and Summary 
Statistics for the Combined 
Treatment Comparison Phase 
and Extension Phase 
Combined data from Treatment 
Comparison and Extension Phases, 
VeraCept data only 
Shortcut: PT 
Previous Shortcut: 
PT1 
S.VAR: Treatment 
Noncompartmental 
Pharmacokinetic Parameters for 
Baseline-Corrected Serum 
Copper and Summary Statistics 
for the Combined Treatment 
Comparison Phase and 
Extension Phase 
Combined data from Treatment 
Comparison and Extension Phases, 
VeraCept data only 
Shortcut: PT 
Previous Shortcut: 
PT1 
S.VAR: Treatment 
11.2 List of Figures 
11.2.1 In-text Figures 
Caption 
Comments 
Notes for  
Programming  
Mean Serum Copper 
Concentration vs Time Plot 
with Treatments Overlaid for 
the Treatment Comparison 
Phase (Linear Scale) 
Separate line for each Treatment 
Treatment Comparison Phase only 
 
 
Shortcut: SPO 
Previous Shortcut: 
SP1 
S.VAR: Treatment  


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Mean Serum Copper 
Concentration vs Time Plot 
with Treatments Overlaid for 
the Treatment Comparison 
Phase (Semi-log Scale) 
Separate line for each Treatment 
Treatment Comparison Phase only 
Shortcut: SPO 
Previous Shortcut: 
SP1 
S.VAR: Treatment 
Mean Serum Copper 
Concentration vs Time Plot for 
the Combined Treatment 
Comparison Phase and 
Extension Phase (Linear Scale) 
Combined data from Treatment 
Comparison and Extension Phases, 
VeraCept data only 
 
Shortcut: SPO 
Previous Shortcut: 
SP1 
S.VAR: Treatment  
Mean Serum Copper 
Concentration vs Time Plot for 
the Combined Treatment 
Comparison Phase and 
Extension Phase (Semi-log 
Scale) 
Combined data from Treatment 
Comparison and Extension Phases, 
VeraCept data only 
 
Shortcut: SPO 
Previous Shortcut: 
SP1 
S.VAR: Treatment  
11.2.2 Post-text Figures 
Caption 
Comments 
Notes for  
Programming  
Mean Baseline-Corrected 
Serum Copper Concentration vs 
Time Plot with Treatments 
Overlaid for the Treatment 
Comparison Phase (Linear and 
Semi-log Scale) 
Separate line for each Treatment 
Treatment Comparison Phase only 
Shortcut: SPO 
Previous Shortcut: 
SP1 
S.VAR: Treatment 
Overlay of Individual Subject 
Serum Copper Concentration vs 
Time Plot by Treatment for the 
Treatment Comparison Phase 
(Linear and Semi-log Scale) 
Treatment Comparison Phase only 
Shortcut: IOP 
Previous Shortcut: 
IO1 
S.VAR: Treatment 
Overlay of Individual Subject 
Baseline-Corrected Serum 
Copper Concentration vs Time 
Plot by Treatment for the 
Treatment Comparison Phase 
(Linear and Semi-log Scale) 
Treatment Comparison Phase only 
Shortcut: IOP 
Previous Shortcut: 
IO1 
S.VAR: Treatment 
Boxplot Comparing Serum 
Copper Cmax by Treatment for 
Treatment Comparison Phase only 
Shortcut: BP 


Sebela Pharmaceuticals, Inc. 
 Amended Pharmacokinetic Analysis Plan 
 Study CMDOC-0045 
CONFIDENTIAL 
Page 23 of 25 
the Treatment Comparison 
Phase (Linear Scale) 
Previous Shortcut: 
BP1 
S.VAR: Treatment 
Boxplot Comparing Baseline-
Corrected Serum Copper Cmax 
by Treatment for the Treatment 
Comparison Phase (Linear 
Scale) 
Treatment Comparison Phase only 
Shortcut: BP 
Previous Shortcut: 
BP1 
S.VAR: Treatment 
Boxplot Comparing Serum 
Copper Cmean by Treatment 
for the Treatment Comparison 
Phase (Linear Scale) 
Treatment Comparison Phase only 
Shortcut: BP 
Previous Shortcut: 
BP1 
S.VAR: Treatment 
Boxplot Comparing Baseline-
Corrected Serum Copper 
Cmean by Treatment for the 
Treatment Comparison Phase 
(Linear Scale) 
Treatment Comparison Phase only 
Shortcut: BP 
Previous Shortcut: 
BP1 
S.VAR: Treatment 
Boxplot Comparing Serum 
Copper AUC0-56 Days by 
Treatment for the Treatment 
Comparison Phase (Linear 
Scale) 
Treatment Comparison Phase only 
Shortcut: BP 
Previous Shortcut: 
BP1 
S.VAR: Treatment 
Boxplot Comparing Baseline-
Corrected Serum Copper 
AUC0-56 Days by Treatment 
for the Treatment Comparison 
Phase (Linear Scale) 
Treatment Comparison Phase only 
Shortcut: BP 
Previous Shortcut: 
BP1 
S.VAR: Treatment 
Mean Baseline-Corrected 
Serum Copper Concentration vs 
Time Plot for the Combined 
Treatment Comparison Phase 
and Extension Phase (Linear 
and Semi-log Scale) 
Combined data from Treatment 
Comparison and Extension Phases, 
VeraCept data only 
 
Shortcut: SPO 
Previous Shortcut: 
SP1 
S.VAR: Treatment 
Overlay of Individual Subject 
Serum Copper Concentration vs 
Time Plot for the Combined 
Treatment Comparison Phase 
Combined data from Treatment 
Comparison and Extension Phases, 
VeraCept data only 
Shortcut: IOP 
Previous Shortcut: 
IO1 
S.VAR: Treatment 


Sebela Pharmaceuticals, Inc. 
 Amended Pharmacokinetic Analysis Plan 
 Study CMDOC-0045 
CONFIDENTIAL 
Page 24 of 25 
and Extension Phase (Linear 
and Semi-log Scale) 
Overlay of Individual Subject 
Baseline-Corrected Serum 
Copper Concentration vs Time 
Plot for the Combined 
Treatment Comparison Phase 
and Extension Phase (Linear 
and Semi-log Scale) 
Combined data from Treatment 
Comparison and Extension Phases, 
VeraCept data only 
Shortcut: IOP 
Previous Shortcut: 
IO1 
S.VAR: Treatment 
11.3 Listings  
Caption 
Comments 
Notes for  
Programming  
Listing of Individual Subject 
Demographic Data 
Treatment Comparison and 
Extension Phases  
Include Phase column 
Shortcut: LT 
Previous Shortcut: 
LT1 
S.VAR: None 
Update the previous 
Day 57 listing “Listing 
of Individual Subject 
Demographic Data” 
Listing of Serum Copper 
Concentration Time Data for 
Noncompartmental Analysis by 
Phase and Treatment 
Treatment Comparison and 
Extension Phases  
Include Phase column 
Shortcut: LT 
Previous Shortcut: 
LT1 
S.VAR: None 
Update the previous 
Day 57 listing “Listing 
of Serum Copper 
Concentration Time 
Data for 
Noncompartmental 
Analysis by 
Treatment” 
Listing of Baseline-Corrected 
Serum Copper Concentration 
Time Data for 
Noncompartmental Analysis by 
Phase and Treatment 
Treatment Comparison and 
Extension Phases 
Include Phase column 
Shortcut: LT 
Previous Shortcut: 
LT1 
S.VAR: None 


Sebela Pharmaceuticals, Inc. 
 Amended Pharmacokinetic Analysis Plan 
 Study CMDOC-0045 
CONFIDENTIAL 
Page 25 of 25 
Update the previous 
Day 57 listing “Listing 
of Baseline-Corrected 
Serum Copper 
Concentration Time 
Data for 
Noncompartmental 
Analysis by 
Treatment” 
 
11.4 Appendix Figures 
Caption 
Comments 
Notes for  
Programming  
Individual Subject Serum 
Copper Concentration vs Time 
Plot for the Treatment 
Comparison Phase (Linear 
Scale)  
Separate lines for uncorrected and 
baseline-corrected concentrations 
within each subject on the same 
plot 
Separate plot for each subject 
Treatment Comparison Phase only 
Shortcut: IP 
Previous Shortcut: IP1 
S.VAR: Treatment + 
Concentration Type 
(i.e., Uncorrected or 
Baseline-Corrected) 
Individual Subject Serum 
Copper Concentration vs Time 
Plot for the Combined 
Treatment Comparison Phase 
and Extension Phase (Linear 
Scale)  
Separate lines for uncorrected and 
baseline-corrected concentrations 
within each subject on the same 
plot 
Separate plot for each subject 
Combined data from Treatment 
Comparison and Extension Phases, 
VeraCept data only 
Shortcut: IP 
Previous Shortcut: IP1 
S.VAR: Treatment + 
Concentration Type 
(i.e., Uncorrected or 
Baseline-Corrected) 
 


SAFETY STATISTICAL ANALYSIS PLAN 
CMDOC-0045 SAP 
Confidential 
Page 1 of 26 
Version 2 / 20SEP2024 
 
A Randomized, Single-Blind, Comparative Bioavailability Study to Assess the Pharmacokinetic 
Properties of VeraCept® Intrauterine vs ParaGard® in Healthy, Post-Menarcheal Women 
 
Protocol Number:   
 
CMDOC-0045 
 
Protocol Version / Date: 
 
Version 2.0 / 03JUL2019 
 
Sponsor: 
Sebela Women’s Health Inc.   
645 Hembree Parkway, Suite I  
Roswell, GA 30076 
 
SAP Version: 
Version 2 
 
SAP Date: 
 
 
 
20SEP2024 
 
Previous Version: 
 
 
Version 1/ 01NOV2021 
 
CONFIDENTIAL 
 


SAFETY STATISTICAL ANALYSIS PLAN 
CMDOC-0045 SAP 
Confidential 
Page 2 of 26 
Version 2 / 20SEP2024 
 
A Randomized, Single-Blind, Comparative Bioavailability Study to Assess the Pharmacokinetic 
Properties of VeraCept® Intrauterine vs ParaGard® in Healthy, Post-Menarcheal Women 
Protocol Number:  
 
 
CMDOC-0045 
SAP Version/Date: 
 
 
Version 2 / 20SEP2024 
 
Approvals 
Syneos Health Approval 
 
 
Sebela Women’s Health Inc. Approval 
Name, Title 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-YYYY) 
/25/2024


CMDOC-0045 SAP 
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Page 3 of 26 
Version 2 / 20SEP2024 
Name, Title 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
 
 
 
Name, Title 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
 
/23/2024
23/2024


CMDOC-0045 SAP 
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TABLE OF CONTENTS 
REVISION HISTORY ........................................................................................................................................... 5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................................... 6 
1 
INTRODUCTION ........................................................................................................................................... 7 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................................... 7 
2.1 
Objectives .............................................................................................................................................. 7 
2.2 
Endpoints ............................................................................................................................................... 7 
3 
STUDY DESIGN AND INVESTIGATIONAL PLAN .................................................................................. 8 
3.1 
Study Schedule of Assessments ............................................................................................................ 8 
3.2 
Determination of Sample Size ............................................................................................................... 8 
3.3 
Interim Analyses .................................................................................................................................... 9 
4 
STATISTICAL METHODOLOGY AND ANALYSIS .................................................................................. 9 
4.1 
Definitions and Derivations ................................................................................................................... 9 
4.1.1 
Standard Calculations ............................................................................................................... 9 
4.1.2 
Reference Date and Study Day Calculation.............................................................................. 9 
4.1.3 
Baseline and Change from Baseline ....................................................................................... 10 
4.1.4 
Analysis Windows .................................................................................................................. 10 
4.1.5 
Exposure Periods .................................................................................................................... 11 
4.1.6 
Pearl Index .............................................................................................................................. 13 
4.1.7 
Adverse Event ........................................................................................................................ 13 
4.1.8 
Imputing Missing or Incomplete Dates of Adverse Events and Concomitant Medications ... 14 
4.2 
Analysis Populations ........................................................................................................................... 15 
4.2.1 
Analysis Populations .............................................................................................................. 15 
4.3 
Analysis Population Subgroups ........................................................................................................... 16 
4.4 
General Data Presentation Plan ........................................................................................................... 16 
4.5 
Disposition of Subjects ........................................................................................................................ 16 
4.6 
Protocol Deviations ............................................................................................................................. 17 
4.7 
Baseline Demographics and Characteristics ........................................................................................ 17 
4.7.1 
Baseline Demographics .......................................................................................................... 17 
4.7.2 
Medical/Surgical History ........................................................................................................ 18 
4.7.3 
Baseline Physical Examination ............................................................................................... 18 
4.7.4 
Gynecological History ............................................................................................................ 18 
4.7.5 
Menstrual History ................................................................................................................... 18 
4.7.6 
Cervical Cytology ................................................................................................................... 18 
4.7.7 
Prior and Concomitant Medications ....................................................................................... 18 
4.8 
Pearl Index Analysis ............................................................................................................................ 19 
4.9 
Study Device Placement and Exposure ............................................................................................... 19 
4.10 Multiplicity Adjustment ...................................................................................................................... 20 
4.11 Safety and Tolerability ........................................................................................................................ 20 
4.11.1 Brief Summary of Adverse Events ......................................................................................... 20 
4.11.2 Adverse Events by System Organ Class and Preferred Term ................................................. 20 
4.11.3 Narratives of Deaths, Serious Adverse Events, and Other Significant Adverse Events ......... 21 
4.11.4 Adverse Events Listings ......................................................................................................... 21 
4.11.5 VeraCept Expulsion Rates ...................................................................................................... 21 
4.11.6 Vital Signs and Weight ........................................................................................................... 22 
4.11.7 Physical Examination ............................................................................................................. 22 
4.11.8 Physical examination results indicating significant abnormalities will be presented in a data 
listing. Pregnancy Results ....................................................................................................... 22 
4.11.9 Pelvic Examination and Transvaginal Ultrasound .................................................................. 22 
5 
CHANGES FROM PROTOCOL .................................................................................................................. 23 
6 
REFERENCES .............................................................................................................................................. 24 
 
 


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REVISION HISTORY 
Version 
Date 
Reason for Revision 
2.0 
20SEPT2024 
• Cross referenced shells and updated sections to 
match what is currently being produced.  
o Added Incidence of TEAEs by SOC and 
PT by closest relationship to study device 
for the Safety population will be presented. 
o Updated AEs to TEAEs where appropriate 
o Included BMI in vital signs section 
o Added Pelvic Examination and 
Transvaginal Ultrasound 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
AESI 
adverse event of specific interest 
AUC0-56 days 
area under the concentration-time curve from study time 0 
(study Day 1) to Day 56 (study Day 57) 
BE 
bioequivalence 
BMI 
body mass index 
CHG 
change from baseline 
Cmax 
maximum observed concentration 
Cmean 
mean total serum copper concentration of samples collected 
after Day 1 (Days 2-56) 
CRF 
case report form 
CSR 
clinical study report 
EP 
evaluable for pregnancy 
EVTDY 
Study Day of Event 
EXDUR 
Exposure Duration in Days 
ICH 
International Council for Harmonization 
INT 
Integer 
ITT 
intent to treat 
IUD 
intrauterine device 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCYCC 
Number of Completed Cycles 
NCYCEV 
Number of Evaluable Cycles 
NCYCF 
Exposure Duration in Cycles 
NCYCR 
Number Relevant Cycles 
PENDY 
Study Day of Period End 
PK 
pharmacokinetic 
PSTDY 
Study Day of Period Start 
PT  
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
US 
United States 


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1 
INTRODUCTION 
This document presents the planned statistical analyses for Sebela Women’s Health Inc. (Sebela) 
study titled “A Randomized, Single-Blind, Comparative Bioavailability Study to Assess the 
Pharmacokinetic Properties of VeraCept® Intrauterine vs Paragard® in Healthy, Post-Menarcheal 
Women,” protocol number CMDOC-0045, version 2.0, dated July 03, 2019. The statistical 
analysis plan (SAP) summarizes key aspects of the study rationale and design to provide context 
for the statistical methods. It also presents details of the planned statistical methods addressing 
the study aims. The statistical principles applied in the design and planned analyses of this study 
are consistent with the International Council for Harmonization (ICH) guidelines E9 (Statistical 
Principles for Clinical Trials). This analysis plan is specifically for safety analyses as the 
pharmacokinetic (PK) analyses are covered under a separate PK Analysis Plan.  
Syneos Health, will write the clinical study report (CSR) following the guidelines in the ICH E3 
document. 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The primary objective of the study is to assess the relative bioavailability of observed systemic 
copper from VeraCept intrauterine device (IUD) versus Paragard IUD based on maximum 
observed concentration (Cmax), mean copper concentration of samples collected after Day 1 
(Days 2-56) (Cmean), and area under the concentration-time curve from study time 0 (study Day 
1) to Day 56 (study Day 57) (AUC0-56 days). 
The secondary objectives of the study are: 
• To assess the relative bioavailability of baseline-corrected total serum copper from the 
VeraCept IUD versus Paragard based on Cmax, Cmean, and AUC0-56 days. 
• To assess the total serum copper levels within each treatment relative to the normal range 
(49 to 184 µg/dL) [1]. 
• To assess the long-term stability of copper levels following insertion of the VeraCept 
IUD.  
2.2 
Endpoints 
The primary endpoint is the mean total serum concentration, Cmax, and AUC0-56 days for 
observed copper for each treatment. 
Secondary endpoints include: 
• Mean total serum concentration, Cmax, and AUC0-56 days for baseline-corrected copper 
for each treatment.  
• Total serum copper concentrations, Cmax, and AUC0-56 days for baseline-corrected 
copper for each treatment. 
• Mean total serum copper concentrations for observed and baseline-adjusted copper for 
Treatment A (VeraCept IUD only) over 5 years. 


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3 
STUDY DESIGN AND INVESTIGATIONAL PLAN 
This parallel, single-blind study is designed to evaluate the comparative bioavailability of 
systemic copper exposure after insertion of VeraCept IUD versus Paragard in post-menarcheal 
women. Up to 40 subjects will receive one of two treatments (A or B) as described below: 
• Treatment A (N=20): VeraCept® IUD, test (referred to as VeraCept) 
• Treatment B (N=20): Paragard® IUD, reference (referred to as Paragard) 
Subjects will be screened within 60 days prior to the first insertion of study device, and blood 
samples will be collected within 28 days from first insertion of study device at two visits within 
this screening period to establish baseline copper concentrations. At least 24 hours should 
separate each baseline sample. On Day 1 of each treatment period, PK, safety, and baseline 
assessments will be collected prior to IUD insertion. Subjects will return to the clinic at 48 hours 
post-IUD insertion (Day 3 [±24 hours]) and on Days 8 (±1 day), 15 (±1 day), 22 (±1 day), 29 (±1 
day), and 57 (±3 days) for blood collections that will be used to measure total serum copper 
concentrations. 
On Day 57, Paragard subjects will exit the study and may continue Paragard use per standard 
clinical care. VeraCept subjects will continue in the extension phase of the study that is intended 
to assess the long-term stability of serum copper concentrations up to 5 years and to monitor 
safety. During the first 3 years, subjects will return to the clinic every 6 months for clinical 
assessments and blood collections that will be used to measure total serum concentrations. 
Following Year 3, subjects will return annually up to Year 5. During the extension phase, PK 
collections may occur anytime within 30 days of the planned collection time. Subjects 
prematurely discontinuing the study should follow the procedures specified in Section 6.1.7 of 
the protocol, Early Discontinuation Visit. Additional follow-up visits may be scheduled, as 
needed, if a subject has an ongoing significant adverse event (AE) and/or a clinically significant 
laboratory abnormality.  
3.1 
Study Schedule of Assessments 
A schedule of assessments is provided in Table 1. 
3.2 
Determination of Sample Size 
The assumption is that there is no additional systemic exposure of copper when using the IUD. 
The primary analysis will use uncorrected total serum copper parameters (Cmax, Cmean, and 
AUC0-56 days). A secondary analysis will be conducted using baseline-corrected total serum 
copper parameters (Cmax, Cmean, and AUC0-56 days). 
 
No formal hypothesis testing is being done for the analysis using Cmax and Cmean; therefore, a 
precision approach will be taken with boundaries chosen to reflect typical bioequivalence (BE) 
boundaries in the ln scale (±22%). Assuming a normal range of 49 to 184 µg/dL, an estimate of 
the normal (mean) value could be close to 110-120 µg/dL. A comparable boundary would be 
±22. This estimated mean with the added half-width still falls well within the normal range. No 
formal hypothesis testing is being done for the analysis using AUC0-56 day; therefore, a 
precision approach will be taken with boundaries chosen to reflect typical BE boundaries in the 
ln scale (±22%). AUC values will be ln transformed. 
 


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For a two-sided 90% confidence interval for a two-sample normal mean difference, assuming a 
common standard deviation of 25, a sample size of 12 per group is required to obtain a maximum 
half-width of 22 µg/dL with a conditional probability of at least 0.90 given that the interval 
contains the true mean difference. The actual probability is 0.95. Assuming a maximum 
unevaluable rate of 40%, up to 20 subjects will be enrolled in each group. Replacement subjects 
may be enrolled as needed to ensure that at least 24 evaluable subjects complete the study. 
 
3.3 
Interim Analyses 
The primary analysis for this study is covered under the PK SAP and covers the treatment 
comparison phase up to Day 57 (VeraCept vs Paragard) and the VeraCept only treatment 
extension phase that took place after Day 57 up to 5 years. Safety analyses will be performed for 
the treatment comparison phase up to Day 57 and for VeraCept only in the treatment extension 
phase after the last subject completes Year 3, (along with corresponding 120-day Safety updates 
for years 3 -5) and after database lock when all subjects complete Year 5. 
4 
STATISTICAL METHODOLOGY AND ANALYSIS 
4.1 
Definitions and Derivations 
4.1.1 
Standard Calculations 
Variable 
Calculation 
Age (Years) at Informed Consent 
Floor [Date of informed consent – date of birth+1) /365.25]  
Height 
Height entries made in inches (in) are converted to centimeters 
(cm) using the following formula: 
height (cm) = height (in) * 2.54 
Weight 
Weight entries made in pounds (lb) are converted to kilograms 
(kg) using the following formula: 
weight (kg) = weight (lb) / 2.2046 
Temperature 
Temperature entries in degrees Fahrenheit are converted to 
degrees centigrade using the following formula: 
temp (degrees centigrade) = 5/9 * [temp (degrees Fahrenheit) - 
32] 
Body Mass Index (BMI) 
BMI is calculated using height (cm) and weight (kg) using the 
following formula: 
BMI (kg/m2) = weight (kg) / [[height (cm)/100]2] 
 
4.1.2 
Reference Date and Study Day Calculation 
A subject could have 2 study device insertion attempts, which could be on different dates. The 
following 2 study reference dates will be defined to meet the analysis requirements specified in 
this SAP. 
• First study reference date=date of the first insertion attempt 
• Second study reference date=date of successful insertion 


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The first study reference date will be used for Intent-to-Treat (ITT) analysis to include all data 
since first device insertion attempt regardless of insertion success or failure (e.g., AEs related to 
replacement procedure). 
The second study reference date will be used to define exposure period and analysis visit 
windows for all cycle-based analysis and analysis for data with scheduled data collection. 
The second study reference date is Day 1 of Cycle 1. 
For both reference dates, study day will be calculated as follows: 
If event date ≥ study reference date: 
Study day of event = Event date – Study reference date + 1 
If event date < study reference date: 
Study day of event = Event date – Study reference date 
4.1.3 
 Baseline and Change from Baseline 
Baseline is defined as last non-missing observation before or on date of successful insertion 
• Change from baseline (CHG)= post-baseline value – baseline 
• Percent change from baseline =100.0×CHG/Baseline 
4.1.4 
Analysis Windows 
For analysis purposes, early termination visits and unscheduled follow-up visits will be assigned 
analysis visits according to the analysis windows in the following table. This mapping applies to 
labs, vital signs, and all other data planned to be collected and analyzed by visit in the Study 
Data Tabulation Model (SDTM) finding domains. Where multiple measurements for a particular 
parameter appear within an analysis window, the result closest to target day will be used. If 
equidistant, the latter result will be used for the summary measure. All measures may not be used 
in the data summaries (e.g., 2 vital signs measures within the same analysis visit window), but all 
measurements will appear in the datasets and listings. 


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Table 4.1.4.1 Analysis Windows: 
 
Scheduled Visit 
(Subject Visit Window) 
 
Analysis 
Visit 
Analysis 
Window 
Target Day 
Analysis Window 
Lower 
Bound 
Upper 
Bound 
Visit 1/Screening 
Baseline 
1 
N/A 
1 
Visit 2 (Day 1) 
Visit 3 (Day 3± 24 hours) 
Day 3 
3 
2 
5 
Visit 4 (Day 8± 1 day) 
Day 8 
8 
6 
11 
Visit 5 (Day 15± 1 day) 
Day 15 
15 
12 
18 
Visit 6 (Day 22± 1 day) 
Day 22 
22 
19 
25 
Visit 7 (Day 29± 1 day) 
Day 29 
29 
26 
43 
Visit 8 (Day 57± 3 days) 
Day 57 
57 
44 
120 
Visit 9 (Month 6± 30 days) 
Month 6 
182 
121 
273 
Visit 10 (Month 12± 30 days) 
Month 12 
364 
274 
456 
Visit 8 (Month 18± 1 month) 
Month 18 
548 
457 
639 
Visit 9 (Month 24± 1 month) 
Month 24 
730 
640 
822 
Visit 10 (Month 30± 1 month) 
Month 30 
913 
823 
1004 
Visit 12 (Month 36± 1 month) 
Month 36 
1095 
1005 
1278 
Visit 14 (Month 48± 1 month) 
Month 48 
1460 
1279 
1642 
Visit 16 (Month 60± 1 month) 
Month 60 
1825 
1643 
N/A 
 
4.1.5 
Exposure Periods 
The first exposure cycle starts on Day 1 of successful study device insertion. A full exposure 
cycle is comprised of 28 days. One woman-year comprises thirteen 28-day cycles. The following 
exposure periods are defined for analysis in terms of planned study days and study cycles to 
facilitate the efficacy and certain safety analyses. 


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Exposure Period 
Study Day of Period 
Start (PSTDY) 
Study Day of Period End 
(PENDY) 
Year 1 (Cycle 1- Cycle 13) 
1 
364 
Year 2 (Cycle 14-Cycle 26) 
365 
728 
Year 3 (Cycle 27-Cycle 39) 
729 
1092 
Year 4 (Cycle 40-Cycle 52) 
1093 
1456 
Year 5 (Cycle 53-Cycle 65) 
1457 
1820 
First 2 Years (Cycle 1-Cycle 26) 
1 
728 
First 3 Years (Cycle 1-Cycle 39) 
1 
1092 
First 4 Years (Cycle 1-Cycle 52) 
1 
1456 
5 Years (Cycle 1-Cycle 65) 
1 
1820 
 
Type of Events and Study Day During an Exposure Period 
ETYPE 
Event 
Study Day of Event (EVTDY) 
A 
Expulsion 
Study Day of Expulsion date 
B 
Expulsion followed by conception within 7 days 
Study Day of Expulsion date 
C 
Removal 
Study Day of Removal date 
D 
Removal followed by conception within 7 days 
Study Day of Removal date 
E 
Pregnancy before expulsion 
Study Day of Conception date 
F 
Pregnancy before removal 
Study Day of Conception date 
H 
Lost to follow-up without pregnancy, expulsion, 
or removal 
Study Day of Last Date Device in 
Situ 
I 
Complete period without pregnancy, expulsion, 
or removal 
Study Day of Period End Date 
Note: Removal due to partial expulsion will be treated as expulsion 
Exposure Duration in Days (EXDUR): 
if EVTDY-PSTDY>0 then EXDUR = min(EVTDY-PSTDY+1, PENDY-PSTDY+1); 
else EXDUR=.; 
Exposure Duration in Cycles (NCYCF) = EXDUR/28 
Number of Completed Cycles (NCYCC) = INT(NCYCF) 
Number Relevant Cycles (NCYCR) 
=NCYCC+1 if last partial cycle is ≥23 days 
=NCYCC+1 if last partial cycle ETYPE is B, D, E, or F 
=NCYCC, otherwise. 
Number of Evaluable Cycles (NCYCEV) =NCYCR 


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4.1.6 
Pearl Index 
Pearl Index is defined as the number of on-treatment pregnancies per 100 women years. 
On -treatment pregnancy is defined as the estimated conception date being on or after the 
insertion date (must be a successful insertion) and no more than 7 days after the study device is 
removed or expelled. One women year is defined as comprising thirteen 28-day cycles. 
Point estimate of Pearl Index: 𝑥𝑥×
 1300
𝐸𝐸 
where 𝑥𝑥 is the number of on-treatment pregnancies and 𝐸𝐸 is the number of 28-day 
evaluable exposure cycles 
 
If ETYPE is B or D or E or F, then PREGNANCY = 1; else PREGNANCY = 0 
x = sum of PREGNANCY 
E = Number of Evaluable Cycles (NCYCEV) 
4.1.7 
Adverse Event 
4.1.7.1 Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation where a subject has been 
administered an investigational product and which does not necessarily have a causal 
relationship with this treatment. 
The analysis of AEs will be based on the principle of treatment emergence. Treatment-emergent 
AEs (TEAEs) will be defined as events that occur (or worsen) on or after the first treatment date 
of the insertion of the device. 
In this study, Pregnancy is an outcome, and not an AE. 
4.1.7.2 Definition of a Serious Adverse Event 
A serious adverse event (SAE) is any AE occurring within the timelines specified in the protocol 
that results in any of the following outcomes: 
• Death; 
• Life-threatening situation (subject is at immediate risk of death); 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• Persistent or significant disability/incapacity; 
• Congenital anomaly/birth defect in the offspring of a subject who received study device; 
or 
• Important medical events that may not result in death, be immediately life threatening, or 
require hospitalization. Events may also be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 


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4.1.7.3 Adverse Events of Specific Interest 
Adverse events of particular clinical importance (other than SAEs) will be classified as AEs of 
specific interest (AESIs). For this study, AESIs refer to reports of pain during insertion, pelvic 
infection (e.g., pelvic inflammatory disease or endometritis), dysmenorrhea, abdominal pain, 
expulsion, and uterine perforation. AESIs will be identified and assessed by the Medical Monitor 
during the ongoing monitoring of safety data during the trial, and for the CSR. For each AESI, a 
narrative may be written and included in the CSR. 
4.1.7.4 Adverse Event Relationship to Study Treatment 
The relationship of an AE to the drug will be assigned as one of following relationships: 
not related, unlikely related, possibly related, probably related, and related. 
For analysis purposes, “possibly related,” “probably related,” and “related” to an investigational 
medical product are considered adverse reactions and will be reported as "Related." 
“unlikely related” and “not related” do not qualify as a causal relationship and will be reported as 
“unrelated”. 
A missing relationship will be imputed as “related”. 
4.1.7.5 Adverse Events Related to Study Procedures 
Adverse events that occur during the study device placement procedure or removal procedure 
will be reported on the AE case report form and will be assigned one of the relationships noted in 
Section 4.1.7.4 by the study Investigator. Any missing relationships will be imputed as “related 
to the study device placement procedure”. 
4.1.7.6 Adverse Event Severity 
The study investigator will assess the severity of the AE, and severity will be assigned one of the 
following values: Mild, Moderate, Severe, Life-threatening, or Fatal. 
For analysis purposes, Fatal or Life-threatening will be coded as Severe; missing severity will be 
imputed as Severe. 
4.1.8 
Imputing Missing or Incomplete Dates of Adverse Events and Concomitant 
Medications 
The most conservative approach will be systematically considered. If the AE onset date is 
missing or incomplete, it is assumed to have occurred during the study treatment phase (i.e., 
considered a TEAE) except if the partial onset date or other data, such as the stop date, indicates 
differently. Similarly, a medication with partial start and stop dates could be considered as both a 
prior and concomitant treatment. 
The following algorithms will be applied to missing and incomplete start and stop dates: 
Start Dates 
• If the day portion of the start date is missing, then the start date will be estimated to be 
equal to the date of first insertion, provided the start month and year are the same as the 
first insertion and the stop date is either after the first insertion or completely missing. 
Otherwise, the missing day portion will be estimated as "01." 


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• If both the day and month portions of the start date are missing, then the start date will be 
estimated to be equal to the date of first insertion, provided the start year is the same as 
the first insertion and the stop date is either after the first insertion or completely missing. 
Otherwise, the event will be assumed to start on the first day of the given year (e.g., ??-
???-2013 is estimated as 01-JAN-2013). 
• If the start date is completely missing and the stop date is either after the first insertion or 
completely missing, the start date will be estimated to be the day of first insertion. 
Otherwise, the start date will be estimated to be the first day of the same year as the stop 
date. All other non-AE and non-concomitant medication day calculations where only 
partial dates are available will be handled as follows: the first day of the month will be 
used in the calculations if the day part of a start date is missing, and January 1 will be 
employed if both the month and day parts of a start date are missing. 
Stop Dates 
• If only the day of resolution is unknown, the day will be assumed to be the last of the 
month (e.g., ??-JAN-2013 will be treated as 31-JAN-2013). 
• If both the day and month of resolution are unknown, the event will be assumed to have 
ceased on the last day of the year (e.g., ??-???-2013 will be treated as 31-DEC-2013). 
• If the stop date is completely missing or the event is continuing, the event will be 
assumed to be after first insertion and will be imputed using the last known date on the 
study. 
4.2 
Analysis Populations 
4.2.1 
Analysis Populations 
• Intent to Treat (ITT): 
All subjects randomized to the study. This will include subjects who underwent the study 
device placement procedure, regardless of whether the study device was successfully 
placed or not. 
• Safety: 
All subjects who undergo a successful study device placement procedure. 
• Evaluable for Pregnancy (EP): 
Safety subjects who had VeraCept or Paragard placed successfully and meet 
requirements 1, 2 and 3 as follows.  
1. Be post-menarcheal up to 35 years of age (inclusive) at enrollment 
2. Have at least one report of pregnancy status after being enrolled 
3. Do not have pre-treatment pregnancy, which is defined as the estimated 
conception date being before the insertion date. 
Subjects with major protocol violations that are deemed to have had a material impact on 
the assessment of the pearl index will be excluded from the EP analysis population. 


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Exclusions based on major protocol deviations will be reviewed and approved by Sebela 
and its designee. 
4.3 
Analysis Population Subgroups 
No subgroups will be analyzed. 
4.4 
General Data Presentation Plan 
Analyses will be conducted using SAS® software, Version 9.4 or above (SAS Institute Inc, Cary, 
NC). 
Unless otherwise specified, the table summary for the main study will display the following 
columns: 
Analysis Population 
Table Display Columns 
ITT 
VeraCept 
Paragard 
Overall 
Safety 
VeraCept 
Paragard 
Overall 
EP 
VeraCept 
 
 
In general, all efficacy and safety variables will be summarized using descriptive statistics and 
graphs as appropriate. Continuous variables will be summarized by descriptive statistics (sample 
size (n), mean, SD, minimum, median, and maximum). Categorical variables will be summarized 
in frequency tables (frequencies and percentages).  
Means and medians will be displayed with 1 more decimal place than the collected data, and SDs 
will have 1 more decimal place than the means and medians. Minimum and maximum will be 
displayed with the same number of decimal places as the collected data. Percentages will be 
rounded to 1 decimal place. 
No formal statistical testing will be performed on demographic, baseline characteristic, or safety 
data unless stated otherwise for a specific parameter in the SAP. Point estimates will be 
presented with their 95% confidence intervals (CIs) where appropriate. 
Only observed data, with no data imputation, will be used for the efficacy analyses unless 
otherwise specified. Safety analyses will also be conducted on the observed data. However, the 
worst-case scenario will be applied for the start date/time of an AE or medication that is partially 
or completely missing. That is, the AE will be assumed to be treatment emergent, and the 
medication will be considered concomitant. 
4.5 
Disposition of Subjects 
Disposition of subjects will be summarized for the ITT population. 
A disposition table will report the following: 
• The number and percentage of subjects in each analysis population 
• The number and percentage of subjects who discontinued the study prior to Day 57, 
including the reasons for discontinuation 
• The number and percentage of subjects who completed Day 57 


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• The number and percentage of subjects who discontinued the study after Day 57 but prior 
to 1 year of use, including the reasons for discontinuation 
• The number and percentage of subjects who complete 1 year of use 
• The number and percentage of subjects who discontinued the study after 1 year of use but 
prior to 2 years of use, including the reasons for discontinuation 
• The number and percentage of subjects who completed 2 years of use 
• The number and percentage of subjects who discontinued the study after 2 years of use 
but prior to 3 years of use, including the reasons for discontinuation 
• The number and percentage of subjects who completed 3 years of use 
• The number and percentage of subjects who discontinued the study after 3 years of use 
but prior to 4 years of use, including the reasons for discontinuation 
• The number and percentage of subjects who completed 4 years of use 
• The number and percentage of subjects who discontinued the study after 4 years of use 
but prior to 5 years of use, including the reasons for discontinuation 
• The number and percentage of subjects who completed the study (5 years of use) 
Listings will be generated for the following: 
• Subject’s disposition  
• Subject’s membership in each analysis population and reason for exclusion from each 
analysis population 
4.6 
Protocol Deviations 
Number (%) of subjects with major protocol deviations will be summarized and deviation type 
for the ITT population. Details about each protocol deviation (major/minor) will be presented in 
the protocol deviation listing. 
4.7 
Baseline Demographics and Characteristics 
Baseline demographics will be summarized for the ITT, EP, and Safety populations. All other 
baseline characteristic information will be summarized for the ITT population only. 
4.7.1 
Baseline Demographics 
The following variables collected at Screening/Baseline will be included in the baseline 
demographics summary table: 
• Age (years) at enrollment 
• Age group at enrollment (≤35 years old, 36-45 years old) 
• Ethnicity 
• Race 
• Marital status at enrollment 
• Weight (kg) at enrollment 


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• Height (cm) at enrollment 
• Body mass index (BMI) (kg/m2) at enrollment 
• BMI group (<30 kg/m2, ≥30 kg/m2) at enrollment 
All demographic and baseline characteristics will be presented in data listings. 
4.7.2 
Medical/Surgical History 
Number (%) of subjects reporting Medical/Surgical history will be summarized by body system 
and report term. 
Medical/Surgical History will also be presented in a data listing. 
4.7.3 
Baseline Physical Examination 
Physical examination includes examination of general appearance; skin; head, eyes, ears, nose, 
and throat; thyroid; lungs; back; breasts; heart; abdomen; extremities; and neurological system. 
Physical examination results indicating clinically significant abnormalities will be presented in a 
data listing. 
4.7.4 
Gynecological History 
Gynecological history data will be summarized for all questions collected on the case report form 
(CRF). 
All gynecological history will also be presented in a data listing. 
4.7.5 
Menstrual History 
Menstrual history data will be summarized for all questions collected on the CRF. 
All menstrual history will also be presented in a data listing. 
4.7.6 
Cervical Cytology 
Cervical cytology test results will be summarized in the table and presented in a data listing. 
4.7.7 
Prior and Concomitant Medications 
Prior and concomitant medications include any medications taken by subjects from 30 days prior 
to the signing of the informed consent through the end of study participation. These medications 
will be recorded on CRF page and coded using the WHO Drug dictionary. The CSR will include 
the version number of the WHO Drug dictionary. Prior medications are defined as those taken by 
the subject prior to the study device placement. Concomitant medications are defined as those 
taken by the subject from the date of the study device placement to study 
completion/discontinuation. 
In cases where it is not possible to define a medication as prior or concomitant, the medication 
will be classified as concomitant. 
The number (%) of subjects taking prior and concomitant medications will be summarized 
separately according to anatomical therapeutic chemical classification Level 4 and generic term 
for the ITT population. 


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All prior and concomitant medications will also be presented in a data listing. 
4.8 
Pearl Index Analysis 
The pearl index will be utilized to measure contraceptive efficacy through 5 years of use and will 
be analyzed using the Pearl Index with a 95% CI for women in the EP population. A separate 
summary of the Pearl Index in the EP Population through Day 57 will also be provided. 
The Pearl Index is defined as the number of on-treatment pregnancies per 100 women years. On-
treatment pregnancy is defined as the estimated conception date being after the insertion date and 
no more than 7 days after the VeraCept is removed or expelled. One woman year is defined as 
comprising thirteen 28-day cycles. 
Point estimate of Pearl Index: 𝑥𝑥×
 1300
𝐸𝐸 
95% CI: ቀ
1
2 𝜒𝜒(0.025,2𝑥𝑥)
2
×
1300
𝐸𝐸,
1
2 𝜒𝜒(0.975,2(𝑥𝑥+1))
2
×
1300
𝐸𝐸 ቁ 
where 𝑥𝑥 is the number of on-treatment pregnancies, 𝐸𝐸 is the number of 28-day evaluable 
exposure cycles, and 𝜒𝜒(𝑝𝑝,𝑑𝑑𝑑𝑑)
2
 is the 𝑝𝑝𝑝𝑝ℎ quantile of 𝜒𝜒 
2-distribution with 𝑑𝑑𝑑𝑑 degrees of 
freedom. 
x =sum of PREGNANCY 
E =number of Evaluable Cycles (NCYCEV) 
Pearl Index point estimates and 95% CIs will be calculated for Day 57, Years 1, 2, 3, 4, 5, Years 
1-2, Years 1-3, Years 1-4, and for Years 1-5 separately. 
4.9 
Study Device Placement and Exposure 
Study device placement and removal data will be summarized for the ITT and Safety population, 
respectively including the number of relevant and evaluable cycles with device use for subjects 
randomized to VeraCept. The study device placement and removal data will be presented in the 
listings. 
4.9.1.1 Study Device Placement 
The following parameters will be reported in the table for study device placement: 
Number (%) of subjects who 
• Attempted first insertion 
o Had successful first insertion 
o Failed first insertion 
• Attempted second insertion after failed first insertion 
o Had successful second insertion 
o Failed second insertion 
• Had medication during either attempt 
• Required mechanical dilation in either attempt 
• Number of cycles with device in place for Years 1, 2, 3, 4, 5 separately 


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4.9.1.2 Study Device Expulsion/Removal 
The following parameters will be reported in the table for Years 1, 2, 3, 4, and 5 separately: 
Number (%) of subjects who had study device removal 
Number (%) of subjects who had study device expulsion 
Number (%) of subjects with device expelled prior to the visit along with corresponding 
expulsion status (partial or complete) 
Number (%) of subjects who had removal accomplished by pulling the strings without difficulty 
Number (%) of subjects with each reason for difficulty of removal 
Number (%) of subjects with medication given during the procedure. 
4.10 Multiplicity Adjustment 
There is no formal efficacy analysis contained in this SAP, and there is no need for multiplicity 
adjustment for type I error α.  
4.11 Safety and Tolerability 
Adverse events will be coded and classified by system organ class (SOC) and preferred term 
(PT) using the Medical Dictionary for Regulatory Activities (MedDRA) version 24.0. The 
summaries of AEs will be limited to TEAEs. Number (%) of subjects reporting AEs and SAEs 
will be summarized for the Safety population.  
4.11.1 Brief Summary of Adverse Events 
The number (%) of subjects reporting any of the following events during the study will be 
reported in the brief summary of AEs for the Safety population: 
• AE 
• AE related to study device 
• AE related to study device placement/removal procedure 
• SAE 
• SAE related to study device placement/removal procedure 
• AE leading to study device removal 
• AE leading to study discontinuation 
• AE leading to Death 
4.11.2 Adverse Events by System Organ Class and Preferred Term 
The incidence of Treatment-Emergent Adverse Events (TEAE) and SAEs will be summarized by 
MedDRA primary SOC and PT. The summary will include the total number and percentage of 
subjects reporting an AE within an SOC and/or PT. 
The incidence of TEAEs by SOC and PT by maximum severity for the Safety population will be 
presented. 


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Incidence of TEAEs by SOC and PT by closest relationship to study device for the Safety 
population will be presented. 
The incidence of TEAEs by SOC and PT by closest relationship to drug placement/removal 
procedure for the Safety population will be presented. 
The incidence of Treatment-Emergent SAEs by SOC and PT by closest relationship to drug 
placement/removal procedure for the Safety population will be presented. 
Incidence of TEAEs experienced by at least 10% of subjects by SOC and PT for the Safety 
population 
Incidence of AESIs (pain during insertion, pelvic infection (Pelvic Inflammatory Disease or 
endometritis), expulsions and uterine perforations), which includes the following MedDRA 
preferred terms: abdominal pain, abdominal pain lower, abdominal pain upper, pelvic 
inflammatory disease, procedural pain, device expulsion, dysmenorrhea following IDU 
placement, dysmenorrhea-post-procedural, embedded device, insertion pain, intermittent 
dysmenorrhea, post procedural dysmenorrhea, uterine perforation, worsening of dysmenorrhea, 
endometritis, post procedural discomfort, pelvic discomfort and pelvic pain will be summarized 
for the Safety population.  
Incidence of Allergy-Related AEs, based on Medical Monitor review, will be summarized by PT 
and relationship to study device will be presented in the Safety population.  
4.11.3 Narratives of Deaths, Serious Adverse Events, and Other Significant Adverse 
Events 
Narratives of deaths, SAEs, AESIs, pregnancies, allergic reactions occurring within 30 days of 
insertion and/or related to VeraCept will be provided in the relevant section of the CSR. 
4.11.4 Adverse Events Listings 
A complete subject listing of all AEs will be provided in Appendix 16.2 in the CSR. This listing 
will include treatment, AE verbatim term, MedDRA primary SOC and PT, the time of onset and 
cessation of the event relative to the first insertion of study device, duration of the AE, whether 
serious or not, severity, relationship to study device, action taken, and outcome. Treatment-
emergent and non-treatment-emergent events will be listed separately. 
In addition, separate listings of all SAEs, AEs related to study device, AEs related to study 
device placement/removal procedure, AEs leading to death, AEs leading to study device 
removal, AESIs, Allergy-Related AEs and AEs as primary reason for exiting study will be 
provided. 
4.11.5 VeraCept Expulsion Rates 
Cumulative VeraCept Expulsion Rates for Years 1 through 5 will be estimated via Kaplan-Meier 
method for the Safety population. The complementary log-log transformation will be used to 
construct 95% CIs.  
VeraCept expulsion includes both total expulsion and partial expulsion. Total expulsion is 
defined as cases in which VeraCept is observed in the vagina, not shown in the uterus by 
ultrasound, or if the women confirmed expulsion. Partial expulsion cases are defined as when 


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VeraCept is visible in the cervical canal by gynecologic exam or ultrasound. If partially expelled 
VeraCept is removed, the removal will be considered an expulsion event for this analysis. 
• Time to expulsion in cycles will be defined as time to total expulsion discovered or 
removal of the partially expelled VeraCept from the date of successful insertion 
• Removal of VeraCept for any other reason will be censored at the removal cycle. 
• If a subject discontinued because of pregnancy, the subject will be censored at the cycle 
of conception 
• Lost-to-follow-up will be censored at the last cycle where VeraCept is in Situ, defined as 
the date the subject was deemed lost to follow-up as entered on the Study Exit Status 
CRF page. 
• Those with VeraCept still in place for protection at the end of exposure period will be 
censored at the end of exposure period. 
4.11.6 Vital Signs and Weight 
The observed values and changes from baseline in the following vital signs and weight 
parameters will be summarized by visit for the Safety population: 
• Systolic blood pressure (mm Hg) 
• Diastolic blood pressure (mm Hg) 
• Pulse rate (bpm) sitting 
• Respiration rate (breaths/min) 
• Body temperature 
• Body weight (kg) 
• BMI (kg/m2) 
• BMI (underweight, normal, overweight, obese) 
Vital signs, weight, and BMI will be included in a data listing. 
4.11.7 Physical Examination 
Physical examination includes examination of general appearance; skin; head, eyes, ears, nose, 
and throat; thyroid; lungs; back; breasts; heart; abdomen; extremities; and neurological system. 
4.11.8 Physical examination results indicating significant abnormalities will be presented 
in a data listing. Pregnancy Results 
All pregnancy testing data will be presented in the listings. 
Pregnant subjects with clinical outcome data including infant abnormalities will be presented in 
the listings. 
4.11.9 Pelvic Examination and Transvaginal Ultrasound 
All pelvic examination and transvaginal ultrasound data will be presented in a data listing. 


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5 
CHANGES FROM PROTOCOL 
The pearl index based on safety cycles was added as a measure of the contraceptive efficacy.  
The reference product labeling was updated after the study initiated and removed capitalization 
of the G.  
 


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6 
REFERENCES 
1. Salwen, M.J., Vitamins and Trace Elements 23 ed. Henry's Clinical Diagnosis and 
Management by Laboratory Methods, 23rd Edition. 2017, St. Louis, Missouri: Elsevier 
Health Sciences. 1700. 
 


 
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Table 1: 
Study Schedule of Assessments 
Visit 
Screening 
Enrollment/IUD 
Placement 
Clinic PK visits 
Clinic PK visits 
(VeraCept 
Subjects 
ONLY) 
Month 60 
OR 
Exit Visit 
Day 
Day -28 to 1 
Day 1 
Day 3  
(±24 hrs) 
Days 8, 15, 
22, 29 (±1 
day) 
Day 576 
(±3 days) 
Months 6, 12, 
18, 24, 30, 36 
and 48 
(±30 days) 
Month 60 
(±30 
days) 
OR 
Exit Visit 
Assessment of Eligibility 
X 
X 
 
  
 
 
Distribution of subject materials (if applicable) 
X 
  
 
  
 
 
Informed Consent/Assent/PHI and Bill of Rights  
X 
  
 
  
 
 
Demographics and baseline characteristics 
X 
  
 
  
 
 
Medical/surgical, gynecologic, and menstrual 
history 
X 
  
 
  
 
 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
Height 
X 
 
  
 
 
General physical exam 
X 
  
 
  
 
 
Pelvic exam (string check if post IUD insertion) 
X 
 X1 
 
 X 
X 
X 
Cervical cytology 
X 
  
 
  
 
 
Cervical infection tests 
X2,3 
  
 
  
 
 
Transvaginal, ultrasound, only if clinically indicated 
  
X 
 
 X 
X 
X 
Pregnancy test – urine 
 X 
X 
 
  
 
X 
Prior and concurrent medication 
X 
X 
X 
 X 
X 
X 
Adverse events 
X 
X 
X 
 X 
X 
X 
IUD placement 
  
X 
 
 
 
IUD removal 
  
  
 
  
 
X7 
Concomitant contraception 
X 
 
 
X 
Subject education – need for contraception 
X 
X 
X 
X 
X 
X 
Blood draw for PK analysis (serum copper sample) 
X4 
X5 
X5 
X5 
X5 
X5 


 
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Footnotes 
1. Pelvic exam for IUD string check by palpation or visualization. 
2. Screening for cervical infection tests are to be done at screening unless these tests have been previously completed within 3 months of the screening visit and were negative. 
If a subject tests positive prior to IUD insertion, the subject should be treated prior to IUD placement. The subject may be inserted 7 days post-treatment. A cervical infection 
retest should be done 3-months post-IUD insertion to assure there is not a case of re-infection.3a. This first e-diary review, prior to VeraCept placement, to be used as training with the 
subject. This diary data is not part of data collection or analysis. It is intended to ensure the subject understands how to complete the diary and determine subject compliance throughout e-
diary collection. 
3. Insertion can occur without receipt of test results if there is no clinical evidence of infection. If, after IUD insertion, the screening cervical infection test results are positive, 
the subject should be treated. A cervical infection retest should be done 3 months post-treatment. 
4. Subjects will be screened within 60 days prior to the first insertion of study drug, , and two blood samples will be collected within 28 days from Day 1, and at least 24 hours 
apart within this screening period (can be performed on Screening and Day 1 visit prior to IUD insertion). to establish baseline copper concentrations. 
5. On Day 1, collect blood samples for pharmacokinetic analysis prior to intrauterine insertion. On Day 3, collect samples 48 hours ±24 hours after IUD insertion. PK samples 
on Day 8, 15, 22, and 29 should be collected within 1 day of the planned collection day while Day 57 should be collected within 3 days of planned collection day, at approximately the same 
time as the Day 3, 48-hr ±1 day PK sample collection. Following the PK collections on Day 57, the PK samples should be collected within 30 days 
of the planned collection day. 
6. Paragard subjects will have Exit Visit procedures completed on Day 57. 
7. Paragard subjects may continue Paragard use per standard clinical care or have the device removed.