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A Multicenter, Domestic & International Trial of the
International Maternal Pediatric Adolescent AIDS
Clinical Trials (IMPAACT) Network
IMPAACT P1111
A Phase I/II, Open-Label Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and
Antiviral Activity of Rilpivirine in Antiretroviral Naïve
HIV-1 Infected Children, < 12 Years of Age
Version 1.0, dated September 9, 2013
LoA #1, dated April 07, 2014
MANUAL OF PROCEDURES (MOP)
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P1111 MOP v1.0
TABLE OF CONTENTS
List of Commonly Used Abbreviations and Definitions ............................................................ 3
1
INTRODUCTION ............................................................................................................. 4
1.1
Sources of Procedural Information ................................................................................ 4
1.2
Site-Specific Study Activation Process ........................................................................... 4
2
PROTOCOL OVERVIEW................................................................................................... 5
2.1
Study Overview....................................................................................................... 5
2.2
Target Enrollment ................................................................................................... 5
3
SCREENING AND ENROLLMENT ...................................................................................... 5
3.1
Obtaining a Screening Slot ...................................................................................... 5
3.2
Screening and Enrollment Logs ................................................................................ 6
3.3
Obtaining An Enrollment Slot .................................................................................. 6
4
STUDY IMPLEMENTATION ............................................................................................. 6
4.1
General Information Regarding Clinic Visits and Procedures .................................... 6
4.2
ACTH stimulation testing (fasting) ........................................................................... 6
4.3
Tanner Stage Assessment ........................................................................................ 7
4.4
Subject Medication Diary ........................................................................................ 7
4.5
Intensive PK Day ..................................................................................................... 7
4.6
Population PK ......................................................................................................... 8
4.7
Stage 1: Week 4 visit and Step 2 .............................................................................. 8
4.8
Virologic Failure Visit .............................................................................................. 8
4.9
Long-term Follow-up ............................................................................................... 9
PHARMACY AND STUDY DRUG CONSIDERATIONS .......................................................... 9
5
5.1
Overview of dosing ......................................................................................................... 9
5.2
Communications with Study Team ................................................................................ 9
6
SAFETY MONITORING .................................................................................................... 9
6.1
ECG reporting .................................................................................................................. 9
7
LABORATORY CONSIDERATIONS .................................................................................... 9
7.1
Introduction .................................................................................................................... 9
7.2
General Overview and Guidelines ............................................................................... 10
7.3
Specimen Chain of Custody .......................................................................................... 10
7.4
Labeling Specimens....................................................................................................... 10
7.5
Laboratory Data Management System (LDMS) ........................................................... 10
8
DATA MANAGEMENT .................................................................................................. 11
8.1
Assignment of a Patient Identification Number (PID)................................................. 11
8.2
Source Documents ........................................................................................................ 11
8.3
Case Report Forms ........................................................................................................ 11
8.4
Resources ...................................................................................................................... 11
Appendix I: Tanner Scales ................................................................................................... 12
Appendix II: Medication Diary Template.............................................................................. 15
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List of Commonly Used Abbreviations and Definitions
ACTN
AIDS Clinical Trials Network
AE
Adverse Event
CDC
Center for Disease Control
CRF
Case Report Form
DAIDS
Division of AIDS
DMC
Data Management Center
FSTRF
Frontier Science & Technology Research Foundation
HIPAA
Health Insurance Portability and Accountability Act
IATA
International Air Transport Association
ICF
Informed Consent Form
IMPAACT
International Maternal, Pediatric & Adolescent AIDS Clinical Trials
Network
IND
Investigational New Drug
IRB
Institutional Review Board
LDMS
Laboratory Data Management System
LPC
Laboratory Processing Chart
PI
Principal Investigator
PID
Patient Identification Number
RCHSPB
Regulatory Compliance and Human Subjects Protection Branch
RSC
Regulatory Support Center
SAE
Serious Adverse Event
SES
Subject Enrollment System
SOP
Standard Operating Procedures
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1
1.1
INTRODUCTION
Sources of Procedural Information
All study procedures must be conducted in accordance with the P1111 protocol and this Manual.
The purpose of this manual is to supplement the protocol, not to replace or substitute for it. In the
event that this manual is inconsistent with the protocol, the specifications of the protocol take
precedence. Please alert the P1111 Protocol Team of any such inconsistencies.
The P1111 protocol and related protocol documents are available on the IMPAACT website:
http://www.impaactnetwork.org/index.htm
Please contact the P1111 Protocol Team following the guidance in Table 1-1 for general questions
on protocol implementation or study procedures, including clinical, lab, and/ or CRF/ data-related
procedures.
Table 1-1: Communications with the P1111 Study Team
•
The P1111 Protocol Team is composed of study team members including the IMPAACT Operations Center,
Data Management Center, and Central Laboratory. These team members have been designated by the
protocol team to receive and reply to study implementation questions. These team members will consult with
the Protocol Chair, Co-Chair and/or other team members to ensure that complete and accurate responses are
provided to each question.
•
Submit study implementation, clinical, laboratory and/ or procedural questions via email to
[email protected].
•
Include the protocol number in the subject line of your email message.
•
State your question in the body of your email message. When the question relates to a specific study
participant, include the participant identification number (PID) and relevant background information about
the participant.
•
The responding group member will reply to your question via return email. All persons copied on the original
question will be copied on the reply. Other protocol team members may also be copied when relevant.
•
Replies can generally be expected within one business day. When it may not be possible to provide a
complete response within one business day, the person who submitted the question will be provided with an
interim response and informed that more time is needed to provide a complete response.
•
When a question relates to a specific study participant, a copy of the email exchange should be printed and
filed in the participant’s study chart.
1.2
Site-Specific Study Activation Process
Each site must obtain approval to conduct the P1111 study from all responsible IRBs/ECs and Drug
Regulatory Agencies (DRA), as applicable. Additionally, a Site Implementation Plan (SIP) is required
from each site for review and approval by the P1111 Protocol Team. The study-specific SIP will
include access to ECG, ACTH testing, PK rooms/suites and site experience in conducting long PK
visits/ days. The P1111 SIP template may be obtained from the FHI 360 Clinical Trials Specialist
(CTS). NIAID-funded IMPAACT/ACTG sites should email their completed SIP to the FHI 360 CTS.
NICHD-funded IMPAACT sites should email their completed SIP to the site’s Westat Clinical
Research Associate (CRA). Sites are asked to review their SIP internally for completeness prior to
submission. The FHI 360 CTS will receive completed SIPs from the Westat CRA, and coordinate all
P1111 SIPs for Protocol Team review/ approval.
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Upon approval of the SIP, the Operations Center will notify the site that DAIDS registration can
occur. Each site must then complete protocol registration procedures and requirements with the
DAIDS RSC Protocol Registration Office. Further information on the protocol registration process is
provided in the DAIDS Protocol Registration Policy and Procedures Manual which is available on the
RSC web site.
The SIP approval and DAIDS PRO registration are two steps within the overall site activation process
for study implementation. The FHI 360 CTS will coordinate site activation requirements with
relevant site staff. Upon site completion of the required activities, FSTRF will be informed by the
FHI 360 CTS that the Screening and Enrollment System may be opened for the site. This process
must be done in order for site staff to request a screening ID number for a potential participant
(refer to Section 3.0 of this manual for more information regarding screening procedures).
2
2.1
PROTOCOL OVERVIEW
Study Overview
IMPAACT P1111 is a Phase I/II, multi-center, open-label, pharmacokinetic (PK) and safety study of
rilpivirine (RPV). Subjects will be enrolled into the study cohorts according to their age with Cohort
1 participants passing safety and PK criteria prior to opening enrollment in Cohort 2:
Cohort I:
≥ 6 years to < 12 years of age
Cohort II:
≥ 2 years to < 6 years of age
Each Cohort incorporates two stages (Stage 1 and Stage 2), which follow different schedules of
evaluations as detailed throughout protocol Appendix I (protocol Appendix I-A, I-B, and I-C). Note
that Stage 1 incorporates two steps, and this is applicable to both Cohorts. Not all participants
enrolled in Stage 1 are anticipated to complete both steps of Stage 1. Some Stage 1 participants
will remain on the Step 1 visit schedule, while other Stage 1 participants may move to the Step 2
visit schedule.
2.2
Please refer to protocol Section 3.0 for details on the study design, protocol Section 3.2 for a
description of the Steps for Stage 1, and the Schedule of Evaluations in protocol Appendix I.
Target Enrollment
This study will take place in multiple countries through the IMPAACT Network. Across all
participating sites, target enrollment is for a total of approximately 60 subjects for a minimum of 40
evaluable subjects, with a minimum of 20 evaluable subjects per Cohort. The study population will
be HIV-infected treatment-naïve children aged < 12 years, and per eligibility criteria outlined in
protocol Section 4.0.
Please refer to the protocol Schema and Section 3.0 for further details on projected evaluable
subjects enrolled per Cohort and per Stage.
3
3.1
SCREENING AND ENROLLMENT
Obtaining a Screening Slot
•
Sites must complete all processes outlined in Section 1.2 of this manual prior to moving
forward with obtaining a screening slot for this study.
•
Per protocol Section 4.6, potential subjects may only be screened upon approval by the P1111
Protocol Team. Sites must utilize the PS2001 (IMPAACT Screening system) to obtain a
screening number, and submit this number along with a screening request to the P1111
Protocol Team.
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3.2
•
The team will review the status of the study and decide whether the subject may be screened
or not. Sites MUST wait to receive permission from the protocol team in order to proceed with
screening evaluations, including consent.
•
Sites will have 30 days after screening to enroll the subject. Sites should contact the protocol
team with any screening timeline deviations. A slot may be recalled if deviations from the
timeline are not approved by the protocol team.
Screening and Enrollment Logs
Per the DAIDS policy for Essential Documents, study sites are required to document screening
(including screening failures) and enrollment activity on screening and enrollment logs. Screening
and enrollment/randomization logs may be separate or combined. A screened subject is defined as
having signed the study consent.
Logs should include the following information:
• Initials of all patients screened for each study
•
PID if patient receives one
•
Date screened
•
Date enrolled
•
If not enrolled, indicate reason
For additional information, refer to the NIAID/DAIDS website
http://www3.niaid.nih.gov/about/organization/daids/
3.3
Obtaining An Enrollment Slot
Subjects meeting all the study inclusion criteria and none of the exclusion criteria will be enrolled in
IMPAACT P1111 by utilizing the Subject Enrollment System (SES) located on the IMPAACT DMC
Website at www.fstrf.org.
The screening number will be required to be entered in the eligibility checklist.
For subjects who do not enroll after receiving a screening number, sites will enter the form
“IMPAACT P1111 Screening Failure/Non-Enrollment Tracking” (SCR0032) into the database.
4
4.1
STUDY IMPLEMENTATION
General Information Regarding Clinic Visits and Procedures
Protocol Appendix I details the visit schedules for participants according to their Stage, Step, and
Cohort. Study staff are responsible for being familiar with these Schedules of Evaluations (SOE),
and the many details regarding study implementation which are described in the SOE footnotes.
Both clinic and lab staff should be familiarized with the LPC, as this document contains additional
details of the required blood draws and laboratory evaluations.
4.2
ACTH stimulation testing (fasting)
At the time points specified in the Schedule of Evaluations (Appendices IA, IB and IC) an ACTH
stimulation test will be done for all subjects including measurements of cortisol and 17hydroxyprogesterone. After a baseline sample for cortisol and 17-hydroxyprogesterone (See LPC
for processing instructions) has been drawn (T0), 250 micrograms of tetracosactide or cosyntropin
is injected intravenously over 2 minutes (or intramuscularly or subcutaneously- formulation and
brand dependent) and an additional blood sample is collected 60 minutes (T60) after injection for
the determination of cortisol and 17- hydroxyprogesterone.
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The ACTH stimulation test should be conducted in the morning such that the baseline cortisol
sample is taken between 7:30 and 9:30 am. The subject should be fasting (only water for the 8
hours prior to the testing). However, if the subject did not come in fasting, the ACTH stimulation
testing can still be performed. The ACTH stimulation testing does not have to be rescheduled.
The route of administration (IV, SC or IM) of the cosyntropin or tetracosactide depends on the
brand and formulation. The proposed formulation and route of administration must be approved
by the P1111 team prior to initiating the ACTH stimulation testing.
4.3
Tanner Stage Assessment
At the time points specified in the Schedule of Evaluations (Appendices IA, IB and IC), Tanner
staging should be done. Pictorial Tanner Scales are included in MOP Appendices I-A, I-B, I-C.
4.4
Subject Medication Diary
The Subject Medication Diary is a tool for participant’s to use for tracking adherence to the study
drug. From Day 1 through and including the Intensive PK Day (day 14-18), subjects should
complete a medication diary which includes the time the study RPV was given and the time of the
accompanying meal. Subjects should take the study RPV in the morning during the days prior to
the Intensive PK day. The diary should be reviewed with the participant and/ or the caregiver at
the Week 1 visit and at the Intensive PK visit. The medication diary should be completed at the
Intensive PK visit as well, either by the participant/ caregiver or site staff. Sample medication
diaries are included in MOP Appendix II. These can be modified to address to best meet the site
and participants’ needs.
4.5
Intensive PK Day
The Intensive PK Day visit will be scheduled between Days 14 – 18 of study participation. Protocol
Appendix I outlines the procedures to be conducted at that visit.
4.5.1 Prior to the Intensive PK Day
At Entry (Day 0), remind the subject that they will undergo the intensive PK visit on Days 14-18 and
they will need to come to the clinic in order to complete the 24-hour PK sampling.
Prior to the scheduled PK visit, study staff must contact the subject to remind them of the
following:
• The visit dates and times for the PK visit
•
No missed dose(s) of rilpivirine during the 10 days prior to the scheduled PK visit; otherwise the
PK visit needs to be rescheduled
•
Per protocol Appendix I, contact the subjects via telephone or email each of the 3 days prior to
the PK visit to assess adherence.
•
If the subject has missed a dose within 10 days prior to the PK visit, the visit must be
rescheduled to allow for steady state of RPV to be reached (approximately 11 days).
•
Remind the subject that they will be provided breakfast when they arrive at the clinic, as part
of the intensive PK visit.
•
Remind the subject to bring their rilpivirine medicine for dosing and not to take the dose prior
to coming to the clinic.
Protocol Section 6.0 is to be followed should any adverse events or potential adverse events be
reported by the subject, or the subject’s caregiver, and the subject should be assessed as soon as
possible by study staff.
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4.5.2 General Comments
Please refer to the footnotes in the Schedule of Evaluations, protocol Appendix I, as well as the LPC
for details on procedures to be conducted during the Intensive PK Day.
Each institution is expected to have their own policy on the maximum number of times it is
acceptable to attempt a blood draw outside of a medical emergency, however, the team suggests
no more than 2-3 attempts by each of 2 phlebotomists (maximum of 6 tries).
When should an intensive PK visit be rescheduled?
If a dose was missed on any one of the 10 previous days
•
•
The subject did not take the RPV dose in the clinic
•
The subject vomited within 30 minutes after dosing
What is the timeframe for rescheduling an intensive PK visit?
• The intensive PK visit MUST be rescheduled AND completed within 14-18 days of the original
intensive PK visit. If this timeline cannot be met, sites should contact the team for guidance
4.6
Population PK
Please refer to the footnotes in the Schedule of Evaluations, protocol Appendix I, as well as the LPC
for details on the Population PK sample collection.
4.7
Stage 1:
Week 4 visit and Step 2
Protocol Sections 3.1 and 3.2 describe the Study Design, as well as Step 1 and Step 2. After the
Week 4 safety evaluations and the PK results from the Intensive PK Day are available, the protocol
team will review the results to determine whether any dosing adjustments are needed for Stage 1,
Step 1 participants.
Note that the safety and PK results from the Week 4 visit will be assessed for a possible dose
adjustment for all participants in Stage 1. Individual participant safety will be monitored as
outlined in protocol Section 6.0.
Per protocol Section 6.21, in the instance of a failed dose determination for Step 1, the dose will be
adjusted for the cohort and new subjects will be enrolled onto this new dose for Stage 1, Step 1.
Participants from the failed dose in Step 1 will be assessed on an individual basis as to whether
they are able to stay within therapeutic range on this new dose:
• If so, participants will switch to Step 2 and follow protocol Appendix I-B Schedule of Evaluations
on the new dose.
•
If not, participants will no longer receive RPV and switch to follow protocol Appendix I-E
Schedule of Evaluations.
See Section 5.2 of this manual for details on how dose adjustments will be communicated to study
staff.
4.8
Virologic Failure Visit
Protocol Section 6.23 provides the definition for virologic failure for patient management. Subjects
will have HIV-1 RNA PCR conducted at study visits per the Schedules of Evaluations. The Virologic
Failure Visit will be scheduled between 2 to 4 weeks after the study visit in which potential virologic
failure is determined.
For example, a participant comes to the clinic for the Week 32 visit and based on results from this
visit study staff determine that the participant has potential to meet the virologic failure definition,
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per protocol Section 6.23. A Virologic Failure Visit will then be scheduled between 2 to 4 weeks
after the participant’s Week 32 visit.
Virologic Failure Visits will be conducted per the appropriate Schedule of Evaluations in protocol
Appendix I. Refer to protocol Section 6.23 for study drug management based on the results from
the Virologic Failure Visit.
4.9
Long-term Follow-up
Participants who successfully complete 48 weeks of RPV treatment will continue on study and can
receive RPV up to the total treatment duration of 240 weeks, per protocol Sections 3.4, 6.4, and
protocol Appendix I-D.
5
5.1
PHARMACY AND STUDY DRUG CONSIDERATIONS
Overview of dosing
Protocol Section 5.0 describes the study treatment, drug regimen and administration and relevant
pharmacy information for obtaining the study drug. Instructions for administering the RPV tablets
may be found in protocol Section 5.1; the instructions for administering the RPV granules may be
found in protocol Section 5.3. These instructions are also included on the Medication Diary,
Appendix II of this manual.
5.2
Communications with Study Team
As outlined in protocol Sections 5.1 and 6.21, all dose modifications (including treatment
discontinuations for subjects who fail the PK targets) will be recommended by the protocol team
and the protocol pharmacologist, and communicated to designated site staff by PID-specific emails.
Sites are asked to respond to these emails to acknowledge the receipt of the specific dosing
instructions. These emails are considered official study communication and should be printed and
filed in the study’s essential files and in the participant’s binder.
6
6.1
SAFETY MONITORING
ECG reporting
ECGs conducted for IMPAACT P1111 will be transmitted to the centralized reading agency,
Quintiles. This Manual will be updated as the centralized ECG reading contract and processes are
finalized. Specific details on this process and MOP updates will be communicated to participating
sites by the FHI 360 CTS.
7
LABORATORY CONSIDERATIONS
This section contains general information related to laboratory considerations for P1111. For
detailed information on tests and specimens required for each visit, please refer to the Schedule of
Evaluations (protocol Appendix I) and the P1111 LPC.
7.1
Introduction
Regardless of where tests are performed, personnel who collect specimens and/or perform assays
must be trained in proper collection, handling, testing and associated QA/QC procedures prior to
performing the tests for study purposes. Training documentation must be available for inspection
at any time.
All laboratory activities should be conducted in accordance with accepted Good Clinical Laboratory
Practice (GCLP), the IMPAACT and ACTG Network Laboratory Joint Laboratory Manual and sitespecific Standard Operating Procedures (SOPs) for proper collection, processing, labeling, and
transport of specimens. Transport of all specimens must comply with federal, state, local, IATA and
ACTG/IMPAACT specimen shipping regulations.
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As the transmission of HIV and other blood-borne diseases can occur through contact with
contaminated needles, blood and blood products, appropriate precautions should be employed by
all personnel when drawing blood and handling clinical specimens for this study in both the clinical
and laboratory setting, as recommended by the Centers for Disease Control and Prevention (CDC).
Respiratory infections may be transmitted by droplet aerosolization and fomites. All study staff
should take appropriate precautions when collecting and handling biological specimens. Guidance
on Universal Precautions/ Body Substance Isolation is available from the US Centers for Disease
Control and Prevention:
http://www.cdc.gov/ncidod/dhqp/bp_universal_precautions.html
http://www.cdc.gov/ncidod/dhqp/gl_isolation_standard.html
Additional laboratory reference information can be found in the joint ACTG/IMPAACT Laboratory
Manual, which is available at:
http://www.hanc.info/labs/Pages/actgimpaactlabmanual.aspx
7.2
General Overview and Guidelines
Key elements of specimen management include collection, transport, storage and shipping. Also
essential for clinical trials is a Chain of Custody which refers to the tracking of specimens and
results.
It is essential that all staff collecting P1111 specimens have been trained in proper collection
techniques, container types, and any special requirements. Specimens must be transported within
predefined time limits to the laboratory under proper conditions.
7.3
Specimen Chain of Custody
All IMPAACT sites must have a Standard Operating Procedure (SOP) for Chain of Custody in place.
The Chain of Custody must track when specimens are transferred between clinics, processing units,
and laboratories. Internal movements of specimens within the same laboratory do not need to be
tracked. Laboratories with Laboratory Information Management Systems (LIMS) or the Laboratory
Data Management System (LDMS) may be able to track most Chain of Custody information
electronically. Tracking forms with specific information must accompany specimens. Required
information includes the following: the PID/SID, collection time and date, and visit code for each
specimen. Subject names or initials may NOT be used on research samples or the accompanying
tracking forms.
7.4
Labeling Specimens
All samples collected at a study visit must be labeled at the time of collection with the PID, visit
number, and collection date. If collecting PK specimens, time and time unit are also required. PID
and visit numbers may be pre-printed on these labels; however study staff must write the
specimen collection date and time (if needed) on each label. Information on the specimen
containers must match the information on the tracking forms. All samples must be entered into
the LDMS system and aliquots must be labeled using standard LDMS-generated barcode labels.
7.5
Laboratory Data Management System (LDMS)
The LDMS must be used at all sites to track the collection, storage, and shipment of the laboratory
specimens. Detailed instructions for use of the LDMS are available at:
http://www.fstrf.org/ldms
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All sites should upgrade to the most current version of the LDMS as soon as possible. For supported
label and printer options, refer to the product listing documents located on the LDMS Client
Reference Guides page on the FSTRF Portal. Contact LDMS user support for further information.
Questions about LDMS, shipping and storage for this protocol should be raised with the Laboratory
Data Manager at FSTRF:
Andrew Lohrum, FSTRF
Phone: (716) 834-0900
Email: [email protected]
24-Hour LDMS User Support
Technical support is also available from LDMS User Support. Usual business hours from LDMS user
support are 12 AM - 6:00 PM Eastern Time in the US (ET) Monday through Friday. During business
hours, please contact LDMS User support as follows:
Email: [email protected]
Phone: (716) 834-0900, extension 7311
Fax: (716) 898-7711
Off-Hours Contact Information
If you are locked out of your LDMS or are experiencing errors that prevent you from completing
your LDMS lab work during off-hours, page LDMS User Support using the LDMS Web Pager utility.
Alternatively, you may e-mail the paging system directly at [email protected]. Please allow at
least 15 minutes to get a response before sending another e-mail to the paging system.
8
8.1
DATA MANAGEMENT
Assignment of a Patient Identification Number (PID)
The PID is assigned at the site from a list that is generated by the DMC (FSTRF) and sent to the sites.
If a subject has been on another IMPAACT or ACTG study, the same PID is carried with them for use
in the new study; a new PID number will not be assigned. Contact the DMC if you find a participant
has been assigned more than one PID.
8.2
Source Documents
Demographic, sample collection, clinical examination, and AE data must be collected and recorded
by the Investigator’s designated personnel, directly on chart documents or investigator
spreadsheets, and maintained as source documents.
Medical charts and/or subject charts, temperature cards, and any other collection tool may be used
for verification of information recorded in the source documents or on Investigator spreadsheets.
All documentation must be made available to the monitor at scheduled monitoring visits.
8.3
Case Report Forms
Site staff can find the schedule of case report forms for this study on the FSTRF website, under the
Forms Management Utility:
www.fstrf.org
8.4
Resources
Questions regarding data mangement, case report forms etc should be directed to the P1111 Data
Manager, Bonnie Zimmer, who can be reached via the contact information below:
Email: [email protected]
Phone: 716-834-0900 ext 07260
Fax: 716-834-8675
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Appendix I: Tanner Scales
Appendix I-A: Five Stages of Female Breast Development
1. Breasts during childhood. The breasts are flat and show no signs of development
2. Breast bud stage. Milk ducts and fat tissue forms a small mound.
3. Breasts continue to grow. Breasts become rounder and fuller.
4. Nipple and areola form separate small mound. Not all girls go through this stage. Some skip
stage 4 and go directly to stage 5.
5. Breast growth enters final stage. Adult breast is full and round shape
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Appendix I-B: The Five Stages of Female Pubic Hair Development
1. No pubic hair.
2. Pubic hair is sparse, lightly pigmented, straight, medial border of labia
3. Pubic hair is darker, beginning to curl, and increases in amount
4. Pubic hair is coarse, curly, abundant but the amount is less that in an adult woman
5. Pubic hair is that of an adult woman forming a triangle spread to medial surface of thighs
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Appendix I-C: The Five Stages of Male Pubic Hair Development
1. No pubic hair. Penis and testicles of a child. Testicles between 1 and 3 milliliters in volume.
2. First signs for penis, testicle growth, and pubic hair beginning to grow. Pubic hair appears sparse
and downy straight. Testicles become larger. Testicles between 4 and 6 milliliters in volume.
3. Pubic hair appears curlier and coarser with increased pigmentation. Penis continues to grow
getting wider and longer. Testicles continue to grow larger. Testicles between 7 and 16 milliliters
in volume.
4. Penis continues to grow getting wider and longer. Pubic hair becomes adult type, but less. Testicles
continue to grow larger. Penis gland or head is more developed. Testicles between 12 and 24
milliliters in volume. Testicles are about 1 1/2 inches long.
5. Penis growth enters final stage. Average erect penis length 6 1/4 inches. 90% are 5 - 7 inches. Pubic
hair is thick spreading to medial thighs. Glans penis or head is fully developed. Testicles 16 to 27
milliliters in volume. Testicles are about 1-3/4 inches.
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Appendix II: Medication Diary Template
Medication Instructions and Diary
These instructions on the medication and diary are provided to you to help you keep track of when you give
your child their rilpivirine dose.
Medication instructions:
When and how should I give the study rilpivirine to my child?
Rilpivirine should be given once a day with a meal.
• If your child is enrolled into Stage 1 of the study, rilpivirine should be given in the morning with
breakfast until the intensive PK visit (to be scheduled between Days 14-18). After this visit you can
give the rilpivirine at any meal of the day that is easiest for you, such as with the main meal of the
day. On the day of changing to the easier time, rilpivirine should be taken with breakfast and then
again at the new time.
Rilpivirine should be given around the same time each day. Each dose should be given approximately 24
hours from the next dose.
Rilpivirine may be given as tablets or as granules, depending on the dose your child needs.
• Tablets should be taken as a whole, and cannot be chewed, broken, or crushed.
• Rilpivirine granules are measured with a small scoop which will be given to you.
o Measure the number of scoops you were told to give by your doctor
o Each scoop must be leveled off with the back edge of a table knife to get the correct dose.
o Excess granules can be put back into the original container.
o The granules may be mixed with liquids or foods. The amount of liquid or food should be small
enough to make sure your child gets all of the medicine. You should mix the dose right before
you give it to your child.
The study medicine is for your child and must not be taken by anyone else.
What happens if I miss giving a dose of rilpivirine to my child?
If your child misses a dose of rilpivirine and it is within 12 hours of when it was due, you should give the
missed dose with a meal as soon as you realize.
If the dose is more than 12 hours overdue, please skip that dose and give the next dose when it is due.
Make sure you do not give double the amount of rilpivirine at any one time.
Please tell the study doctor about any missed doses or changes in the amount of rilpivirine given to your
child.
Storage
The rilpivirine study medication should be stored in the original packaging at room temperature (15° to
30°C or 29° to 86°F) and high above the reach of children or pets.
Other Treatment Medicines
Rilpivirine should be given along with the other medicines ordered by your doctor.
• Your study doctor will decide which other treatment medicines will be best for your child.
• Study staff will review with you all medications to be given to your child.
Questions?
Please do not hesitate to contact the study clinic or the study doctor with any questions.
16 September 2014
Page 15 of 16
P1111 MOP v1.0
The following are examples of the subject medication diary, literate and pictorial, showing Day 1. A complete template (Days 1 to 18) may be requested from the
FHI 360 CTS by emailing the Protocol Team at [email protected].
Medication diary (literate example):
Please complete this medication diary each time your child takes his/her study rilpivirine medication until the day of the intensive PK visit (to be scheduled between
days 14-18). Remember: do NOT give the medicines to your child on the day of PK visit. Bring the medicines with you to the study clinic, and they will be given to your
child by study staff.
Please circle whether your child is taking:
Day Date
(MM/DD/YY)
1
tablets
Rilpivirine
taken? (pls
circle)
Time dose taken
Yes
No
__ __ : __ __ AM/ PM
Hour Min
or
granules
Amount taken Was the rilpivirine
(# of tablets,
taken with a meal?
or # of
(pls circle)
scoops)
Yes
No
Time meal finished
__ __ : __ __ AM/ PM
Hour Min
If granules, was the
dose mixed with
food or drink? (pls
circle)
Food
Drink/ liquid
Medication diary (pictorial example):
Please complete this medication diary each time your child takes his/her study rilpivirine medication until the day of the intensive PK visit (to be scheduled between
days 14-18). Remember: do NOT give the medicines to your child on the day of PK visit. Bring the medicines with you to the study clinic, and they will be given to your
child by study staff.
Please circle whether your child is taking:
Day Date
(MM/DD/YY)
1
Rilpivirine
taken? (pls
circle)
Yes
No
or
Time dose taken
__ __ : __ __
Hour Min
16 September 2014
Amount taken Was the rilpivirine
(# of tablets,
taken with a meal?
or # of
(pls circle)
scoops)
/
Yes
No
Page 16 of 16
Time meal finished
__ __ : __ __
Hour Min
/
P1111 MOP v1.0
If granules, was the
dose mixed with
food or drink? (pls
circle)