Conditions: Scabies
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 280
Healthy volunteers: no

Brief summary:
To assess the safety and efficacy of Natroba (spinosad) topical suspension versus placebo for the complete cure of scabies after a single treatment.

Detailed description:
This is a double blind, two-arm, 28-day, placebo-controlled study with approximately 120 infested "index" subjects randomized 1:1 to Natroba™ or Placebo. All members of a household (no more than 6 individuals) with a suspected "index" subject must be screened at the first visit. In this study, "index" subjects are defined as the youngest infested household member (≥4 years). If the members have an active scabies infestation and meet all other criteria, they must agree to participate in the study. Household members who do not present with scabies at the screening visit must also agree to apply the same blinded investigational product (IP) as household members who present with scabies. All infested household members must agree to participate in the study or none will be enrolled. Screening procedures include informed consent, medication and medical history, urine pregnancy test for females of childbearing potential, scabies assessment (visual evidence of burrows, inflammatory/non-inflammatory lesions and pruritus), microscopic examination of skin scraping, or dermatoscopy, to demonstrate the presence of mites, eggs, and/or scybala (dermatoscopy must confirm burrows), vital signs, general skin and eye assessment, randomization, and IP dispensing and instruction.

After screening on Day 1, all randomized subjects will be dispensed IP (Natroba™ or Placebo) to apply at home later the same day as a single treatment over the entire body from the neck down to the toes (including the soles of the feet) and to the scalp (if balding) or hairline, temples and forehead on the same day. Subjects less than 12 years of age should be assisted with administration by a parent, guardian or caregiver. Subjects will rub the treatment into the skin followed by a 10-minute wait period before getting dressed. Showering or bathing must not occur earlier than 6 hours after treatment and no later than at least 1 hour prior to Day 2 visit.

On Day 2 (Visit 2), all household members will return for general skin and eye assessments of possible irritation, and to confirm that all IP was left on for a minimum of 6 hours before bathing or showering. If a subject reports an adverse event assessed as related by the PI on Day 2 (Visit 2) then a follow-up visit with the investigator must be scheduled within 7 days of visit. All household members will receive a well-being phone call on Day 14 to continue to emphasize instructions to prevent re-infestation, determine if any concomitant medications have been used, and check for adverse events. If a subject reports an adverse event assessed as related by the PI on the Day 14 well-being phone call, then a follow-up visit with the investigator must be scheduled within 7 days of phone call.

On Day 28 (Visit 3), all household members will return to the clinic for safety and efficacy assessments. The primary endpoint of complete cure will be assessed in the "index" subject and any infested household members. If the infested subject is completely cured at Day 28, he or she will have completed the study and termination procedures will be conducted. If the subject is not completely cured at Day 28 (with Natroba™ or Placebo), the subject will receive 5% Permethrin and will be directed to their primary care physician for follow-up.

Safety assessments will be made for all household members and will include monitoring of adverse events (AEs) throughout the study, vital signs recording (Days 1 and 28), clinical laboratory analyses (Days 1 and 28), and general skin and eye irritation assessments (Days 1, 2, and 28). The Day 28 procedures will also be completed for early termination (ET) except subjects will not receive rescue Permethrin but will be directed to follow-up with their primary care physician.

Arms:
arm 1: spinosad topical suspension, 0.9% up to 120 mL (enough product is used to cover the body from the neck down to the soles of the feet), one treatment left on for 6 hours arm 2: placebo is a topical suspension that is the same formulation as Natroba without the active ingredient spinosad (vehicle). Up to 120 mL (enough product is used to cover the body from the neck down to the soles of the feet), one treatment left on for 6 hours.

Interventions: intervention 1: spinosad topical suspension, 0.9% intervention 2: Placebo
Intervention descriptions: intervention 1: Topically apply 0.9% suspension up to 120 mL (enough to cover the body from the neck down to the soles of the feet). One application for six hours. intervention 2: Placebo is the same as the drug minus the active ingredient spinosad (vehicle). Topically apply up to 120 mL (enough to cover the body from the neck down to the soles of the feet). One application for six hours.

Protocol document:
Prot_000.pdf: 
Phase 3, Double-Blind, Placebo-Controlled Study to Assess  
SPN-304-15 Amendment No. 6 
Safety and Efficacy of Natroba™ (spinosad) for Scabies Treatment 
23 March 2018 
Page 1 of 61 
ParaPRO, LLC  Confidential 
CLINICAL STUDY PROTOCOL 
A Phase 3, Randomized, Double Blind, Placebo-Controlled Study to Assess the 
Safety and Efficacy of Natroba™ (spinosad) for the Treatment of Scabies 
Investigational Product: Natroba™ (spinosad) Topical Suspension, 0.9% 
 
IND No.: 66,657 
 
Phase: 3 
Protocol Number: SPN-304-15 
Document Dates 
Original Protocol: 
11 March 2015 
Amendment No.1: 
07 July 2015 
Amendment No. 2: 
08 April 2016 
Amendment No. 3: 
14 November 2016 
Amendment No. 4: 
27 February 2017 
Amendment No. 5: 
20 September 2017 
Amendment No. 6: 
23 March 2018 
 
 
 
Sponsor: 
ParaPRO LLC 
11550 North Meridian Street 
 Suite 290 
 Carmel, IN 46032 USA 
 
Telephone: (317) 810-6205 
Fax: (317) 810-0216 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written consent of ParaPRO 
LLC except to the extent that disclosure would be required by law and for the purpose of evaluating and/or conducting 
a clinical study for ParaPRO LLC. You are allowed to disclose the contents of this document only to your Institutional 
Review Board (IRB) and study personnel directly involved with conducting this protocol. Persons to whom the 
information is disclosed must be informed that the information is confidential and proprietary to ParaPRO LLC and 
that it may not be further disclosed to third parties. 


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Safety and Efficacy of Natroba™ (spinosad) for Scabies Treatment 
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PRINCIPAL INVESTIGATOR SIGNATURE SHEET 
A Phase 3, Randomized, Double Blind, Placebo-Controlled Study to Assess the 
Safety and Efficacy of Natroba™ (spinosad) for the Treatment of Scabies 
Protocol Number: SPN-304-15 
 
By my signature below, I attest that I have read, understood, and agree to abide by all conditions, 
instructions, and restrictions contained in this protocol (including appendices). I will not initiate 
this study without approval from the appropriate Institutional Review Board (IRB) and I 
understand that any changes in the protocol must be approved in writing by the ParaPRO LLC 
and the IRB before they can be implemented, except where necessary to eliminate immediate 
hazards to the subject. 
 
Approval Signature 
Principal Investigator: _________________________________ Date _____________ 
 
Signature 
 
 
_________________________________ 
 
Printed Name 
 
 
_________________________________ 
 
Name of Facility 
 
 
_________________________________ 
 
Address 
 
 
_________________________________ 
 
 
City, State, Zip Code 
 
 
_________________________________ 
 
Phone Number 
 
 
_________________________________ 
 
Fax Number 
 
 
 
_________________________________ 
 
 
Email Address 






Phase 3, Double-Blind, Placebo-Controlled Study to Assess  
SPN-304-15 Amendment No. 6 
Safety and Efficacy of Natroba™ (spinosad) for Scabies Treatment 
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PROTOCOL SYNOPSIS 
TITLE: 
A Phase 3, Randomized, Double Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of 
Natroba™ (spinosad) for the Treatment of Scabies 
PROTOCOL NUMBER: 
SPN-304-15 
INVESTIGATIONAL PRODUCT: 
Natroba™ (spinosad) Topical Suspension, 0.9% 
U.S. IND No. 
66,657 
PHASE: 
3 
INDICATION: 
Treatment of scabies 
OBJECTIVES: 
The primary objective is to assess the safety and efficacy of topical Natroba™ (spinosad) versus 
Placebo for the complete cure of scabies after a single treatment. 
 
ENDPOINTS: 
The primary efficacy endpoint is the proportion of “index” subjects completely cured of scabies by Day 
28. The “index” subject is defined as the youngest infested household member (≥4 years). Complete 
cure is defined as demonstration of both clinical cure (all signs and symptoms have completely 
resolved, including burrows, inflammatory/non-inflammatory lesions and pruritus) and microscopic or 
dermatoscopic cure demonstrating the absence of mites, eggs, and/or scybala, and negative 
dermatoscopy for burrows. 
Safety endpoints include the evaluation of adverse events, general skin and eye irritation, clinical 
laboratory assessments, vital signs, and use of prior and concomitant medications. 
POPULATION: 
Approximately 360 subjects will be enrolled in the study. The approximate 360 total is based on: 
120 households, each with an “index” subject and approximately 2 additional subjects per household 
(infested or not) for 360 total. The 120 “index” subjects with confirmed scabies infestation will 
comprise the primary efficacy population in order to achieve, with attrition, 48 subjects completed per 
treatment group (Natroba™ versus Placebo). In this study, “index” subjects will be defined as the 
youngest infested household member (≥4 years). All household members of the “index” subject will be 
randomized to the same treatment.  
STUDY DESIGN AND DURATION: 
This is a double blind, two-arm, 28-day, placebo-controlled study with approximately 120 infested 
“index” subjects randomized 1:1 to Natroba™ or Placebo.  All members of a household (no more than 
6 individuals) with a suspected “index” subject must be screened at the first visit. In this study, “index” 
subjects are defined as the youngest infested household member (≥4 years). If the members have an 
active scabies infestation and meet all other criteria, they must agree to participate in the study. 
Household members who do not present with scabies at the screening visit must also agree to apply the 
same blinded investigational product (IP) as household members who present with scabies (see Table 
6-1 Schedule of Procedures for status assessment). All infested household members must agree to 
participate in the study or none will be enrolled. Screening procedures include informed consent, 
medication and medical history, urine pregnancy test for females of childbearing potential, scabies 
assessment (visual evidence of burrows, inflammatory/non-inflammatory lesions and pruritus), 


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microscopic examination of skin scraping, or dermatoscopy, to demonstrate the presence of mites, 
eggs, and/or scybala (dermatoscopy must confirm burrows), vital signs, general skin and eye 
assessment, randomization, and IP dispensing and instruction. 
After screening on Day 1, all randomized subjects will be dispensed IP (Natroba™ or Placebo) to apply 
at home later the same day as a single treatment over the entire body from the neck down to the toes 
(including the soles of the feet) and to the scalp (if balding) or hairline, temples and forehead on the 
same day. Subjects less than 12 years of age should be assisted with administration by a parent, 
guardian or caregiver. Subjects will rub the treatment into the skin followed by a 10-minute wait period 
before getting dressed. Showering or bathing must not occur earlier than 6 hours after treatment and no 
later than at least 1 hour prior to Day 2 visit. 
On Day 2 (Visit 2), all household members will return for general skin and eye assessments of possible 
irritation, and to confirm that all IP was left on for a minimum of 6 hours before bathing or showering.  
If a subject reports an adverse event assessed as related by the PI on Day 2 (Visit 2) then a follow-up 
visit with the investigator must be scheduled within 7 days of visit. All household members will 
receive a well-being phone call on Day 14 to continue to emphasize instructions to prevent re-
infestation, determine if any concomitant medications have been used, and check for adverse events.  If 
a subject reports an adverse event assessed as related by the PI on the Day 14 well-being phone call, 
then a follow-up visit with the investigator must be scheduled within 7 days of phone call.  . 
On Day 28 (Visit 3), all household members will return to the clinic for safety and efficacy 
assessments. The primary endpoint of complete cure will be assessed in the “index” subject and any 
infested household members. If the infested subject is completely cured at Day 28, he or she will have 
completed the study and termination procedures will be conducted. If the subject is not completely 
cured at Day 28 (with Natroba™ or Placebo), the subject will receive 5% Permethrin and will be 
directed to their primary care physician for follow-up. 
Safety assessments will be made for all household members and will include monitoring of adverse 
events (AEs) throughout the study, vital signs recording (Days 1 and 28), clinical laboratory analyses 
(Days 1 and 28), and general skin and eye irritation assessments (Days 1, 2, and 28). The Day 28 
procedures will also be completed for early termination (ET) except subjects will not receive rescue 
Permethrin but will be directed to follow-up with their primary care physician. 
The trial design is presented in the Study Flow Diagram (Figure 3-1) and the visit assessments are 
described in the Schedule of Procedures (Table 6-1). 
 
INCLUSION CRITERIA: 
All household members who have provided written informed consent and an authorization for 
disclosure of protected health information must meet all the following criteria: 
1. Male or female, age 4 years and upward. 
2. At least one household member must have active scabies infestation confirmed by clinical 
signs and symptoms (evidence of burrows or presence of scabies inflammatory/non-
inflammatory lesions and pruritus) as well as by microscopic examination of skin scraping, or 
dermatoscopy, to demonstrate the presence of mites, eggs, and/or scybala. If dermatoscopy is 
used it should also confirm there are burrows on the skin. 
3. Generally in good health based on medical history and clinical assessments. 
4. Normal-appearing skin in noninfested areas. 
5. No history of chronic or recurrent dermatologic disease. 


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6. Willingness to comply with the study procedures including application of study treatment at 
home as instructed. 
7. Willing and able to practice an acceptable measure of contraception during the study, if female 
of childbearing potential. Examples of acceptable contraceptive methods include abstinence, 
intrauterine device (IUD), double barrier method, oral or implantable or injectable 
contraceptives. Must have been using systemic (oral, injectable, or implantable) contraceptives 
for at least 3 months. If abstinent and planning to become sexually active must agree to use a 
double barrier method. 
8. Subject agrees to inform their sexual partners to seek an examination for scabies and treatment 
if, and when, symptoms present. 
9. Household members must be 6 or fewer and all members must be willing to attend clinic visits 
and be randomized to treatment (blinded, but same for all). 
EXCLUSION CRITERIA: 
All household members must be excluded if any of the following conditions are met: 
1. Household has greater than 6 residents. 
2. Has a household member(s) who is not willing or not eligible to enroll. 
3. Presence of scabies on the scalp. 
4. Presence of crusted scabies (Norwegian scabies). 
5. Allergies or intolerance to ingredients in the IPs. 
6. Current pregnancy (as assessed by urine pregnancy test) or currently nursing. 
7. The household has sexually active subjects who do not agree to restrict prolonged skin to skin 
contact with non-household members during the trial period. 
8. Known renal or hepatic impairment. 
9. Treatment with scabicide within the prior 4 weeks. 
10. Immunodeficiency (including HIV infection) as reported by the subject in Medical History. 
11. Signs or symptoms of systemic infection. 
12. Administration of any systemic therapy for infectious disease within the prior 2 weeks. 
13. Receipt of any other investigational product (IP) within the prior 4 weeks. 
14. Any other conditions that, at the investigator’s discretion, may interfere with the study conduct, 
or which might confound the interpretation of the study results, or which may put the subject at 
undue risk. 
15. Does not have a known household affiliation with their household members (stays in one 
household inconsistently, i.e., sleeps at one place several nights and then other places on other 
nights). 
16. Household member is unwilling to treat scabies. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Natroba™ or Placebo applied in a single topical application to the entire body from the neck down to 
the toes (including the soles of the feet) and to the scalp (if balding) and/or hairline, temples, and 
forehead. 
EFFICACY VARIABLES: 
The primary efficacy assessment is the proportion of “index” subjects completely cured of scabies by 
Day 28. Complete cure is defined as demonstration of clinical cure (all signs and symptoms have 
completely resolved, including burrows, inflammatory/non-inflammatory lesions and pruritis) and 
microscopic or dermatoscopic cure demonstrating the absence of mites, eggs, and/or scybala, and 
negative dermatoscopy for burrows. 
 


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SAFETY ASSESSMENTS: 
Safety assessments include monitoring of AEs on study Days 1, 2, 14 (phone call) and 28, general skin 
and eye irritation assessments on Days 1, 2 and 28, vital signs on Days 1 and 28, laboratory 
assessments on Days 1 and 28, prior medications on Day 1 and concomitant medications on Days 2 and 
Day 28. For early termination (ET), the Day 28 procedures will also be completed. 
STATISTICAL ANALYSES: 
The primary efficacy endpoint is the proportion of “index” subjects completely cured of scabies by Day 
28. The primary analysis set will be the “index” intent-to-treat (ITT) population which is defined as all 
randomized “index” subjects regardless of whether they have had any post-baseline assessments and 
the primary efficacy endpoint will be the proportion of “index” subjects completely cured of scabies by 
Day 28. The number and percentage of “index” subjects who exhibit complete cure (Yes or No) by 
Day 28 will be presented by treatment group. A Cochran-Mantel-Haenszel general association test 
stratified by study site (possibly pooled) will be used to compare the complete cure rates between the 
two treatment groups. The primary analysis will be performed at a significance level of 0.05. 
The safety endpoints include the evaluation of adverse events, general skin and eye irritation 
assessments, vital signs, and use of prior and concomitant medications. Additionally, the descriptive 
changes from baseline (pre-dose) to final assessment (Day 28) will be calculated for applicable 
parameters. 
SAMPLE SIZE DETERMINATION: 
For the primary efficacy analysis, approximately 120 “index” subjects will be enrolled (including 
possible 20% attrition) from 120 households and randomized 1:1 to each of Natroba™ (spinosad) and 
Placebo control. The index subject will be the youngest infested member of a household (≥4 years). 
Referencing to the Sponsor’s Proof of Concept (POC) study (SPN-401-12) and published literature,5-10 
out of 60 completed subjects, the cure rate is 70% for Natroba™ and 30% for Placebo control.  Based 
upon a reasonable assumption of 60% cure rate for Natroba™ and 30% for placebo, a sample size of 48 
study-completed “index” subjects per group will provide 80% power to declare the non-equivalency 
using a delta of 30% and Type I error rate of 0.05.   Fisher exact test was used to calculate the sample 
size and the specified power in the following Table 8-1 (PASS 14; 2015, NCSS, LLC., Kaysville, Utah, 
USA. www.ncss.com). 
SITES: 
This study will be conducted at approximately 5-10 sites in the United States. 
SPONSOR: 
ParaPRO LLC 


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Safety and Efficacy of Natroba™ (spinosad) for Scabies Treatment 
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STUDY FLOW DIAGRAM 
120 ‘index” subjects 
 with confirmed scabies infestation 
Day 1 
Dispense Natroba™ 
Randomize 
1:1 
Day 1 
Day 1 
Dispense Placebo 
 
Day 2 
Assess safety 
and compliance 
Day 2 
Assess safety 
and compliance 
Day 28 
Assess Efficacy 
Day 28 
Assess Efficacy 
Complete Cure 
Subject 
Completes Study 
Not Cured 
Provide 5% Permethrin  
rescue medication 
Not Cured 
Provide 5% Permethrin  
rescue medication 
 
Day 14 
Phone Call 


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SCHEDULE OF PROCEDURES AND ASSESSMENTS 
Period 
Screening,  
Randomizat
ion and 
Treatment 
Treatment/Follow-up 
Visit 
1 
2 
AE 
follow-
up 
Phone 
Call 
AE 
follow-
up 
3 
Day ± 
1 
2 
3+6 
14 ± 2 
14 +712 
28 ± 
2/ET 
Informed consent 
X 
 
 
 
 
 
Prior medications 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Urine pregnancy test1 
X 
 
 
 
 
X 
Scabies diagnosis2 
X 
 
 
 
 
 
Efficacy assessments3 
 
 
 
 
 
X 
Vital signs4 
X 
 
 
 
 
X 
General skin assessment5 
X 
X 
 
 
 
X 
Eye irritation assessment5 
X 
X 
 
 
 
X 
Review eligibility criteria 
X 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
Weigh and dispense IP bottle; 
provide application instructions6 
X8 
 
 
 
 
 
Instruct on waiting ≥6 hrs post-
treatment (IP) before showering6 
X 
 
 
 
 
 
Collect and weigh used IP bottle 
 
X 
 
 
 
X8 
Review subject compliance7 
 
X 
 
 
 
 
Instructions to prevent re-
infestation 
X 
X 
 
X 
 
 
Concomitant medications 
 
X 
 
X 
 
X 
Adverse events9 
 
X 
X11 
X 
X11 
X 
5% Permethrin dispensed to 
subjects not completely cured at 
Day 28 
 
 
 
 
 
X10 
ET = Early Termination; IP = investigational product.  
1. Only for females of childbearing potential. 
2. Scabies diagnosis (Inclusion #2) – At least one household member with active scabies infestation 
confirmed by clinical signs and symptoms (evidence of burrows or presence of scabies inflammatory/non-
inflammatory lesions and pruritus) as well as by microscopic examination of skin scraping or dermatoscopy 
to demonstrate the presence of mites, eggs, and/or scybala. If dermatoscopy is used it should also confirm 
there are burrows on the skin. 
3. Primary Endpoint – Complete cure is defined as demonstration of clinical cure (all signs and symptoms 
have completely resolved, including inflammatory/non-inflammatory lesions and pruritus) and microscopic 


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or dermatoscopic cure with demonstration of the absence of mites, eggs, and/or scybala, and dermatoscopy 
negative for burrows.  
4. Vital signs – height (only Visit 1), weight, blood pressure (BP), and heart rate. 
5. Assessment at Visit 1 for eligibility (skin) and eye for baseline, Visit 2 for skin and eye irritation 
assessments and to confirm IP was washed off, and Visit 3/ET (if applicable) for skin and eye irritation. 
See Section 7.7 for rating eye irritation. 
6. IP Treatment – dispense IP and instruct subject to administer single topical application of IP over entire 
body from the neck down to the toes (including soles of the feet) and on the scalp/hairline, temples and 
forehead while at home. Subjects will not shower for at least 6 hours after application and no later than at 
least 1 hour before Day 2 visit. Subjects less than 12 years of age should be assisted with administration by 
a parent, guardian or caregiver. 
7. Confirm that all IP was left on for a minimum of 6 hours before bathing or showering and washed off at 
least 1 hour before Day 2 visit. Instruct/re-instruct subjects how to prevent re-infestation, to stay in one 
household, as well as to follow all study procedures and expectations. 
8. Collect and weigh used bottle if not collected at Visit 2. 
9. Assessed starting post-treatment. Investigators will follow all AEs until the final study visit (Day 28). All 
SAEs, and all AEs deemed by the Investigator to be related to IP or treatment, will be followed until the 
event has resolved (even if beyond Day 28). 
10. Subjects who are not completely cured at this visit (Day 28) will be provided with 5% Permethrin as rescue 
medication. Subjects who terminated early will not receive rescue medication. All subjects will be directed 
to their primary care physician for follow-up. 
11. If a subject reports an adverse event assessed as related by the PI on Day 2 (Visit 2) then a follow-up visit 
with the investigator must be scheduled within 7 days of visit.  If a subject reports an adverse event 
assessed as related by the PI on the Day 14 well-being phone call, then a follow-up visit with the 
investigator must be scheduled within 7 days of phone call.    
12. It is intended for the AE follow-up to occur within 7 days of the day 14 call.  The Day 14 call may occur 
between study day 12 and 16. 
 
 
 
 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................... 1 
PRINCIPAL INVESTIGATOR SIGNATURE SHEET .................................................. 2 
CLIENT COMPANY SIGNATURE SHEET .................................................................. 3 
PROTOCOL SYNOPSIS ................................................................................................. 5 
STUDY FLOW DIAGRAM ............................................................................................. 9 
SCHEDULE OF PROCEDURES AND ASSESSMENTS ............................................ 10 
TABLE OF CONTENTS ................................................................................................ 12 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................... 16 
1 
BACKGROUND AND RATIONALE .................................................................... 18 
1.1 
Background ................................................................................................. 18 
1.2 
Rationale ...................................................................................................... 19 
2 
OBJECTIVES .......................................................................................................... 20 
2.1 
Primary ........................................................................................................ 20 
3 
INVESTIGATIONAL PLAN .................................................................................. 21 
3.1 
Overall Study Design .................................................................................. 21 
3.2 
Discussion of Study Design ........................................................................ 23 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................... 25 
4.1 
Inclusion Criteria ......................................................................................... 25 
4.2 
Exclusion Criteria ........................................................................................ 26 
4.3 
Subject Withdrawal Criteria ........................................................................ 26 
5 
STUDY TREATMENTS......................................................................................... 28 
5.1 
Identity of Investigational Products ............................................................ 28 
5.2 
Investigational Product Storage and Accountability ................................... 28 
5.3 
Methods of Assigning Subjects to Treatment Groups................................. 29 
5.4 
Administration of Investigational Product .................................................. 29 
5.5 
Treatment Accountability and Compliance ................................................. 30 
5.6 
Blinding and Unblinding Method ................................................................ 30 
6 
SCHEDULE OF PROCEDURES AND ASSESSMENTS ..................................... 32 
6.1 
Screening, Randomization and Treatment (Visit 1; Day 1) ........................ 34 
6.2 
Follow-up Safety Assessment Visit (Visit 2, Day 2) .................................. 34 
6.3 
AE Follow-up Visit (Day 3 + 6 days; conducted only if a subject reports an adverse 
event assessed as related by the PI on Day 2) ......................................... 35 


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6.4 
Phone Call (Day 14 +/- 2 days) ................................................................... 35 
6.5 
AE Follow-up Visit (Day 14 + 7 days; conducted only if a subject reports an adverse 
event assessed as related by the PI on the Day 14 well-being phone call)35 
6.6 
Final Visit (Visit 3/ET, Day 28 + 2 days) ................................................... 35 
6.7 
Early Termination Procedures ..................................................................... 35 
6.8 
Subject Completion Criteria ........................................................................ 36 
6.9 
Protocol Deviations ..................................................................................... 36 
7 
DETAILED DESCRIPTION OF ASSESSMENTS ................................................ 37 
7.1 
Informed Consent ........................................................................................ 37 
7.2 
Medical History ........................................................................................... 37 
7.3 
Prior Medications and Concomitant Medications ....................................... 37 
7.4 
Prohibited Medications ................................................................................ 38 
7.5 
Pregnancy and Contraceptive Use ............................................................... 38 
7.6 
Scabies Assessment ..................................................................................... 38 
7.7 
General Skin and Eye Assessments ............................................................. 39 
7.8 
Application of IP ......................................................................................... 39 
7.9 
Vital Signs ................................................................................................... 39 
7.10 
Eligibility Review ........................................................................................ 39 
7.11 
Randomization and Treatment Assignment ................................................ 40 
7.12 
Counseling to Prevent Re-Infestation .......................................................... 40 
7.13 
Prophylactic and Rescue 5% Permethrin .................................................... 41 
7.14 
Study Compliance ....................................................................................... 41 
8 
STATISTICAL METHODS .................................................................................... 42 
8.1 
Sample Size Determination ......................................................................... 42 
8.2 
Randomization ............................................................................................. 42 
8.3 
Analysis Populations ................................................................................... 43 
8.4 
Missing Values ............................................................................................ 44 
8.5 
Statistical Analyses ...................................................................................... 44 
8.5.1 Subject Disposition ............................................................................... 44 
8.5.2 Demographics and Baseline Characteristics ......................................... 45 
8.5.3 Efficacy Analyses.................................................................................. 45 


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8.5.3.1 Primary Efficacy ................................................................................ 45 
8.5.3.2 Exploratory Efficacy .......................................................................... 45 
8.5.3.3 Pooling of Study Sites ........................................................................ 47 
8.5.4 Safety Analyses ..................................................................................... 47 
9 
ADVERSE EVENT MONITORING ...................................................................... 49 
9.1 
Definition ..................................................................................................... 49 
9.2 
Procedures ................................................................................................... 49 
9.3 
Severity ........................................................................................................ 50 
9.4 
Relationship ................................................................................................. 50 
9.5 
Action Taken and Outcome ......................................................................... 50 
9.6 
Adverse Event Follow-up ............................................................................ 50 
9.7 
Serious Adverse Events ............................................................................... 50 
9.7.1 Serious Adverse Event Reporting ......................................................... 51 
9.7.2 Serious Adverse Event Follow-up ........................................................ 52 
9.8 
Unexpected Adverse Event ......................................................................... 52 
9.9 
Pregnancy .................................................................................................... 53 
10 INVESTIGATOR OBLIGATIONS ........................................................................ 54 
10.1 
Ethical and Regulatory Considerations ....................................................... 54 
10.2 
Institutional Review Board .......................................................................... 54 
10.3 
Informed Consent ........................................................................................ 54 
10.4 
Subject Confidentiality ................................................................................ 55 
11 STUDY MONITORING ......................................................................................... 56 
11.1 
Clinical Monitoring ..................................................................................... 56 
11.2 
Auditing Procedures .................................................................................... 56 
12 CHANGES TO THE PROTOCOL AND STUDY TERMINATION .................... 57 
12.1 
Protocol Amendment and Administrative Change ...................................... 57 
12.2 
Termination of the Study ............................................................................. 57 
13 SOURCE DOCUMENTS, CASE REPORT FORMS AND RECORD RETENTION 58 
13.1 
Source Documents ....................................................................................... 58 
13.2 
Electronic Case Report Forms ..................................................................... 58 
13.3 
Record Retention ......................................................................................... 58 


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14 FINAL REPORT/PUBLICATION STATEMENT ................................................. 59 
15 REFERENCES ........................................................................................................ 60 
16 APPENDIX [1]: EXAMPLE OPEN-LABEL PRODUCT LABEL ........................ 61 
 
LIST OF TABLES 
Table 6-1 
SCHEDULE OF PROCEDURES AND ASSESSMENTS .................. 32 
Table 8-1 
SAMPLE SIZE NEEDED TO DECLARE NON-EQUIVALENCY WITH 
RESPECT TO THE PROPORTION OF SUBJECTS ACHIEVING 
COMPLETE CURE WITH A TYPE I ERROR RATE=0.05 AND SPECIFIED 
POWER ................................................................................................ 42 
 
LIST OF FIGURES 
Figure 3-1: FLOW DIAGRAM ...................................................................................... 21 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation/Term 
Definition 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance  
ANOVA 
Analysis of Variance  
BP 
Blood Pressure 
C 
Celsius 
CDC 
Center for Disease Control 
CGMP 
Current Good Manufacturing Practices 
CRA 
Clinical Research Associate 
CRF 
Case Report Form  
CFR 
Code of Federal Regulations 
EMEA 
European Medicines Agency 
ET 
Early Termination 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice  
HDPE 
High Density Polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigators’ Brochure 
IC 
Informed Consent 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IP 
Investigational Product (Natroba™ or Placebo) 
IRB 
Institutional Review Board or Independent Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device  
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
PI 
Principal Investigator 
POC 
Proof of Concept 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 


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Abbreviation/Term 
Definition 
SOC 
System Organ Class 
TEAE 
Treatment-emergent AE 
WHO 
World Health Organization 
WHO-DD 
WHO Drug Dictionary 
WOCF 
Worst Observation Carried Forward 
 


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1 
BACKGROUND AND RATIONALE 
1.1 
Background 
Human scabies is caused by an infestation of the skin by the human itch mite (Sarcoptes scabiei 
var. hominis). The microscopic scabies mite burrows into the upper layer of the skin where it 
lives and lays its eggs. The most common symptoms of scabies are intense itching and a pimple-
like skin rash. The itching and rash each may affect much of the body or be limited to common 
sites such as the wrist, elbow, armpit, webbing between the fingers, nipple, penis, waist, belt-
line, and buttocks. The rash also can include tiny blisters (vesicles) and scales. Scratching the 
rash can cause skin sores; sometimes these sores become infected by bacteria. Tiny burrows 
sometimes are seen on the skin which are caused by the female scabies mite tunneling just 
beneath the surface of the skin. These burrows appear as tiny raised and crooked (serpiginous) 
grayish-white or skin- colored lines on the skin surface. Mites are often few in numbers (only 10-
15 mites per person) and the burrows may be difficult to find. The burrows are found most often 
in the webbing between the fingers, in the skin folds on the wrist, elbow, or knee, and on the 
penis, breast, or shoulder blades. The head, face, neck, palms, and soles often are involved in 
infants and very young children, but usually not adults and older children.1,2 
The scabies mite is usually spread by direct, prolonged, skin-to-skin contact with a person who 
has scabies. Scabies occurs worldwide and affects people of all races and social classes. 
Worldwide prevalence has been estimated at about 300 million cases yearly.2 Scabies can spread 
rapidly under crowded conditions where close body contact is frequent. Institutions such as 
nursing homes, extended-care facilities, and prisons are often sites of scabies outbreaks. Current 
treatment recommended by Centers for Disease Control (CDC) is a single overnight topical 
application of 5% Permethrin.1 
Natroba™ (spinosad) Topical Suspension, 0.9% has been approved by the Food and Drug 
Administration for the treatment of head lice in patients 6 months of age and older.3 Spinosad is 
derived from the fermentation of a soil actinimycete bacterium, and acts by causing neuronal 
excitation in insects. After periods of hyperexcitation, the lice become paralyzed and die. This 
same mode of action applies to the scabies mite. After topical application in infested pediatric 
subjects, spinosad levels in plasma were below the limits of quantitation. Preclinical testing for 
carcinogenesis, mutagenesis and impairment of fertility were negative. Clinical studies with 
subjects infested with head lice showed Natroba™ (spinosad) Topical Suspension, 0.9% to be 
more effective than Permethrin 14 days after treatment.3 


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1.2 
Rationale 
ParaPRO conducted a proof-of-concept trial that was a double-blinded, two-arm 28-day placebo 
controlled study of subjects randomly assigned 3:1 to NatrobaTM or Placebo.4 Subjects applied a 
single treatment over the entire body from the neck down to the toes (including the soles of the 
feet) in-clinic on Day 1, rubbing the investigational product (IP) into the skin and waiting 10 
minutes before getting dressed. Showering or bathing was to occur no earlier than 6 hours after 
treatment. Efficacy assessments included visual skin assessment of scabies infestation (visual 
assessment of burrows, lesion counts, and presence of new lesions), skin scraping for 
microscopic examination (for evidence of mites) and a pruritus score by a subjective scale. The 
scabies scores were changed by -1.4 with Natroba (p=0.0020), compared to -1.0 with Placebo 
(p=0.2500). The count of lesions was significantly decreased with Natroba (-28.1, p=0.0020), 
however, not with Placebo (-9.8, p=0.6250). Microscopy showed significant improvement, 13/15 
negative with Natroba (p=0.0074), compared to 3/5 with Placebo (p=1.000). 
The design for the current Phase 3 trial is similar to the phase 3 trials evaluating efficacy of 
Natroba™ Topical Suspension for treatment of head lice, although subjects in this trial received 
only one application of the Natroba™ Topical Suspension.3 In the two phase 3 studies of 
individuals with lice, all subjects who were treated on Day 0 returned for efficacy evaluation at 
Day 7. Subjects with live lice present at Day 7 received a second treatment. Subjects who were 
lice free on Day 7 were to return on Day 14 for evaluation. Subjects with live lice and who 
received a second treatment on Day 7 were to return on Days 14 and 21 for evaluation. Efficacy 
was assessed as the proportion of primary subjects who were free of live lice 14 days after the 
initial/final treatment. 
Based on the safety and efficacy of Natroba™ (spinosad) Topical Suspension, 0.9% in the 
treatment of head lice,3 the present study is designed to evaluate pivotal phase 3 data on the 
safety and efficacy of the topical suspension against scabies, an infestation by Sarcoptes scabiei 
var. hominis. The effect of the Natroba™ (spinosad) Topical Suspension, 0.9% will be compared 
to that of a Placebo control. 
 


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2 
OBJECTIVES 
2.1 
Primary 
The primary objective is to assess the safety and efficacy of topical Natroba™ (spinosad) versus 
Placebo for the complete cure of scabies after a single treatment.  


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design 
The study is a double blind, two-arm, 28-day, placebo-controlled study randomizing 
approximately 120 infested “index” subjects 1:1 to Natroba™ or Placebo in order to have at least 
96 subjects completed (Figure 3-1). 
 
Figure 3-1: FLOW DIAGRAM 
 
 
 
120 ‘index” subjects 
 with confirmed scabies infestation 
Day 1 
Dispense Natroba™ 
 
Randomize 
1:1 
Day 1 
Day 1 
Dispense Placebo 
 
Day 2 
Assess safety 
and compliance 
Day 2 
Assess safety 
and compliance 
Day 28 
Assess Efficacy 
Day 28 
Assess Efficacy 
Complete Cure 
Subject 
Completes Study 
Not Cured 
Provide 5% Permethrin 
rescue medication 
Not Cured 
Provide 5% Permethrin  
rescue medication 
 
Day 14 
Phone Call 


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All members of a household (no more than 6 individuals) with a suspected “index” subject must 
be screened at the first visit. In this study, “index” subjects are defined as the youngest infested 
household member (≥4 years). If the household has at least one member with active scabies 
infestation and meet all other criteria, they must all agree to participate in the study. Household 
members who do not present with scabies at the screening visit must also agree to apply the same 
blinded investigational product (IP) as household members who present with scabies (see Table 
6-1 Schedule of Procedures for status assessment). All household members must agree to 
participate in the study or none will be enrolled. Screening procedures include informed consent, 
medication and medical history, urine pregnancy test for females of childbearing potential, 
scabies assessment (visual evidence of burrows, inflammatory/non-inflammatory lesions and 
pruritus), microscopic examination of skin scraping or dermoscopy to demonstrate the presence 
of mites, eggs, and/or scybala (dermatoscopy must confirm burrows), vital signs, general skin 
and eye assessment, randomization, and IP dispensing and instruction. 
After screening on Day 1, all randomized subjects will be dispensed IP (Natroba™ or Placebo) 
to apply at home later the same day as a single treatment over the entire body from the neck 
down to the toes (including the soles of the feet) and to the scalp (if balding) or hairline, temples 
and forehead on the same day. Subjects less than 12 years of age should be assisted with 
administration by a parent, guardian or caregiver. Subjects will rub the treatment into the skin 
followed by a 10-minute wait period before getting dressed. Showering or bathing must not 
occur earlier than 6 hours after treatment and no later than at least 1 hour prior to Day 2 visit. 
On Day 2 (Visit 2), all household members will return for general skin and eye assessments of 
possible irritation, and to confirm that all IP was left on for a minimum of 6 hours before bathing 
or showering. If a subject reports an adverse event assessed as related by the PI on Day 2 (Visit 
2) then a follow-up visit with the investigator must be scheduled within 7 days of visit. All 
household members will receive a well-being phone call on Day 14 to continue to emphasize 
instructions to prevent re-infestation, determine if any concomitant medications have been used, 
and check for adverse events.  If a subject reports an adverse event assessed as related by the PI 
on the Day 14 well-being phone call, then a follow-up visit with the investigator must be 
scheduled within 7 days of phone call. 
On Day 28 (Visit 3), all household members will return to the clinic for safety and efficacy 
assessments. The primary endpoint of complete cure as well as the key secondary endpoint to 
determine improvement based on lesion count will be assessed in the “index” subject and any 
infested household members. If the infested subject is completely cured at Day 28, he or she will 
have completed the study and termination procedures will be conducted. If the subject is not 
completely cured at Day 28 (with Natroba™ or Placebo), the subject will receive 5% Permethrin 
and will be directed to their primary care physician for follow-up. 


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Safety assessments will be made for all household members and will include monitoring of 
adverse events (AEs) throughout the study, vital signs recording (Days 1 and 28), and general 
skin and eye irritation assessments (Days 1, 2, and 28). 
The Day 28 procedures will also be completed for early termination (ET) except subjects will not 
receive rescue Permethrin but will be directed to follow-up with their primary care physician. 
The trial design is presented in the Study Flow Diagram (Figure 3-1) and the visit assessments 
are described in the Schedule of Procedures (Table 6-1). 
3.2 
Discussion of Study Design 
The phase 3 study design is a generally accepted clinical approach to provide sufficient pivotal 
results for the evaluation of safety and efficacy. The design for this trial is similar to the phase 3 
trials evaluating efficacy of Natroba™ Topical Suspension for treatment of head lice except that 
in this study the subjects will receive only one application of Natroba™ Topical Suspension.3 In 
the two phase 3 studies of individuals with lice, all subjects who were treated on Day 0 returned 
for efficacy evaluation at Day 7. Subjects with live lice present at Day 7 received a second 
treatment. Subjects who were lice free on Day 7 were to return on Day 14 for evaluation. 
Subjects with live lice and who received a second treatment on Day 7 were to return on Days 14 
and 21 for evaluation. Efficacy was assessed as the proportion of primary subjects who were free 
of live lice 14 days after the initial and/or final treatment. 
The primary efficacy endpoint will be the proportion of “index” subjects completely cured of 
scabies by Day 28 after a single application of IP on Day 1. In households where efficacy results 
are likely to be correlated, selecting one subject (“index” subject) from each unit provides for 
efficacy results that are more independent. These subjects are selected according to a consistent 
criterion; in this study “index” subjects will be defined as the youngest (≥4 years) infested 
member of the household. Thus the primary analysis population will be the “index” intent-to-
treat (I-ITT) population which is defined as all randomized “index” subjects regardless of 
whether they have had any post-baseline assessments and the primary efficacy endpoint will be 
the proportion of “index” subjects completely cured of scabies by Day 28. 
A large open-label, randomized, comparative, parallel clinical trial conducted in 315 patients 
with uncomplicated scabies assessed the efficacy and safety of topical Permethrin, oral 
ivermectin, and topical ivermectin.5 The first group received Permethrin 5% cream as single 
application, second group received tablet ivermectin 200 mcg/kg as single dose, and third group 
received ivermectin 1% lotion as single application. All the patients received anti-histaminic for 
pruritus. The patients were followed up at intervals of 1, 2, 3, and 4 weeks. Primary efficacy 
variable was clinical cure of lesions. Statistical analysis was done by chi square test and one-way 


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ANOVA test. At the end of first week, cure rate was 74.8% in Permethrin group, 30% in oral 
ivermectin group, and 69.3% in topical ivermectin group (P < 0.05). At the end of second week, 
cure rate was 99% in Permethrin group, 63% in oral ivermectin group, and 100% in topical 
ivermectin group (P < 0.05). At the end of third week, 100% cure rate was observed in 
Permethrin and topical ivermectin group while 99% in oral ivermectin group (P = 0.367). While 
oral ivermectin was found to be significantly less effective than the 2 topical treatments, there 
was no difference in effectiveness of topical Permethrin and topical ivermectin, each achieving a 
faster cure rate than oral ivermectin with one treatment. 
Based on the safety and efficacy of Natroba™ (spinosad) Topical Suspension (0.9%) in the 
treatment of head lice,3 and published trials of other scabicides,6,7,8 the present study is designed 
to evaluate pivotal phase 3 data on the safety and efficacy of a single topical application of 
NatrobaTM.  The effectiveness of Natroba™ (spinosad) will be compared to that of a Placebo 
control at 28 days. If complete cure is not attained at 28 days, 5% Permethrin will be 
administered to those subjects and the subjects will be directed to their primary care physician 
for follow up. 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS  
The study will enroll approximately 120 “index” subjects to ensure that at least 96 subjects 
complete the study. Subjects will be recruited from the general population, meeting criteria as 
described below. All subjects from a single household may be enrolled provided there are 6 or 
fewer members and all enrolled members meet the criteria below. All household 
members/parents/guardians will be asked to attend Visit 1 and to sign appropriate Informed 
Consent forms (IC). 
4.1 
Inclusion Criteria 
All household members who have provided written informed consent and an authorization for 
disclosure of protected health information must meet all of the following criteria to qualify for 
entry into the study: 
1. 
Male or female, age 4 years and upward. 
2. 
At least one household member must have active scabies infestation confirmed by 
clinical signs and symptoms (evidence of burrows or presence of scabies 
inflammatory/non-inflammatory lesions and pruritus) as well as by microscopic 
examination of skin scraping or dermatoscopy to demonstrate the presence of mites, 
eggs, and/or scybala. If dermatoscopy is used it should also confirm there are 
burrows on the skin. 
3. 
Generally in good health based on medical history and clinical assessments. 
4. 
Normal-appearing skin in noninfested areas. 
5. 
No history of chronic or recurrent dermatologic disease. 
6. 
Willingness to comply with the study procedures including application of study 
treatment at home as instructed. 
7. 
Willing and able to practice an acceptable measure of contraception during the 
study, if female of childbearing potential. Examples of acceptable contraceptive 
methods include abstinence, intrauterine device (IUD), double barrier method, oral 
or implantable or injectable contraceptives. Must have been using systemic (oral, 
injectable, or implantable) contraceptives for at least 3 months. If abstinent and 
planning to become sexually active must agree to use a double barrier method. 
8. 
Subject agrees to inform their sexual partners to seek an examination for scabies and 
treatment if, and when, symptoms present. 


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9. 
Household residents must be 6 or fewer and all residents must be willing to attend 
clinic visits and be randomized to treatment (blinded, but same for all). 
4.2 
Exclusion Criteria 
All household members must be excluded if any of the following conditions are met: 
1. 
Household has greater than 6 residents. 
2. 
Has a household member(s) who is not willing or not eligible to enroll. 
3. 
Presence of scabies on the scalp. 
4. 
Presence of crusted scabies (Norwegian scabies). 
5. 
Allergies or intolerance to ingredients in the investigational product (IPs). 
6. 
Current pregnancy (as assessed by urine pregnancy test) or currently nursing. 
7. 
The household has sexually active subjects who do not agree to restrict prolonged 
skin to skin contact with non-household members during the trial period. 
8. 
Known renal or hepatic impairment. 
9. 
Treatment with scabicide within the prior 4 weeks. 
10. Immunodeficiency (including HIV infection) as reported by the subject in Medical 
History. 
11. Signs or symptoms of systemic infection. 
12. Administration of systemic therapy for infectious disease within the prior 2 weeks. 
13. Receipt of any IP within the prior 4 weeks. 
14. Any other conditions that, at the investigator's discretion, may interfere with the 
study conduct, or which might confound the interpretation of the study results, or 
which may put the subject at undue risk. 
15. Does not have a known household affiliation with their household members (stays 
in one household inconsistently, i.e., sleeps at one place several nights and then 
other places on other nights). 
16. Household member is unwilling to treat scabies. 
4.3 
Subject Withdrawal Criteria  
Subjects may be removed from the study for reasons including the following: 
1. Significant protocol violation on the part of the Investigator or subject. 


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2. Significant noncompliance on the part of the subject as determined by the 
Investigator in consultation with the Medical Monitor. 
3. Subject withdrawal of consent. 
4. During the study, subject has the need for medications, supplements, or other products 
that are excluded (see Section 7.4, “Prohibited Medications”). 
5. Occurrence of any AE or condition that could, in the Investigator’s opinion, interfere 
with the evaluation of the treatment effect or put the subject at undue risk. 


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5 
STUDY TREATMENTS 
5.1 
Identity of Investigational Products 
The IPs for the study are Natroba™ (spinosad) Topical Suspension (0.9%) and Placebo 
control. Both of the IPs will be manufactured by Ei LLC, Kannapolis, NC and provided by 
ParaPRO LLC, Carmel, IN. 
Clinical packaging will be a 4-oz. High Density Polyethylene (HDPE) bottle with an orifice 
reducing plug and a screw on cap with liner. 
Natroba™ Topical Suspension contains 9 mg spinosad per gram in a viscous, slightly opaque, 
light orange colored vehicle consisting of water, isopropyl alcohol, benzyl alcohol, hexylene 
glycol, propylene glycol, cetearyl alcohol, stearalkonium chloride, ceteareth-20, hydroxyethyl 
cellulose, butylated hydroxytoluene, FD&C Yellow #6. The vehicle (Placebo) lacks spinosad. 
The methods used in, and the facilities and controls used for the manufacturing, processing, 
packaging, and holding of this drug substance conform with Current Good Manufacturing 
Practices (cGMP) in accordance with 21 CFR Parts 210 and 211. ParaPRO LLC will maintain 
certificates of analysis for each ingredient, documenting its purity and potency, and will 
provide Concentrics Research with Certificates of Analysis for both test and control products. 
The following will be printed on the product label (Appendix 1): 
 
 
 
5.2 
Investigational Product Storage and Accountability 
Investigational product will be stored at room temperature 15 ⁰C – 30 ⁰C (59 ⁰F – 86 ⁰F) in a 
locked area with limited access. 


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All IP will be shipped to the study site(s). The Principal Investigator or designee will inventory 
and acknowledge receipt of all shipments of IP. The Principal Investigator or designee must keep 
accurate records of IP via the master IP accountability logs and the subject IP accountability 
logs. The PI or designee must also maintain a record of all IP supplied to all subjects. The PI or 
designee must also maintain a record of 5% Permethrin supplied to household members for use 
as a rescue medication. Supplies of IP will be checked and accountability records will be 
reviewed by the Clinical Research Associate (CRA) at monitoring visits. The original, completed 
accountability logs will be collected by the CRA at the close of the study. At the end of the 
study, all unused, partially used, empty or unopened kits or bottles will be returned to ParaPRO 
LLC or its designee for destruction. A written explanation will be required for any missing 
product. 
Investigational supplies are to be used only in accordance with this protocol and under 
supervision of the Principal Investigator. All records must be available for inspection by 
Concentrics Research and ParaPRO LLC personnel or their designees, and are subject to 
inspections by the regulatory authorities (e.g., FDA) at any time. 
5.3 
Methods of Assigning Subjects to Treatment Groups 
As “index” subjects and other infested or non-infested household members become eligible for 
randomization at Visit 1 (Day 1), the site will locally assign a unique subject number to each of 
the qualified household members that combines a 3-digit site number (xxx), a 2-digit household 
number (yy), and a 2-digit household member number (zz). For example, the first subject of the 
first household at site 101 would be randomized to subject number 101-01-01, the second 
member to 101-01-02, the third member to 101-01-03, and so on. Since all household members 
receive the same treatment, each household is randomized to either Natroba™ (spinosad) or 
Placebo control. Non-infested household members will be assigned the same IP treatment as the 
infested members and will be assigned a subject number and randomization number. The 
assigned subject numbers to each household will correspond to unique bottle numbers on a 
scheme that unblinded site personnel will assign and distribute to ensure approximately equal 
randomization of households to either treatment. Subject numbers must not be re-used once 
assigned, even if the subject does not take the IP. 
5.4 
Administration of Investigational Product 
For both treatment groups, the blinded Natroba™ (spinosad) or Placebo control will be 
administered by the subject on Day 1 at the subject’s home. All “index” and other infested and 
non-infested household members will be assigned the same IP treatment, either blinded 
Natroba™ (spinosad) or Placebo control. The “index” subjects and all household members will 
be instructed to apply the IP over entire body from the neck down to the toes (including the soles 


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of the feet) and to the scalp (if balding) or hairline, temples, and forehead. Subjects should not 
shower for at least 6 hours after application. Subjects less than 12 years of age should be assisted 
with administration by a parent, guardian or caregiver. 
If complete cure is not achieved by Day 28 visit, 5% Permethrin will be dispensed to all uncured 
subjects and they will be directed to their primary care physician for follow up. All uncured 
subjects will be instructed to apply the 5% Permethrin as per manufacturer’s instructions. 
Subjects who early terminate (ET) will not receive 5% Permethrin and will be directed to their 
primary care physician for follow up. 
5.5 
Treatment Accountability and Compliance 
At Visit 1, each subject’s bottle of IP will be weighed and recorded (application instructions 
provided) as well as the height and weight of the subject before each subject takes the IP home. 
All household members will be provided with the same blinded study treatment. The IP will be 
applied at the subject’s home. 
Each subject’s bottle will be returned the next day at Visit 2. An accounting of the amount of IP 
used by the subject (by weight) will be documented by the clinic staff. At Visit 2, subjects will 
be asked to confirm that IP was applied from neck down and to the scalp (if balding) or hairline, 
temples, and forehead and washed/rinsed off no earlier than 6 hours after application, and no 
later than at least 1 hour before Visit 2. The used IP bottle will be collected at Visit 3 if not 
returned at Visit 2. 
If subjects are not completely cured by Visit 3 (Day 28), the 5% Permethrin and application 
instructions will be provided at this visit and subjects will be directed to follow-up with their 
primary care physician. 
5.6 
Blinding and Unblinding Method 
Eligible households will be assigned to either Natroba™ (spinosad) or Placebo control, by 
pre-specified un-blinded site personnel. The un-blinded site personnel will assign all eligible 
members from the same household to the same treatment group. While the treatment bottles for 
each household will have unique numbers, the numbers for that household will correspond to a 
specific treatment, Natroba™ (spinosad) or Placebo control. Un-blinded site staff will maintain 
the randomization scheme with treatment code and associated bottle numbers, and will not reveal 
the information to the subjects, blinded study personnel or ParaPRO LLC until after the database 
lock. 
In an emergency, the study blind may be broken only if: 


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• in the opinion of the investigator and/or the Medical Monitor, it is in the subject's best 
interest to do so; 
• knowledge of the treatment will alter the clinical management of the subject; 
• approval has been granted by the Medical Monitor and/or ParaPRO LLC. 
Whenever possible, the Medical Monitor should be notified prior to unblinding a treatment 
assignment. In the event that unblinding is necessary for the medical management of the subject, 
the pre-specified un-blinded site personnel will access the randomization code by a treatment 
code list provided by Concentrics Research to each site. If a treatment assignment is unblinded, 
the date and reason for the unblinding must be recorded on the subject’s source document, and 
the Medical Monitor notified within 24 hours. The emergency contact telephone number for the 
Medical Monitor, Dr. William Miller, is (800) 210-5734. If Dr. Miller’s phone is not answered at 
the time of your call, PLEASE leave a message so Dr. Miller can return your call immediately. 
For those subjects not completely cured by Day 28, 5% Permethrin will be dispensed and the 
subjects will be directed to their primary care physician for follow up. 
 
 
 
 


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6 
SCHEDULE OF PROCEDURES AND ASSESSMENTS 
Table 6.1 represents the schedule of procedures and assessments at each of the scheduled visits. Details of each visit 
are provided in Sections 6.1 through 6.5. 
Table 6-1 
SCHEDULE OF PROCEDURES AND ASSESSMENTS 
Period 
Screening,  
Randomizat
ion and 
Treatment 
Treatment/Follow-up 
Visit 
1 
2 
AE 
follow-
up 
Phone 
Call 
AE 
follow-
up 
3 
Day ± 
1 
2 
3+6 
14 ± 2 
14 +712 
28 ± 
2/ET 
Informed consent 
X 
 
 
 
 
 
Prior medications 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Urine pregnancy test1 
X 
 
 
 
 
X 
Scabies diagnosis2 
X 
 
 
 
 
 
Efficacy assessments3 
 
 
 
 
 
X 
Vital signs4 
X 
 
 
 
 
X 
General skin assessment5 
X 
X 
 
 
 
X 
Eye irritation assessment5 
X 
X 
 
 
 
X 
Review eligibility criteria 
X 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
Weigh and dispense IP bottle; 
provide application instructions6 
X8 
 
 
 
 
 
Instruct on waiting ≥6 hrs post-
treatment (IP) before showering6 
X 
 
 
 
 
 
Collect and weigh used IP bottle 
 
X 
 
 
 
 
Review subject compliance7 
 
X 
 
 
 
X8 
Instructions to prevent re-
infestation 
X 
X 
 
X 
 
 
Concomitant medications 
 
X 
 
X 
 
X 
Adverse events9 
 
X 
X11 
X 
X11 
X 
5% Permethrin dispensed to 
subjects not completely cured at 
Day 28 
 
 
 
 
 
X10 
ET = Early Termination; IP = investigational product.  
1. Only for females of childbearing potential. 
2. Scabies diagnosis (Inclusion #2) – At least one household member with active scabies infestation 
confirmed by clinical signs and symptoms (evidence of burrows or presence of scabies inflammatory/non-
inflammatory lesions and pruritus) as well as by microscopic examination of skin scraping or dermatoscopy 


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to demonstrate the presence of mites, eggs, and/or scybala. If dermatoscopy is used it should also confirm 
there are burrows on the skin. 
3. Primary Endpoint – Complete cure is defined as demonstration of clinical cure (all signs and symptoms 
have completely resolved, including inflammatory/non-inflammatory lesions and pruritus) and microscopic 
or dermatoscopic cure with demonstration of the absence of mites, eggs, and/or scybala, and dermatoscopy 
negative for burrows.  
4. Vital signs – height (only Visit 1), weight, blood pressure (BP), and heart rate. 
5. Assessment at Visit 1 for eligibility (skin) and eye for baseline, Visit 2 for skin and eye irritation 
assessments and to confirm IP was washed off, and Visit 3/ET (if applicable) for skin and eye irritation. 
See Section 7.7 for rating eye irritation. 
6. IP Treatment – dispense IP and instruct subject to administer single topical application of IP over entire 
body from the neck down to the toes (including soles of the feet) and on the scalp/hairline, temples and 
forehead while at home. Subjects will not shower for at least 6 hours after application and no later than at 
least 1 hour before Day 2 visit. Subjects less than 12 years of age should be assisted with administration by 
a parent, guardian or caregiver. 
7. Confirm that all IP was left on for a minimum of 6 hours before bathing or showering and washed off at 
least 1 hour before Day 2 visit. Instruct/re-instruct subjects how to prevent re-infestation, to stay in one 
household, as well as to follow all study procedures and expectations. 
8. Collect and weigh used bottle if not collected at Visit 2. 
9. Assessed starting post-treatment. Investigators will follow all AEs until the final study visit (Day 28). All 
SAEs, and all AEs deemed by the Investigator to be related to IP or treatment, will be followed until the 
event has resolved (even if beyond Day 28). 
10. Subjects who are not completely cured at this visit (Day 28) will be provided with 5% Permethrin as rescue 
medication. Subjects who terminated early will not receive rescue medication. All subjects will be directed 
to their primary care physician for follow-up. 
11. If a subject reports an adverse event assessed as related by the PI on Day 2 (Visit 2) then a follow-up visit 
with the investigator must be scheduled within 7 days of visit.  If a subject reports an adverse event 
assessed as related by the PI on the Day 14 well-being phone call, then a follow-up visit with the 
investigator must be scheduled within 7 days of phone call.    
12. It is intended for the AE follow-up to occur within 7 days of the day 14 call.  The Day 14 call may occur 
between study day 12 and 16. 
 
 


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6.1 
Screening, Randomization and Treatment (Visit 1; Day 1) 
Procedures as identified in Table 6-1: 
• Informed consent 
• Prior medications 
• Medical history 
• Urine pregnancy test (females of child-bearing potential only) 
• Scabies assessment 
• Vital signs (height at Visit 1 only)  
• General skin assessment for eligibility 
• Eye assessment 
• Review eligibility criteria 
• Randomization 
• Weigh, dispense and instruct on IP application at home the same day*  
• Instruct on showering ≥6 hours post-treatment and at least 1 hour prior to Visit 2 
• Instructions to prevent re-infestation 
• Concomitant medications 
*Subjects less than 12 years of age should be assisted with administration by a parent, guardian 
or caregiver. 
6.2 
Follow-up Safety Assessment Visit (Visit 2, Day 2) 
• General skin and eye assessments for irritation and wash-off confirmation 
• Collect and weigh used IP bottle 
• Confirm compliance 
• Instructions to prevent re-infestation 
• Concomitant medications 
• Adverse events 
 


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6.3 
AE Follow-up Visit (Day 3 + 6 days; conducted only if a subject reports an adverse 
event assessed as related by the PI on Day 2) 
• PI assessment of reported AE 
6.4 
Phone Call (Day 14 +/- 2 days) 
• Instructions to prevent re-infestation 
• Concomitant medications 
• Adverse events 
6.5 
AE Follow-up Visit (Day 14 + 7 days; conducted only if a subject reports an adverse 
event assessed as related by the PI on the Day 14 well-being phone call) 
• PI assessment of reported AE 
6.6 
Final Visit (Visit 3/ET, Day 28 + 2 days) 
• Urine Pregnancy Test (females of child bearing potential) 
• Efficacy assessments  
• Vital signs 
• General skin and eye assessments for irritation  
• Review subject compliance 
• Concomitant medications 
• Adverse events 
• If subjects are not completely cured at this visit (Day 28), those subjects will be 
provided 5% Permethrin as rescue medication. 
• For those subjects with an ET visit, 5% Permethrin will not be dispensed and the 
PI will refer the subject to their primary care physician for follow-up. 
6.7 Early Termination Procedures 
The term "Early Termination" refers to a subject’s non-completion of a study whether by his or 
her own choice or the investigator’s decision or due to discontinuation of the study by ParaPRO 
LLC. In the absence of a medical contraindication or significant protocol violation, every effort 
will be made by the Investigator to keep the subject in the study. Should the subject decide to 
withdraw, an early termination visit should be conducted, which will include all procedures 


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normally done at Visit 3. The ET subject will not be dispensed 5% Permethrin and the PI will 
refer the subject to their primary care physician for follow-up. 
The primary reason for a subject withdrawing prematurely should be selected from the 
following categories: 
Adverse Event or Serious Adverse Event—events that are associated with discontinuation. 
Noncompliance with protocol—the subject failed to adhere to the protocol requirements. The 
deviation necessitated premature termination from the study. 
Withdrawal of Consent—subject desires to withdraw from further participation in the study in 
the absence of an adverse event or a medical need to withdraw. 
Lost to Follow-up—the subject did not return for one or more follow-up visit(s) following 
dispensing of test drug. The reason was unknown and appropriate due diligence was exerted 
by the investigator to contact the subject and encourage their return. 
Other—causes of premature termination from the study other than the above, such as theft or 
loss of IP, termination of study by ParaPRO LLC, etc. The details of the premature 
termination in this “other” category should be documented fully. 
The investigator should notify Concentrics Research promptly when a subject is withdrawn, or if 
the study is stopped at his/her site by the IRB or if the investigator elects to stop the study. 
6.8 
Subject Completion Criteria 
Successful completion of the study by “index” subjects will occur at Day 28 (Visit 3) if the 
“index” subject is completely cured of scabies. Other household members will complete the 
study at Day 28 after safety assessments are completed.  
6.9 
Protocol Deviations 
This study is intended to be conducted as described in this protocol. Any changes/deviations to 
the protocol must be reported to the IRB (Schulman IRB Cincinnati, OH 45242). In the event of a 
significant deviation from the protocol due to an emergency, accident, or mistake, the investigator 
or designee must also notify the Medical Monitor within 24 hours from when the deviation was 
identified. 


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7 
DETAILED DESCRIPTION OF ASSESSMENTS 
7.1 
Informed Consent 
Written informed consent will be obtained from subjects who are 12 years of age and older as 
well as the parent or legal guardian of subjects who are 4-17 years of age before any study 
procedures are performed. In addition to the parent or legal guardian signing the informed 
consent, verbal and written assent will be obtained from subjects who are between the ages of 7-
11 years of age. Assent is not required for subjects 4-6 years of age; however, the parent or legal 
guardian must sign consent. All potential subjects for the study (or their legal guardians) will be 
given a copy of the Institutional Review Board (IRB)-approved informed consent form to read. 
The IRB is Schulman IRB (Cincinnati, OH 45242). 
The assent and/or consent forms will be discussed in detail with each potentially eligible subject 
and the parent or legal guardian of subjects 4-17 years of age, if applicable. The PI or qualified 
designee will explain all aspects of the study in lay language and answer all the subject's 
questions regarding the study. The PI or designee will inform the subject as to the nature, aims, 
duration, potential hazards, and procedures to be performed during the study and that his or her 
medical records may be reviewed. The PI or designee will also explain that the subject is 
completely free to refuse to enter the study or to withdraw from it at any time. Subjects who 
refuse to participate or who withdraw from the study will be treated without prejudice. 
No study procedures will be performed nor IPs released to any subject who has not signed the 
assent or IC form or whose parent or legal guardian has not signed the IC form. 
7.2 
Medical History 
A complete medical history will be obtained at Screening (Visit 1). 
7.3 
Prior Medications and Concomitant Medications 
Investigator’s need to be aware that patients often have severe pruritus and will be prescribed 
medications as well as take OTC medications to treat this condition. The PI needs to inform 
the subject of prohibited topical medications used for itching or other indication, including 
over-the-counter (OTC) cortisone products, as these may interfere with efficacy evaluations. 
Non-medicated lotions are allowed after IP is washed off (e.g., non-scented, hypoallergenic, 
etc.). Subjects will be instructed not to take any oral prescription medications without prior 
consultation with the Investigator unless their primary physician otherwise instructs. Oral 
Benadryl® (diphenhydramine) and other oral OTC anti-pruritics are allowed for itch relief. 
Subjects will be instructed to tell their primary physician of their participation in this study if 
they consult their physician during the study. Any therapy taken by the subject in the 4 weeks 
before randomization (Visit 1) will be reported as prior medication. Any therapy started or 


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stopped by the subject during the study after randomization will be regarded as concomitant 
therapy. 
All prior and concomitant medications including topical treatments (prescription and over the 
counter, vitamins, and mineral supplements, and/or herbs) will be documented and must include 
the following information: 
• Medication name 
• Indication 
• Start date 
• Stop date or “Ongoing” 
7.4 
Prohibited Medications 
Subjects should not use any scabicide within 4 weeks before Visit 1, or use any scabicide, or 
rescue Permethrin, prescription or OTC medicated lotions, other than the IP during the study, 
through Day 28. There will be no washout of prohibited medications, subjects will be excluded 
or withdrawn from the study for use of prohibited medications. 
7.5 
Pregnancy and Contraceptive Use 
Urine pregnancy tests will be conducted on women of childbearing potential at screening (Visit 
1) and end of study (Visit 3/ET). Such subjects should be willing and able to practice an 
acceptable method of contraception during the study. Examples of acceptable contraceptive 
methods include abstinence, intrauterine device (IUD), double barrier method, oral or 
implantable or injectable contraceptives. Must have been using systemic (oral, injectable, or 
implantable) contraceptives for at least 3 months. If abstinence is their primary method of birth 
control they should be instructed to use a double barrier method if they become sexually active 
with another household member. 
7.6 
Scabies Assessment 
Skin will be examined at Visits 1 and 3/ET to establish positive or negative evidence of active 
scabies infestation.  
• Scabies diagnosis – active scabies infestation confirmed by clinical signs and symptoms 
(evidence of burrows or presence of scabies inflammatory/non-inflammatory lesions and 
pruritus) as well as by microscopic examination of skin scraping or dermatoscopy to 
demonstrate the presence of mites, eggs, and/or scybala. If dermatoscopy is used it should 
also confirm there are burrows on the skin.  


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• Primary Efficacy Endpoint – complete cure is defined as demonstration of clinical cure 
(all signs and symptoms have completely resolved, including burrows, 
inflammatory/non-inflammatory lesions and pruritus) and microscopic or dermatoscopic 
cure with demonstration of the absence of mites, eggs, and/or scybala, and dermatoscopy 
negative for burrows. 
7.7 
General Skin and Eye Assessments 
At Visit 1, the skin will be assessed to determine eligibility – no evidence of crusted scabies, 
normal skin in non-infested areas. At Visits 1, and 2, the skin and eye assessments will include 
documentation of presence or absence of irritation, and verbal subject-reported verification that 
the treatment topical suspension remained on for at least 6 hours before being washed off. At 
Visit 3/ET, skin and eye assessments will include evidence of irritation. 
Eye irritation will be rated: 
0 
no irritation 
1 
mild scleral, lid and/or conjunctiva injection 
2 
moderate scleral and or lid injection with conjunctival erythema 
3 
severe scleral and/or lid injection with conjunctival erythema and purulent drainage 
7.8 
Application of IP 
The bottle will be weighed before and after application. One bottle of IP (blinded Natroba™ 
[spinosad] or Placebo control) contains 4-oz. of treatment product. The subject should use as 
much of one bottle as needed. The subject should apply a thin layer of IP from the neck down to 
the toes (including soles of the feet) and to the scalp (if balding) or hairline, temples, and 
forehead at their home on the same day it is dispensed on Visit 1. The IP should be allowed to 
soak into the skin or dry for 10 minutes before getting dressed. Subjects less than 12 years of age 
should be assisted with administration by a parent, guardian or caregiver. Showering or bathing 
should occur no earlier than 6 hours after treatment and no later than at least 1 hour before Visit 
2. 
7.9 
Vital Signs 
Height (Visit 1 only), weight, resting blood pressure (BP) and heart rate will be measured at 
Visits 1 and 3/ET. 
7.10 Eligibility Review 
Eligibility criteria will be reviewed at Visit 1 prior to randomization, and the subject should 
qualify prior to randomization. 


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Screen Failure: A screen failure is defined as a subject who consented but who has not been 
randomized. Screen failures may re-screen after review and approval by the sponsor. Re-
screening may also be necessary due to timing/scheduling or washout of other treatments (except 
scabicides which exclude the subject) that may have occurred within the prior 4 weeks. 
7.11 Randomization and Treatment Assignment 
Eligible subjects will be assigned to either treatment group, Natroba™ (spinosad) or Placebo 
control, by pre-specified un-blinded site personnel that may perform no other study specific 
duties. The un-blinded site personnel will assign all members from the same household to the 
same treatment group. The assigned subject numbers in each household will correspond to 
unique bottle numbers on a scheme that unblinded site personnel will assign and distribute to 
ensure approximately equal randomization of households to either treatment. Subjects, blinded 
site personnel and ParaPRO LLC will remain blinded to the treatment until after database lock. 
Randomization will be stratified by study site. 
7.12 Counseling to Prevent Re-Infestation 
 
Subjects should be informed about methods to minimize risk of re-infestation: including 
avoiding skin contact with others who are infested and avoiding bedding or linens of an infested 
person, and simultaneous treatment of all household contacts. The following information from 
the Centers for Disease Control and Prevention may be used as reference: 
“When a person is infested with scabies mites the first time, symptoms may not appear for up to 
two months after being infested. However, an infested person can transmit scabies, even if they 
do not have symptoms. Scabies usually is passed by direct, prolonged skin-to-skin contact with 
an infested person. However, a person with crusted (Norwegian) scabies can spread the 
infestation by brief skin-to-skin contact or by exposure to bedding, clothing, or even furniture 
that he/she has used. 
Scabies is prevented by avoiding direct skin-to-skin contact with an infested person or with items 
such as clothing or bedding used by an infested person. Bedding and clothing worn or used next 
to the skin anytime during the 3 days before treatment should be machine washed and dried 
using the hot water and hot dryer cycles or be dry-cleaned. Items that cannot be dry-cleaned or 
laundered can be disinfested by storing in a closed plastic bag for several days to a week. Scabies 
mites generally do not survive more than 2 to 3 days away from human skin. Children and adults 
usually can return to child care, school, or work the day after treatment.” 


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7.13 Prophylactic and Rescue 5% Permethrin 
All household members that are not infested at the screening visit will be given the same blinded 
study treatment as household members that are infested.  Subjects not cured at Day 28 will be 
provided with 5% Permethrin as rescue medication, which is the recommended treatment per the 
current standard of care, and will be directed to their primary care physician for follow-up. 
Subjects with an ET visit will not receive rescue medication and will be directed to their primary 
care physician for follow-up. 
7.14 Study Compliance 
Study compliance will be confirmed at Visit 2. 
 
 


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8 
STATISTICAL METHODS 
8.1 
Sample Size Determination 
Approximately 120 “index” subjects will be enrolled (including possible 20% attrition) from 120 
households and randomized 1:1 to each of Natroba™ (spinosad) and Placebo control. The index 
subject will be the youngest infested member of a household (≥4 years). Referencing to the 
Sponsor’s Proof of Concept (POC) study (SPN-401-12) and published literature,5-10 out of 60 
completed subjects, the cure rate is 70% for Natroba™ and 30% for Placebo control.  Based 
upon a reasonable assumption of 60% cure rate for Natroba™ and 30% for placebo, a sample 
size of 48 study-completed “index” subjects per group will provide 80% power to declare the 
non-equivalency using a delta of 30% and Type I error rate of 0.05.  Fisher exact test was used to 
calculate the sample size and the specified power in the following Table 8-1 (PASS 14; 2015, 
NCSS, LLC., Kaysville, Utah, USA. www.ncss.com). 
Table 8-1 
SAMPLE SIZE NEEDED TO DECLARE NON-EQUIVALENCY WITH 
RESPECT TO THE PROPORTION OF SUBJECTS ACHIEVING COMPLETE CURE WITH A 
TYPE I ERROR RATE=0.05 AND SPECIFIED POWER 
Proportion in 
Required 
Sample Size per 
Group 
Power 
Natroba TM 
Placebo 
Difference vs. 
Placebo 
55% 
30% 
25% 
69 
80.4% 
60% 
30% 
30% 
48 
80.0% 
65% 
30% 
35% 
37 
80.6% 
Assuming a drop-out rate could be at most 20%, 120 subjects should guarantee at least 48 
evaluable subjects for each treatment group at Day 28 assessment. 
8.2 
Randomization 
This study will investigate 2 treatment groups: Natroba™ (spinosad) Topical Suspension, 0.9% 
or Placebo control. A randomization scheme will be used locally at each site (stratified by study 
site) to obtain a balanced allocation of treatments (approximately 1:1) to the households. 
 
 
 


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8.3 
Analysis Populations 
Safety Population 
The safety population will comprise all subjects who received one dose of IP. Subjects will be 
analyzed as treated. The safety population includes the “index” subjects along with any 
household members enrolled in the study. All safety analyses will utilize the safety population. 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will comprise all subjects who were randomized regardless 
of whether they have post-baseline assessments. Subjects will be analyzed as randomized. This 
population includes the “index” subjects along with any household members enrolled in the 
study. 
Index Intent-to-Treat Population 
The “index” intent-to-treat (I-ITT) population will comprise all index subjects who were 
randomized. Subjects will be analyzed as randomized. The index subject will be the youngest 
infested member of a household (≥4 years). This analysis population will be used for the efficacy 
analysis. 
Index Per Protocol Population 
The “index” Per Protocol (I-PP) population is a subset of the I-ITT population. Index subjects 
will be excluded from the I-PP population for the following reasons: 
1. Protocol deviations that would be in violation with the established Inclusion or 
Exclusion Criteria. 
2. Protocol deviations that could confound the evaluation of efficacy outcomes:  
o Scabies assessment not performed (i.e. burrows, lesions, pruritis, skin 
scraping).  
o Subject received the wrong treatment. 
o Discontinuation prior to acquisition of Visit 3 (Day 28) efficacy 
measurements. 
3. Protocol deviations that are a result of subject non-compliance:   
o Missed Day 2 appointment. 
o Use of another scabicide during the study. 
o Use of prescription or OTC medicated lotions during the study. 
Prior to database lock, a memo will be generated identifying any subjects that were excluded 
from the I-PP population along with the reason why they were excluded. 
 


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8.4 
Missing Values 
There will be no imputation for missing events and assessments in handling safety data. 
If a subject has observed data for complete cure at Day 28, the observed cases (OC) will be used 
at Day 28.  If a subject discontinues the study before Day 28, the imputation method for 
complete cure at Day 28 depends on the reasons of missing, i.e. informative or non-informative 
missing.  Please refer to the SAP for more details.  
For other missing efficacy data at Day 28 (e.g., clinical cure, microscopic cure, new lesions and 
total lesions), Last Observation Carried Forward (LOCF) imputation will be used.  
Details of imputation rules for efficacy analyses and other missing data handling conventions 
will be included in the SAP. 
8.5 
Statistical Analyses 
A statistical analysis plan (SAP), in addition to this section of the study protocol, will describe 
statistical methodology for analyses and data reporting. A version of the SAP will be prepared at 
the same time as the protocol is finalized. However, the primary and secondary efficacy 
endpoints and analyses on them will not be altered unless agreed upon with the FDA. SAP will 
be finalized before the database is unblinded. 
Data collected in this study will be presented using summary tables, figures, and subject data 
listings. Summary tables will present data by treatment group and, if applicable, by scheduled 
time of data collection. Continuous variables will be summarized using descriptive statistics, 
presenting the number of subjects, mean, standard deviation, median, minimum, and maximum. 
Categorical variables will be summarized by frequencies and percentages. Figures may be used 
to support the presentation of certain data. 
For efficacy analyses, small study sites may be pooled together. Details on the pooling 
algorithms are provided in Section 8.5.3.3. 
All statistical tests and confidence intervals will be 2-sided at an alpha level of 0.05. 
 
8.5.1 Subject Disposition 
The tabulation of number of subjects in each treatment group and overall will be displayed for all 
subjects who are screened, randomized, and in each analysis population.   
The number and percent of subjects who completed or discontinued the study will be displayed 
for each treatment group and overall together with reasons for early termination. Percentages will 
be based on the total number of randomized subjects in each treatment group and overall. 


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8.5.2 Demographics and Baseline Characteristics 
Descriptive statistics will be provided for demographic and baseline characteristics (gender, age, 
race/ethnicity, baseline assessments of scabies infestation, previous infestations, and microscopic 
results).  
8.5.3 Efficacy Analyses 
8.5.3.1 Primary Efficacy 
The primary efficacy endpoint is the proportion of index subjects completely cured of scabies by 
Day 28. Complete cure is defined as demonstration of clinical cure (all signs and symptoms have 
completely resolved, including burrows, inflammatory/non-inflammatory lesions and pruritus) 
and microscopic or dermatoscopic cure with demonstration of the absence of mites, eggs, and/or 
scybala, and dermatoscopy negative for burrows. 
The primary analysis will be based on the data by Day 28 from the I-ITT population. The 
number and percentage of index subjects who exhibit complete cure (Yes or No) at Day 28 will 
be summarized by treatment group. A Cochran-Mantel-Haenszel general association test adjusted 
by study site (small sites pooled) stratification will be performed to compare the complete cure 
rates between the two treatment groups.  
Sensitivity analyses will be performed on the primary efficacy endpoint to evaluate the 
robustness of the results using different methods of analysis. 
A logistic regression analysis will be used assessing the treatment group differences.  The model 
will include clinical site and treatment group as factors, and possibly additional baseline 
characteristics or a covariate, if appropriate.   
Other additional sensitivity analyses include repeating the above analyses on I-PP population and 
ITT population. 
8.5.3.2 Exploratory Efficacy 
All exploratory efficacy endpoints will be summarized by the treatment group at each scheduled 
visit.  Descriptive statistics for continuous variables consists of mean, standard deviation (SD), 
median, minimum, and maximum. For categorical variables, numbers and percentages will be 
summarized.  
Additional analysis may be performed as appropriate for the following exploratory efficacy 
endpoints.   
 


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Clinical Cure 
Clinical cure is the proportion of subjects who exhibit clinical cure at Day 28.  
Clinical cure is defined as having all signs and symptoms completely resolved, including 
inflammatory/non-inflammatory lesions and pruritus. 
A Cochran-Mantel-Haenszel general association test adjusted by study site (small sites pooled) 
stratification will be performed to compare the complete cure rates between the two treatment 
groups. 
This analysis will be performed on the I-ITT population. 
Microscopic Cure 
Microscopic cure is defined as microscopic or dermatoscopic demonstration of the absence of 
mites, eggs, and/or scybala, and negative for burrows. 
The number and percent of subjects who exhibit microscopic cure (Yes or No) at Day 28 will be 
presented by treatment group.  
Additional analyses can be performed on the I-ITT population by applying a logistic regression 
model adjusted for baseline factors.  
Number of New Lesions 
The number of new lesions at Day 28 will be analyzed using a negative binomial regression 
model to compare the treatment difference. The model will include treatment group and study 
site (small sites pooled) as fixed factors, and baseline total lesion count as a covariate.   
This analysis will be performed on the I-ITT population.  
Total Lesion Counts 
Total lesion counts will be calculated as the sum of pre-existing lesions and new lesions. The 
baseline captures the total lesions on the day of first study drug administration.  
The change from baseline to Day 28 will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment and study site (small sites pooled) as factors and baseline total 
lesion counts as a covariate.  
This analysis will be performed on the I-ITT population.  
 
Complete Cure in ITT subjects who were infested at baseline 


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A subset of subjects in ITT population who were infested at baseline will be summarized to 
display the proportion of the completely cured subjects. 
More analysis can be performed to further examine the treatment differences for this subset of 
ITT subjects. Details will be provided in the SAP.   
8.5.3.3 Pooling of Study Sites 
This is a study conducted at multiple study sites.  Every effort will be made to have each site 
enroll at least 8 subjects per arm.  In case there are “small” sites with fewer-than-8 “index” 
subjects, these sites will be pooled together as a single, combined site for efficacy analyses if the 
combined site has at least 8 “index” subjects per arm.  In the situation when the combined site 
still has less than 8 “index” subjects per arm, the smallest site with at least 8 “index” subjects per 
arm will be pooled to this combined site for efficacy analyses.  The complete cure rates at Day 
28 will be summarized descriptively by treatment groups and by sites before and after pooling 
the sites.  Assessment of site-to-site variability will be conducted on the original sites prior to 
pooling.  In addition, the above demographics and baseline characteristics will be presented by 
site before and after pooling sites. 
8.5.4 Safety Analyses 
Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by System Organ Class (SOC) and Preferred Term (PT) for each treatment 
group. All AEs will be captured throughout the study period from the enrollment to the final visit 
(Visit 3) or the ET visit. Any AEs reported before treatment will be captured as medical 
history. AEs that occur after the first dose of study treatment will be considered as treatment-
emergent adverse events (TEAE). Within each SOC or PT, subjects will be counted only once 
if they had one or more than one event reported during the treatment period (the subject is 
counted for the event with the greatest severity).  
Adverse events will be summarized by presenting: 
• the number and percentage of subjects experiencing any TEAE 
• the number and percentage of subjects experiencing any TEAE grouped by SOC 
and PT 
• the number and percentage of subjects experiencing any SAE 
• the number and percentage of subjects experiencing any TEAE grouped by SOC 
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• the number and percentage of subjects experiencing any TEAE grouped by SOC 
and PT and maximum relationship to IP 
• the number and percentage of subjects experiencing any TEAE leading to study 
medication discontinuation. 
• The number and percentages of subjects experiencing any unexpected life-
threatening adverse reaction 
A listing will be produced for all subjects who reported SAEs or who discontinued study 
medication due to TEAEs. 
All AEs (ie, pretreatment AEs and TEAEs) will be listed by subject. However, only TEAEs will be 
included in the summary tables. 
General Skin and Eye Irritation Assessments 
Skin and eye irritation will be captured as adverse events, as defined in Section 9.1. Eye 
irritation assessment ratings will be summarized descriptively for each treatment group by 
visit. 
Vital Signs  
Vital signs will be summarized descriptively for each treatment group by visit for the observed 
value as well as for the change from baseline value. 
Prior and Concomitant Medications  
The number and percent of subjects who took prior medications will be summarized 
descriptively by the ATC class and Preferred Term as coded in the WHO-Drug dictionary 
(WHO-DD) for each treatment group. Concomitant medications will be summarized similarly.  


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9 
ADVERSE EVENT MONITORING 
9.1 
Definition 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
(vital signs, physical change, etc.) following the subject’s first dose of IP that does not 
necessarily have a causal relationship with this treatment. An AE can be any unfavorable or 
unintended sign (including an abnormal finding on vital signs, physical change, etc.), 
symptom, or disease temporally associated with the use of an IP, whether or not related to the 
IP. 
This includes any adverse occurrence that is new in onset or aggravated in severity, duration or 
frequency from the baseline condition (including the physical examination), or abnormal results 
of diagnostic procedures (including vital sign abnormalities). 
Examples of untoward medical events that should be considered AEs are those that: 
• resulted in discontinuation from the study, 
• required treatment or any other therapeutic intervention, 
• required further diagnostic evaluation (excluding a repetition of the same 
procedure to confirm the abnormality), 
• are associated with clinical signs or symptoms judged by the Investigator to 
have a significant clinical impact. 
Examples of what an AE is not: 
• A surgical procedure 
• A situation where an untoward event did not occur, (e.g. a social hospitalization) 
• The disease being studied, unless progression is more severe than anticipated 
• Lack of efficacy 
• Baseline conditions that have not worsened in severity or frequency 
• Abnormal findings or test results (unless considered clinically significant in the 
opinion of the investigator or specifically defined elsewhere in the protocol) related 
to the disease being studied (unless more severe than expected). 
9.2 
Procedures 
Subjects will be queried at every visit through the last visit regarding the occurrence and nature 
of any AEs. All AEs will be reported, whether or not they are deemed to be related to IP. 


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A description of the event or diagnosis including dates, severity, relationship to the IP, action 
taken and outcome, and whether or not the event was also serious, must be reported on the AE 
Case Report Form (CRF) for each adverse event recorded in the subject’s chart. 
9.3 
Severity 
Adverse events are graded according to seriousness and severity. The seriousness of an event is 
determined by the regulatory criteria in Section 9.7.  
The Investigator will evaluate the severity of each AE. Adverse event severity will be graded as 
follows: 
Mild:   
Awareness of symptoms but easily tolerated  
Moderate: 
Discomfort enough to interfere with but not prevent daily activity 
Severe: 
Unable to perform usual activity 
9.4 
Relationship 
The Investigator will judge the likelihood that the AE was related to the IP according to the 
following criteria: 
• Not related: There is no possible temporal and/or causal relationship to the IP. 
• Related: There is a possible temporal and/or causal relationship to the IP. 
9.5 
Action Taken and Outcome 
The Action Taken with IP for every AE will be reported as Dose Not Changed or Dose 
Withdrawn. The Outcome of each AE will be entered as either: Recovered/Resolved, 
Recovered/Resolved with Sequelae, Not Recovered/Not Resolved, Fatal, or Unknown. 
9.6 
Adverse Event Follow-up 
Investigators will follow unrelated AEs until the final study visit (Day 14 or Day 28). All SAEs, 
and AEs deemed by the Investigator to be related to IP or treatment, will be followed until the 
event has resolved. 
9.7 
Serious Adverse Events 
An AE that results in any of the following outcomes is serious: 
• Death (note that death is the outcome of an SAE and the cause of death should be listed as 
the AE) 
• Life-threatening event. An event, in the view of either the investigator or sponsor, which 
places the patient or subject at immediate risk of death. (It does not include an adverse event 


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or suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death) 
• In-patient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity, permanent damage or disability or substantial 
disruption of the ability to conduct normal life functions 
• Congenital anomaly or birth defect 
• Other important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, it may jeopardize the subject or may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
Hospitalization for elective surgery for a prior condition that did not worsen or for social 
reasons will not be treated as serious. 
9.7.1 Serious Adverse Event Reporting 
Any SAE which occurs after the first dose is administered until the last visit must be reported to 
Concentrics Research whether or not it is judged related to the IP. Concentrics Research must be 
notified within 24 hours after the site/investigator becomes aware of the SAE. Concentrics 
Research has the responsibility to notify ParaPRO LLC of the event. 
If the Principal Investigator determines that the event is serious, the following procedures are to 
be implemented: 
• 
The Investigator will report the SAE directly to Concentrics Research via the SAE fax 
number (317-672-1271), and/or by emailing to 
gio.events.reporting@concentricsresearch.com . 
Concentrics Research’s Medical Monitor contact is: 
Medical Monitor 
 
William Miller, MD 
 
Medical Director 
 
Concentrics Research 
 
9335 Delegates Row 
 
Indianapolis, IN  46240 
 
Cell: 800-210-5734 
 
Email: bill.miller@concentricsresearch.com 
 
• 
Investigator will provide, at a minimum, the protocol number, subject’s initials, subject 


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number, date of the SAE, SAE term and relationship to IP. The SAE report form should be 
submitted with any supporting data available or copies of CRF pages. 
Schulman IRB will be notified of the SAE by the site within the timeframes described below: 
1. Unanticipated problems that are serious adverse events should be reported to the 
IRB within 10 business days of the investigator becoming aware of the event 
2. Any other unanticipated problem should be reported to the IRB within 10 
business days of the investigator becoming aware of the problem. 
An initial report followed promptly by a complete report will be forwarded Schulman IRB. 
9.7.2 Serious Adverse Event Follow-up 
Investigators will follow all SAEs until the SAE has resolved. 
The Investigator and Medical Monitor will determine if additional follow-up is required. 
Follow-up information relating to an SAE must be submitted to Concentrics Research as soon 
as additional data related to the event are available. All efforts must be taken to obtain follow-
up information promptly. 
Follow-up information may consist of: 
• A hospital discharge summary for subjects who are hospitalized or hospitalized 
over a prolonged period due to the SAE. If possible, the discharge summary should 
be obtained when it becomes available. 
• A copy of the autopsy report, if a death occurs and an autopsy is performed, should 
be obtained if possible when it becomes available. 
Any SAE that is ongoing at Visit 3 or ET should be followed as described above. Data after 
Visit 3 should be recorded on the source documents and submitted to Concentrics Research on 
a SAE report form. For ongoing SAEs, the Principal Investigator must submit follow-up 
reports to Concentrics Research regarding the subject’s subsequent course until the case is 
closed. 
9.8 
Unexpected Adverse Event 
As defined by 21 CFR 312.32 (a), an unexpected adverse drug experience is:  
“An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as amended. 


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For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the investigator brochure listed only cerebral vascular accidents. 
"Unexpected," as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation.” 
The study sponsor will expedite reporting all serious unexpected suspected adverse reactions 
(SUSARs): initial reporting by the sponsor for nonfatal or non-life-threatening SUSARs must be 
submitted as soon as possible but no later than within 15 calendar days following the sponsor’s 
initial receipt of the information, and for fatal or life-threatening SUSARs, initial reports must be 
submitted no later than 7 calendar days following the sponsor’s initial receipt of the information. 
Any relevant additional information obtained by the sponsor that pertains to a previously submitted 
IND safety report must be submitted as a Follow-up IND Safety Report without delay as soon as 
the information is available but no later than 15 calendar days after the sponsor receives the 
information. 
Such expedited reports will comply with the applicable regulatory requirements and with the 
FDA’s Guidance for Industry and Investigators Safety Reporting Requirements for INDs and 
BA/BE Studies (21 CFR 312.32). 
9.9 
Pregnancy 
If a subject becomes pregnant during the study, the investigator must notify the Medical Monitor 
immediately upon learning of the pregnancy.  The outcome of any pregnancies occurring on the 
study must be followed up to term.  The investigator will be provided with a Pregnancy Outcome 
Form by the Medical Monitor.  This form must be completed fully and returned to the Medical 
Monitor. Any spontaneous miscarriage or congenital anomaly or birth defect must be recorded as 
a Serious Adverse Event and full details will be requested. Any complications during pregnancy 
should be recorded as an AE and may constitute an SAE if they fulfill any of the specified 
criteria for an SAE. 


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10 INVESTIGATOR OBLIGATIONS 
10.1 Ethical and Regulatory Considerations 
This study will be conducted in accordance with Good Clinical Practice (GCP) Guidelines, 21 
CFR Parts 11, 50 Subparts A and B, 54, 56, and 314, and the Consolidated Guidance for 
Industry, GCP E6, April 1999; and 1996 ICH GCP E6. 
10.2 Institutional Review Board 
The Concentrics Research will ensure that an appropriately constituted Institutional Review 
Board (IRB), in compliance with the requirements of 21 CFR 56, reviews and approves the 
clinical study before the study is initiated. IRB approval must refer to the study by exact protocol 
title, number, and amendment number (if applicable), identify the documents reviewed, and state 
the date of review. 
Concentrics Research will ensure that ParaPRO LLC approves any changes to the IC template 
prior to submission to the IRB. 
Should changes to the IC form become necessary during the study, Concentrics Research will 
ensure that the changes are approved by ParaPRO LLC prior to submission to the IRB. Should 
changes to the study protocol become necessary, Concentrics Research will ensure that the 
protocol amendment is approved by the IRB prior to implementation. Concentrics Research will 
ensure that protocol administrative changes have been reviewed by the IRB. 
Concentrics Research must be copied on any correspondence initiated by the site to the IRB 
during the course of the study. 
10.3 Informed Consent 
A properly executed, written IC, in compliance with 21 CFR Part 50 and HIPAA authorization, 
will be obtained from each subject prior to enrollment and the initiation of screening 
evaluations required by this protocol. A copy of the IC form planned for use will be reviewed 
by ParaPRO LLC for acceptability and submitted by or on behalf of the Investigator, together 
with the protocol, to the IRB for review and approval prior to the start of the study. Consent 
forms will be written in language fully comprehensible to the prospective subject. 
All revisions of the protocol must be reflected in the IC form, if applicable, and reviewed and 
approved by the IRB. Subjects must be made aware of those applicable changes in the protocol 
and must consent to participate in the revised protocol. 
Household members will sign a properly executed written Informed Consent form approved by 
the IRB as described above. 


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10.4 Subject Confidentiality 
All communications, reports, and subject samples will be identified only by a coded number 
and/or initials to maintain subject confidentiality. All records will be kept confidential to the 
extent permitted by law. If a waiver or authorization separate from the statement in the IC is 
required for permitting access to a subject’s medical records (e.g. HIPAA), the investigator will 
obtain such authorization prior to enrolling a subject in the study. The Principal Investigator 
should keep a separate log of subjects, codes, names, and addresses. Documents which identify 
the subject by name (for example, the IC form) should be kept in strict confidence. 
ParaPRO LLC and its business associates agree to keep all subject information confidential. 
Only coded, blinded data will be released. Data resulting from analyses will be entered into a 
database that is not accessible to the public. Subject data will be identified only by the subject 
screen number, randomization number and initials, and not by any other annotation or 
identifying information. 
ParaPRO LLC and its business associates will take every possible step to reduce the risk of 
releasing information to the public that would enable subjects to be personally identified. 
 


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11 STUDY MONITORING 
11.1 Clinical Monitoring 
An initiation meeting will be conducted by Concentrics Research or an approved representative. 
At this meeting the protocol, the procedure for completing the eCRFs, and pertinent aspects of 
the eCRFs will be reviewed with the Principal Investigator and all study staff. 
Monitoring visits will be conducted during the study. The Principal Investigator will make a 
reasonable amount of time available to the CRA on reasonable notice to assist with monitoring. 
At each visit, the CRA will review the eCRFs and source documents to ensure that all items have 
been completed and that the data provided are accurate and obtained in the manner specified in 
the protocol. 
11.2 Auditing Procedures 
In addition to the monitoring visits outlined above, an investigational site may undergo a quality 
assurance audit. Concentrics Research or ParaPRO LLC representatives or a regulatory agency 
such as the FDA may conduct the audit. If a regulatory agency requests an audit of the study site, 
the Investigator is required to inform Concentrics Research (or ParaPRO LLC) immediately. 
 


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12 CHANGES TO THE PROTOCOL AND STUDY TERMINATION 
12.1 Protocol Amendment and Administrative Change 
All changes to the protocol must be documented by amendments, or administrative changes 
where applicable, and the amended protocol must be signed by ParaPRO LLC and the 
Investigators. The amended protocol and a revised IC form, if necessary, will be submitted to the 
IRB for approval. If the protocol modifications affect the eCRFs, they will also be revised and 
provided to the site. 
12.2 Termination of the Study 
ParaPRO LLC and the Principal Investigator reserve the right to terminate the study at any time. 
In terminating the study, ParaPRO LLC and the Principal Investigator will ensure that adequate 
consideration is given to the protection of each subject’s interest. 
 


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13 SOURCE DOCUMENTS, CASE REPORT FORMS AND RECORD RETENTION 
13.1 Source Documents 
The Investigator will complete and maintain source documents for each subject participating in 
the study. The source documents should contain all demographic and medical information, 
including vital sign data. The subject’s source documents file should also indicate that he/she is 
participating in the clinical study, referencing the study number and the IP. All information 
required by the protocol should be documented in the source records. An explanation must be 
given for any omissions. Each evaluation recorded will be performed at the time specified in the 
protocol. 
13.2 Electronic Case Report Forms  
Electronic Case Report Forms (eCRFs) will be used in this study. The Investigator is responsible 
for the quality of the data recorded in the eCRF. The data recorded should be a complete and 
accurate account of the subject’s record collected during the study.  
The Investigator and other staff who have been delegated responsibility for entering data into the 
eCRF at each visit will be trained in the use of the eCRFs before the first subject at that site is 
enrolled. The Investigator must review all entries for completeness and correctness. The 
electronic data capture system will keep an audit trail of all changes made after the eCRF pages 
are initially completed and submitted. The study monitor will review the eCRFs for 
completeness and adherence to the protocol 
13.3 Record Retention  
The Principal Investigator will maintain adequate records so that the conduct of the study can be 
fully documented and monitored. Copies of protocols, test result originals, all IP accountability 
records, correspondence, subject Informed Consent forms, and any other documents relevant to 
the conduct of the study will be kept on file by the Principal Investigator. Study documents will 
not be destroyed. For regulatory inspections, it will be necessary to have access to complete 
study subject records, provided that subject confidentiality is maintained. 
Per the Clinical Development Agreement between ParaPRO LLC and Concentrics Research, 
investigators must retain subjects’ records for a period of 2 years after FDA approval or until 
written approval to destroy the documentation is provided by ParaPRO LLC. The documentation 
must be retained longer if so required by local law. Investigators must notify Concentrics 
Research and ParaPRO LLC, in writing, of changes in address, sales of practices or site closures 
in order to make arrangements for the maintenance of study files. 


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14 FINAL REPORT/PUBLICATION STATEMENT  
Any formal presentation or publication of data collected as a direct or indirect result of this trial 
will be considered as a joint publication by the investigator(s) and ParaPRO LLC. 
Individual investigators may publish data arising from their own subjects with permission from 
ParaPRO. The Principal Investigator will provide ParaPRO LLC with copies of written 
publications (including abstracts and posters) at least 60 days in advance of submission. This 
review is to permit ParaPRO LLC to review the communication for accuracy (thus avoiding 
potential discrepancies with submissions to regulatory authorities), to verify that confidential 
information is not inadvertently divulged (including patent protection), to allow adequate input 
or supplementary information that may not have been available to the Principal Investigator, and 
to allow establishment of co-authorship. 
Data will be reviewed by all participating investigators prior to publication. ParaPRO LLC will 
have 60 days to review all definitive publications, such as manuscripts and book chapters, and a 
minimum of 30 days to review all abstracts. 
 
 


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15 REFERENCES 
1. Centers for Disease Control: www.cdc.gov/parasites/scabies. 
2. Chosidow, O. Scabies. N Engl J Med 2006: 354: 1718-27. 
3. Natroba (spinosad) Topical Suspension, 0.9%. Prescribing Information revised 
12/2014. 
4. Data on file at ParaPRO, LLC. 
5. Chhaiya SB1, Patel VJ, Dave JN, Mehta DS, Shah HA. Comparative efficacy and 
safety of topical Permethrin, topical ivermectin, and oral ivermectin in patients of 
uncomplicated scabies. Indian J Dermatol Venereol Leprol. 2012 Sep-Oct;78(5):605-
10. 
6. Sharma R, Singal A. Topical Permethrin and oral ivermection in the management of 
scabies: A prospective, randomized, double-blind, controlled study. Indian J Dermatol 
Venereol Leprol 2011: 77: 581-6. 
7. Meinking TL, Taplin D, Hermida JL et al. The treatment of scabies with 
ivermectin. N Engl J Med 1995; 333: 26-30. 
8. Usha V, Nair TVG. A comparative study of oral ivermectin and topical Permethrin 
cream in the treatment of scabies. J Am Acad Dermatol 2000; 42: 236- 40. 
9. A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Effect of 
Natroba™ (spinosad) on the Treatment of Scabies. SPN-401-12; 2013. 
10. Macotela-Ruíz E1, Peña-González G. [The treatment of scabies with oral ivermectin]. 
Gac Med Mex. 1993 May-Jun;129(3):201-5.[Article in Spanish] 
11. http://www.cdc.gov/parasites/scabies. 
12. FitzGerald D, Grainger RJ, Reid A. Interventions for preventing the spread of 
infestation in close contacts of people with scabies. Cochrane Database Syst Rev. 
2014 Feb 24;2:CD009943. 
 


Phase 3, Double-Blind, Placebo-Controlled Study to Assess  
SPN-304-15 Amendment No. 6 
Safety and Efficacy of Natroba™ (spinosad) for Scabies Treatment 
23 March 2018 
Page 61 of 61 
ParaPRO, LLC  Confidential 
16 APPENDIX [1]: EXAMPLE OPEN-LABEL PRODUCT LABEL 
 
 

SAP_001.pdf: 
 
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Statistical Analysis Plan 
 
 
 
Sponsor: 
ParaPRO, LLC 
11550 North Meridian Street 
Suite 290 
Carmel, IN 46032 
USA  
 
Protocol Number: 
SPN-304-15  
 
Protocol Title: 
A Phase 3, Randomized, Double Blind, Placebo-Controlled 
Study to Assess the Safety and Efficacy of Natroba™ 
(spinosad) for the Treatment of Scabies 
 
Protocol Date: 
Original Protocol: 11 March 2015 
 
Protocol Amendment Date: Amendment No. 1:  07 July 2015 
Amendment No. 2:  08 April 2016  
Amendment No. 3:  14 November 2016 
Amendment No. 4:  27 February 2017 
Amendment No. 5:  20 September 2017 
Amendment No. 6: 23 March 2018 
 
 
SAP Date: 
Version 1.0, 14 September 2015 
Version 2.0, 08 April 2016 
Version 3.0, 16 November 2016 
Version 4.0, 16 March 2017 
Version 5.0, 20 September 2017 
Version 6.0, 23 March 2018 
Version 7.0, 24 August 2018 
 
 
 


 
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Statistical Analysis Plan 
Biostatistician Signature Page 
 
 
Version 1.0 and Version 2.0 prepared by: 
 
 
 
 
 
Mark J. Jaros, PhD 
Biostatistician Consultant 
Summit Analytical 
2422 Stout St 
Denver, CO 80205 
 
Tel: (970) 215-2741 
email: mjaros@summitanalytical.com 
 
 
 
 
 
Version 3.0 and Version 4.0 prepared by: 
 
 
 
 
 
Lynn Wang, MS. MA. 
Director, Biostatistics 
FMD K&L 
1300 Virginia Dr., Ste 408, 
Fort Washington, PA 19034 
Tel: (215) 283-6035 
 
email: lynn.wang@klserv.com 
 
 
 
 
 
 
Version 5.0 and Version 6.0 prepared by: 
 
 
 
 
 
Bin Yao, PhD 
Biostatistician 
FMD K&L 
1300 Virginia Dr., Ste 408, 
Fort Washington, PA 19034 
Tel: (215) 283-6035 x175  
email: bin.yao@klserv.com 
 
 
 
 
 








 
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Table of Contents 
 
LIST OF ABBREVIATIONS AND ACRONYMS ..................................................................................... 7 
1. 
PREFACE .............................................................................................................................................. 8 
2. 
PROTOCOL OVERVIEW ................................................................................................................... 8 
2.1. 
Study Objectives ......................................................................................................................... 8 
2.1.1. 
Primary Objective .................................................................................................................... 8 
2.2. 
Trial Design and Visit Structure ............................................................................................... 8 
2.3. 
Study Treatment ....................................................................................................................... 10 
2.3.1. 
Treatment Groups .................................................................................................................. 10 
2.3.2. 
Sample Size Determination ................................................................................................... 10 
2.3.3. 
Method of Treatment Assignment and Randomization ......................................................... 11 
2.3.4. 
Blinding Methods .................................................................................................................. 11 
2.3.5. 
Procedures for Unblinding ..................................................................................................... 11 
2.4. 
Planned Analyses ...................................................................................................................... 12 
3. 
SAFETY PARAMETERS .................................................................................................................. 12 
3.1. 
Adverse Event ........................................................................................................................... 12 
3.2. 
General Skin and Eye Assessments......................................................................................... 12 
3.3. 
Vital Signs ................................................................................................................................. 12 
3.4. 
Prior and Concomitant Medications ...................................................................................... 12 
4. 
EFFICACY PARAMETERS ............................................................................................................. 12 
4.1. 
Scabies Assessment ................................................................................................................... 12 
5. 
ANALYSIS POPULATIONS ............................................................................................................. 13 
5.1. 
Safety Population...................................................................................................................... 13 
5.2. 
Intent-to-Treat Population ...................................................................................................... 13 
5.3. 
Index Intent-to-Treat Population ............................................................................................ 13 
5.4. 
Index Per Protocol Population ................................................................................................ 13 
6. 
STATISTICAL METHODOLOGY .................................................................................................. 14 
6.1. 
Statistical and Analytical Issues .............................................................................................. 14 
6.1.1. 
Statistical Methods ................................................................................................................ 14 
6.1.2. 
Computed Variables .............................................................................................................. 14 
6.1.3. 
Handling of Partial Dates ...................................................................................................... 15 
6.1.4. 
Handling of Early Termination Visit Information ................................................................. 16 
6.1.5. 
Data Imputation Specifications ............................................................................................. 16 
6.1.6. 
Pooling of Study Sites ........................................................................................................... 17 
6.2. 
Subject Characteristics ............................................................................................................ 18 
6.2.1. 
Subject Disposition and Deviations ....................................................................................... 18 
6.2.2. 
Treatment Compliance .......................................................................................................... 18 
6.2.3. 
Demographic and other Baseline Characteristics .................................................................. 18 
6.3. 
Efficacy Analysis ...................................................................................................................... 18 
6.3.1. 
Primary Efficacy Analysis ..................................................................................................... 18 
6.3.2. 
Exploratory Efficacy ............................................................................................................. 20 
6.4. 
Safety Analyses ......................................................................................................................... 21 
6.4.1. 
Adverse Events ...................................................................................................................... 21 
6.4.2. 
General Skin and Eye Irritation Assessments ........................................................................ 22 
6.4.3. 
Laboratory Evaluations ......................................................................................................... 22 
6.4.4. 
Vital Signs ............................................................................................................................. 22 
6.4.5. 
Prior and Concomitant Medications ...................................................................................... 22 


 
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LIST OF ABBREVIATIONS AND ACRONYMS 
TERM 
DEFINITION 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemistry 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel (general association test) 
ET 
Early Termination 
FDA 
Food and Drug Administration 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
I-ITT 
Index Intent-to-Treat 
I-PP 
Index Per Protocol 
LOCF 
Last Observation Carried Forward 
MedDRA   
Medical Dictionary for Drug Regulatory Affairs 
OC 
Observed Cases 
PI 
Principal Investigator 
POC 
Proof of Concept (study) 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
WHO-DD 
WHO-Drug Dictionary 


 
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1. PREFACE 
This document presents a statistical analysis plan (SAP) for ParaPRO Protocol 
SPN-304-15 (A Phase 3, Randomized, Double Blind, Placebo-Controlled Study to Assess 
the Safety and Efficacy of Natroba™ (spinosad) for the Treatment of Scabies).   
  
Reference materials for this statistical plan include the protocol SPN-304-15 (Amendment 
5 Dated: 20 September 2017). 
The SAP described hereafter is an a priori plan.  A version of the SAP will be prepared at 
the same time as the protocol is finalized. However, the primary and secondary efficacy 
endpoints and analyses on them will not be altered unless agreed upon with the Food and 
Drug Administration (FDA). SAP will be finalized before the database is unblinded.   
Statistical programming may occur as study data accumulate in order to have analysis 
programs ready at the time the study finishes.  In such an event, arbitrary treatment group 
assignments must be randomly linked to subjects, effectively rendering any inference 
based upon the output of programs meaningless.   
For the reasons stated here the conduct of the study in the field is considered to be 
independent of any study outcome that might materialize upon enactment of the currently 
proposed statistical plan.  Any deviations from the statistical analysis plan will be 
described in the clinical study report. 
 
2. PROTOCOL OVERVIEW 
2.1. 
Study Objectives 
2.1.1. Primary Objective 
The primary objective is to assess the safety and efficacy of topical Natroba™ (spinosad) 
versus Placebo for the complete cure of scabies after a single treatment.  
 
2.2. 
Trial Design and Visit Structure 
The primary study is a double blind, two-arm, 28-day, placebo-controlled study enrolling 
approximately 120 infested “index” subjects enrolled and randomized 1:1 to Natroba™ or 
Placebo in order to achieve, with attrition, 96 subjects completed in the study. 
 
All members of a household (no more than 6 individuals) with a suspected “index” subject 
must be screened at the first visit. In this study, “index” subjects are defined as the 
youngest infested household member (≥4 years). If the household has at least one member 
with active scabies infestation and meet all other criteria, they must all agree to participate 
in the study. Household members who do not present with scabies at the screening visit 
must also agree to apply the same blinded investigational product (IP) as household 
members who present with scabies (see Table 6-1 Schedule of Procedures in the protocol 


 
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for status assessment). All household members must agree to participate in the study or 
none will be enrolled. 
 
After screening on Day 1, all randomized subjects will be dispensed IP (Natroba™ or 
Placebo) to apply at home later the same day.  IP will be applied as a single treatment over 
the entire body from the neck down to the toes (including the soles of the feet) and to the 
scalp (if balding) or hairline, temples and forehead on the same day. Subjects less than 12 
years of age should be assisted with administration by a parent, guardian or caregiver. 
Subjects will rub the treatment into the skin followed by a 10-minute wait period before 
getting dressed. Showering or bathing must not occur earlier than 6 hours after treatment 
and no later than at least 1 hour prior to Day 2 visit. 
 
On Day 2 (Visit 2), all household members will return for general skin and eye assessments 
of possible irritation, and to confirm that all IP was left on for a minimum of 6 hours before 
bathing or showering.   If a subject reports an adverse event assessed as related by the 
principal investigator (PI) on Day 2 (Visit 2) then a follow-up visit with the investigator 
must be scheduled within 7 days of visit. All household members will receive a well-being 
phone call on Day 14 to continue to emphasize instructions to prevent re-infestation, 
determine if any concomitant medications have been used, and check for adverse events 
 
In the randomized population (all household members), on Day 2 (Visit 2), general skin 
and eye assessments will be made for possible irritation, and to confirm that all IP was left 
on for a minimum of 6 hours before bathing or showering.  Subjects will receive a 
well-being phone call on Day 14 to continue to emphasize instructions to prevent 
re-infestation, determine if any concomitant medications have been used, and check for 
adverse events. If a subject reports an adverse event assessed as related by the PI on Day 2 
(Visit 2) then a follow-up visit with the investigator must be scheduled within 7 days of 
visit. If a subject reports an adverse event assessed as related by the PI on the Day 14 
well-being phone call, then a follow-up visit with the investigator must be scheduled 
within 7 days of the phone call. 
 
On Day 28 (Visit 3), primary population subjects will return to the clinic for safety and 
efficacy assessments. The primary endpoint of complete cure as well as the key secondary 
endpoint to determine improvement based on lesion count will be assessed in the “index” 
subject and any infested household members. If the infested subject is completely cured at 
Day 28, he or she will have completed the study and termination procedures will be 
conducted. If the subject is not completely cured at Day 28 (with Natroba™ or Placebo), 
the subject will receive 5% Permethrin and will be directed to their primary care physician 
for follow-up.   
 
Safety assessments will be made for all household members and will include monitoring of 
adverse events (AEs) throughout the study, vital signs recording (Days 1 and 28), and 
general skin and eye irritation assessments (Days 1, 2, and 28). 
 


 
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The Day 28 procedures will also be completed for early termination (ET) except subjects 
will not receive rescue Permethrin but will be directed to follow-up with their primary care 
physician. 
 
2.3. 
Study Treatment 
2.3.1. Treatment Groups 
Subjects will receive one of two treatments randomized 1:1 to the placebo or 
investigational product.   
Treatments: 
1 
Investigational product: NatrobaTM (spinosad) Topical Suspension (0.9%) 
2 
Placebo: Placebo Control 
 
2.3.2. Sample Size Determination 
 
Approximately 120 “index” subjects will be enrolled (includes anticipated 20% attrition) 
from 120 households and randomized 1:1 to Natroba™ (spinosad) and Placebo control. 
The index subject will be the youngest infested member of a household (≥4 years).  
Referencing to the Sponsor’s Proof of Concept (POC) study (SPN-401-12) and published 
literature, it is reasonable to assume a 60% complete cure rate for Natroba™ and 30% for 
placebo.  A sample size of 48 study-completed “index” subjects per group will provide 
80% power to declare the non-equivalency using a delta of 30% and Type I error rate of 
0.05.   Fisher exact test was used to calculate the sample size and the specified power in the 
following Table 1 (PASS 14; 2015, NCSS, LLC., Kaysville, Utah, USA. www.ncss.com).  
Table 1 
Sample Size Needed to Declare Non-equivalency with Respect to the 
Proportion of Subjects Achieving Complete Cure with a Type I Error Rate=0.05 and 
Specified Power 
Proportion in 
Required Sample 
Size per Group 
Power 
Natroba TM 
Placebo 
Difference vs. 
Placebo 
55% 
30% 
25% 
69 
80.4% 
60% 
30% 
30% 
48 
80.0% 
65% 
30% 
35% 
37 
80.6% 
 
Assuming a drop-out rate could be at most 20%, 120 subjects should guarantee at least 48 
evaluable subjects for each treatment group at Day 28 assessment. 
 
 


 
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2.3.3. Method of Treatment Assignment and Randomization  
As “index” subjects and other infested or non-infested household members become 
eligible for randomization at Visit 1 (Day 1), the site will locally assign a unique subject 
number to each of the qualified household members that combines a 3-digit site number 
(xxx), a 2-digit household number (yy), and a 2-digit household member number (zz). For 
example, the first subject of the first household at site 101 would be randomized to subject 
number 101-01-01, the second member to 101-01-02, the third member to 101-01-03, and 
so on. Since all household members receive the same treatment, each household is 
randomized to either Natroba™ (spinosad) or Placebo control.  Non-infested household 
members will be assigned the same IP treatment as the infested members and will be 
assigned a subject number and randomization number. The assigned subject numbers to 
each household will correspond to unique bottle numbers on a scheme that unblinded site 
personnel will assign and distribute, to ensure approximately equal randomization of 
households to either treatment. Subject numbers must not be re-used once assigned, even if 
the subject does not take the IP.  Randomization will be stratified by study site. 
2.3.4. Blinding Methods 
Eligible subjects will be assigned to either treatment group, Natroba™ (spinosad) or 
Placebo control, by pre-specified un-blinded site personnel that may perform no other 
subject related study specific or subject treatment related study duties. The un-blinded site 
personnel will assign all members from the same household to the same treatment group.  
The assigned subject numbers in each household will correspond to unique bottle numbers 
on a scheme that unblinded site personnel will assign and distribute to ensure 
approximately equal randomization of households to either treatment. Subjects, blinded 
site personnel, and ParaPRO, LLC will remain blinded to the treatment until after database 
lock.   
2.3.5. Procedures for Unblinding 
In an emergency, the study blind may be broken only if: 
 in the opinion of the investigator and/or the Medical Monitor, it is in the subject's 
best interest to do so; 
 knowledge of the treatment will alter the clinical management of the subject; 
 approval has been granted by the Medical Monitor and/or ParaPRO, LLC. 
Whenever possible, the Medical Monitor should be notified prior to unblinding a treatment 
assignment. In the event that unblinding is necessary for the medical management of the 
subject, the pre-specified un-blinded site personnel will access the randomization code by a 
treatment code list provided by Concentrics Research to each site. If a treatment 
assignment is unblinded, the date and reason for the unblinding must be recorded on the 
subject’s source document, and the Medical Monitor notified within 24 hours. 


 
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2.4. 
Planned Analyses 
The analysis of all study data will occur at the end of the trial.  No interim analyses are 
planned.  Study data will remain blinded to treatment assignment until all data have been 
collected and the clinical database has been locked for unblinding and analysis. 
3. SAFETY PARAMETERS 
3.1. 
Adverse Event 
Adverse Events (AEs) will be collected on Days 2, 14 (phone call, and a follow-up visit if 
AE is reported), and 28/ET.  See Section 6.4.1 for further details on which AEs will be 
assigned as treatment-emergent adverse events (TEAEs). 
3.2. 
General Skin and Eye Assessments 
On Day 1, the skin will be assessed to determine eligibility – no evidence of crusted 
scabies, normal skin in non-infested areas. On Days 1 and 2, the skin and eye assessments 
will include documentation of presence or absence of irritation, and verbal verification that 
the treatment topical suspension remained on for at least 6 hours before being washed off.  
On Day 28/ET, skin and eye assessments will include evidence of irritation. 
 
Eye irritation will be rated: 
 
0 no irritation 
1 mild scleral, lid, and/or conjunctiva injection 
2 moderate scleral and or lid injection with conjunctival erythema 
3 severe scleral and/or lid injection with conjunctival erythema and purulent drainage 
 
3.3. 
Vital Signs 
Height (Day 1 only), weight, resting blood pressure and heart rate will be measured on 
Days 1 and 28/ET. 
 
3.4. 
Prior and Concomitant Medications 
For randomized subjects, prior medications will be collected on Day 1 and concomitant 
medications will be collected on Days 2, 14 (by phone), and 28/ET.   
4. EFFICACY PARAMETERS 
4.1. 
Scabies Assessment 
Skin will be examined on Days 1 and 28/ET to establish positive or negative evidence of 
active scabies infestation.  
 Scabies diagnosis – active scabies infestation confirmed by clinical signs and 
symptoms (evidence of burrows or presence of scabies 


 
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inflammatory/non-inflammatory lesions and pruritus) as well as by microscopic 
exam of skin scraping or dermatoscopy to demonstrate the presence of mites, eggs, 
and/or scybala. If dermatoscopy is used it should also confirm there are burrows on 
the skin.  
 
 Primary Efficacy Endpoint – complete cure is defined as demonstration of clinical 
cure (all signs and symptoms have completely resolved, including burrows, 
inflammatory/non-inflammatory lesions and pruritus) and microscopic or 
dermatoscopic cure with demonstration of the absence of mites, eggs, and/or 
scybala, and dermatoscopy negative for burrows.   
Lesions should be indicated on a body diagram and/or marked with skin marker; count of 
existing and new lesions will be recorded. 
 
5. ANALYSIS POPULATIONS 
5.1. 
Safety Population 
The safety population will comprise all study subjects who received one dose of IP.  
Subjects will be analyzed as treated.  The safety population includes the index subjects 
along with any household members enrolled in the study.  Safety analyses will utilize the 
safety population. It is assumed that approximately 360 subjects will be enrolled and 
receive one administration of IP: 120 “index” subjects and 240 “non-index” subjects.  
 
5.2. 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will comprise all subjects who were randomized. 
Subjects will be analyzed as randomized.  This population includes the index subjects 
along with any household members enrolled in the study. 
 
5.3. 
Index Intent-to-Treat Population 
The “index” intent-to-treat (I-ITT) population will comprise of all index subjects who were 
randomized.  Subjects will be analyzed as randomized.  The index subject will be the 
youngest infested member of a household (≥4 years).  Efficacy analyses will be based on 
this population. 
 
5.4. 
Index Per Protocol Population 
The “index” Per Protocol (I-PP) population is a subset of the I-ITT population. Index 
subjects will be excluded from the I-PP population for the following reasons: 
1. Protocol deviations that would be in violation with the established Inclusion or 
Exclusion Criteria. 
2. Protocol deviations that could confound the evaluation of efficacy outcomes:  
o Scabies assessment not performed (i.e. burrows, lesions, pruritis, skin 
scraping).  
o Subject received the wrong treatment. 


 
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o Discontinuation prior to acquisition of Visit 3 (Day 28) efficacy 
measurements. 
3. Protocol deviations that are a result of subject non-compliance:   
o 
Missed Day 2 appointment. 
o 
Use of another scabicide during the study. 
o 
Use of prescription or OTC medicated lotions during the study. 
 
Prior to database lock, a memo will be generated identifying any subjects that were 
excluded from the I-PP population along with the reason why they were excluded. 
 
The I-PP population will be established after a review of protocol deviations. This 
analysis population will be used for sensitivity analyses for the primary efficacy 
analysis. 
6.   STATISTICAL METHODOLOGY 
6.1. 
Statistical and Analytical Issues 
6.1.1. Statistical Methods 
This statistical analysis plan (SAP) will describe statistical analyses for the study and be 
completed at the same time as the protocol. Any revisions (both alternative and additional 
methods) to the SAP, and reasons for such revisions, will be described in the final clinical 
study report. 
 
Data collected in this study will be presented using summary tables, figures, and subject 
data listings. Summary tables will present data by treatment group and, if applicable, by 
time of collection. Continuous variables will be summarized using descriptive statistics, 
specifically the number of non-missing observations, mean, median, standard deviation, 
minimum and maximum. Categorical variables will be summarized by frequencies and 
percentages. Figures may be used to support the presentation of certain data. 
 
All tests of significance, unless otherwise stated, will be performed at a significance level 
of alpha=0.05, two-sided.   
Statistical programming and analyses will be performed using SAS® Software (SAS 
Institute Inc., Cary, NC) Version 9.2 or higher.   
All subject study data, including data not appearing in tables or figures, will be presented in 
data listings. 
6.1.2. Computed Variables 
The following variables will be computed programmatically. 
Age in years (truncated to an integer value) will be calculated using the formula: 


 
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Age = integer part of [(Date of informed consent/assent date – date of birth + 1)/365.25] 
Improvement will be graded post-treatment as follows:  
 
Mild = <50% reduction in total number of lesions 
Moderate = ≥50% in total number of lesions 
Good = complete clearance of lesions 
 
Baseline value will be the last measurement obtained prior to first dose. 
The total number of lesions post-treatment is calculated using the following formula: 
 
Total post-treatment lesions = 
 
 
total number of pre-existing lesions + total number of new lesions  
The change from baseline is calculated using the formula: 
 
Change from baseline to post-treatment = Post-treatment Value – Baseline Value 
The percent reduction in lesions is calculated using the formula: 
 
Percent Reduction = 
 
 
 [(Baseline total number of lesions – Post-treatment total number of lesions) / 
                            (Baseline total number of lesions)] * 100 
 
 
 
6.1.3. Handling of Partial Dates  
The following conventions will be used to impute missing portions of dates for adverse 
events and concomitant medications in determining whether the events occur during 
certain study period. Complete missing date will not be imputed.  
Adverse events 
A. Start Dates 
1) 
If the year is unknown, then the date will not be imputed and 
will be assigned a missing value.  
2)  
If both the month and day is unknown, then: 
i) If the year matches the first dose date year, then set 
the month and day to the same as the first dose date. 
ii) Otherwise, assign ‘1 January.’  
3)   
If only the day is unknown, then: 
i) If the month and year match the first dose date month 
and year, set the day to that of the first dose date. 


 
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ii) Otherwise, assign the first day of the month. 
B. Stop Dates 
1) 
If the year is unknown, then the date will not be imputed and 
will remain a missing date. 
2)  
If the month is unknown, then assign ‘December.’ 
3)  
If the day is unknown, then assign the last day of the month. 
 
Prior/concomitant medications 
 
Partial start dates of the concomitant medications will be assumed to be the earliest 
possible date consistent with the partial date. Partial stop dates of prior and concomitant 
medications will be assumed to be the latest possible date consistent with the partial date. 
In the case of the completely missing stop date, medication will be assumed to be ongoing. 
 
6.1.4. Handling of Early Termination Visit Information 
In the event that a subject is terminated early from this study, the early termination visit 
data will be imputed. The imputation method depends on the reasons of missing, i.e. 
informative or non-informative missing. Please see more details about the reasons in Table 
2 in Section 6.1.5.    
For by visit summaries, the early termination visit data can be analyzed at the closest 
scheduled visit. If the closest visit has observed data, the early termination data will be 
assigned to the next available visit. 
6.1.5. Data Imputation Specifications 
For the safety analyses, no imputation of missing events or assessments are allowed. 
For the primary efficacy endpoint (complete cure rate at Day 28), the algorithms listed 
below will be followed. 
Any informative missing will be counted in as non-responders (failures) in the estimation 
of the treatment complete cure rates. Any non-informative missing will be imputed using 
Last Observation Carried Forward (LOCF) in the estimation of the treatment complete 
cure rates.   
Table 2 
Informative or Non-Informative Missing 
 
Dropouts Due to 
Lack of Efficacy 
Drug Related 
Adverse Event 
Lost to 
Follow-up 
All Other 
Informative 
Informative 
Non-informative 
Non-informative 
 


 
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For sensitivity analyses regarding the primary endpoint, the Observed Cases (OC), LOCF, 
and multiple imputation (MI) method will be used as appropriate approaches in addition to 
the imputation approach described for the primary efficacy analysis above. In addition, the 
Observed Case (OC) and LOCF methods will be used as sensitivity analyses for 
exploratory endpoints. Section 6.3 specifies in detail about imputation methods applicable 
to them. 
 
The MI method assumes data are missing at random (MAR).  The seed number is 626.  The 
number of imputations is 5. 
 
Step 1: Non-monotone missing data will be imputed using the fully conditional 
specification (FCS) method separately for each treatment arm since the response 
missingness could be due to treatment. A logistic regression will be used for binary data, 
and a discriminant function method will be used for ordinal data or classification variable 
with more than two levels if necessary. The following covariates will be included in the 
imputation model: treatment, clinical site (small sites pooled), baseline evidence of 
burrows and baseline score of lesions. In this step, MI procedure with FCS statement will 
be performed using SAS version 9.4. 
 
Step 2: The combined imputed data sets will be analyzed using a Cochran-Mantel- 
Haenszel test and a logistic regression. 
 
Step 3: The results from the analysis based on the multiply-imputed datasets will be 
combined by the MIANALYZE procedure in the SAS version 9.4. The p-value, estimate of 
odds ratio (NatrobaTM vs Placebo), and the 95% confidence interval of odds ratio estimate 
from each multiply-imputed data set will be combined (Wilson & Hilferty, 1931; Goria, 
1992; Rubin, 1987; Li et al., 1991).  
 
6.1.6. Pooling of Study Sites 
This is a study conducted at multiple study sites.  Every effort will be made to have each 
site enroll at least 8 “index” subjects per arm.  In case there are “small” sites each with 
fewer-than-8 “index” subjects per arm, these sites will be pooled together as a single, 
combined site for efficacy analyses if the combined site has at least 8 “index” subjects per 
arm. In the situation when the combined site still has less than 8 “index” subjects per arm, 
the smallest site with at least 8 “index” subjects per arm will be pooled to this combined 
site for efficacy analyses. Assessment of site-to-site variability will be conducted on the 
original sites prior to pooling. 
  


 
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6.2. 
Subject Characteristics 
6.2.1. Subject Disposition and Deviations 
The tabulation of number of subjects in each treatment group and overall will be displayed 
for all subjects who are screened, randomized, and in each analysis population.     
The number and percent of subjects who completed or discontinued the study will be 
displayed for each treatment group and overall together with reasons for early termination, 
where the percent is with respect to the total number of randomized subjects in that 
treatment group.  
Protocol deviations will be listed. 
6.2.2. Treatment Compliance 
The compliance data will be listed for each subject.  Compliance data consist of two parts: 
1. Subject questioning about the application and removal of Investigational Product, and 2.  
Evaluate by investigator as to whether or not the Investigational Product was applied as 
instructed.  
6.2.3. Demographic and other Baseline Characteristics 
Parameters collected at the screening and/or baseline visits will be summarized 
descriptively.   In addition to the safety and efficacy scores listed in Sections 3 and 4, the 
following demographic and baseline characteristics will be presented: 
 Demographic Characteristics 
o Sex (male, female) 
o Age (years) 
o Ethnicity and Race (Hispanic or Latino, American Indian or Alaska Native, 
Asian, Black or African American, Native Hawaiian or Other Pacific Islander, 
or White) 
o Baseline assessments of scabies infestation 
o Previous infestations 
In addition, the above demographic and baseline characteristics will be presented by site 
before and after pooling the sites. 
6.3. 
Efficacy Analysis 
6.3.1. Primary Efficacy Analysis 
The primary efficacy endpoint is the proportion of index subjects completely cured of 
scabies by Day 28.  Complete cure is defined as demonstration of clinical cure (all signs 


 
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and symptoms have completely resolved, including burrows, 
inflammatory/non-inflammatory lesions and pruritus) and microscopic or dermatoscopic 
cure with demonstration of the absence of mites, eggs, and/or scybala, and dermatoscopy 
negative for burrows. 
 
The primary analysis will be based on the data from the I-ITT population.   The proportion 
of index subjects who exhibit complete cure (Yes or No) at Day 28 will be estimated by 
treatment group.  NatrobaTM will be compared versus placebo, and the difference with 
2-sided 95% confidence interval (CI) will be provided. A Cochran-Mantel-Haenszel 
(CMH) general association test adjusted by study site (small sites pooled) stratification will 
be performed to test at an alpha level of 0.05 for equivalence in the complete cure rates 
between the two treatment groups.     
 
Sensitivity analyses will be performed on the primary efficacy endpoint to evaluate the 
robustness of the results using different methods of analysis and other populations. 
 
The similar CMH test will be performed based on observed cases (OC) data, LOCF, and 
imputed data from MI method as sensitivity analyses. 
 
A logistic regression analysis will be used assessing the treatment group difference in 
complete cure rate by Day 28.  The model will include clinical site (or region?) and 
treatment group as factors, and possibly additional baseline characteristics or a covariate, 
only if appropriate.  The odds ratio, 95% CIs and p-value for the comparison will be 
provided.  For logistic regression modelling, the data imputation approach specified in 
Section 6.1.5 for primary analysis will be applied for missing values at Day 28. 
 
The similar logistic regression will also be performed based on observed cases (OC) data, 
LOCF and imputed data from MI method as sensitivity analyses. 
 
The complete cure rates at Day 28 will be summarized descriptively by treatment groups 
and by sites before and after pooling the sites. 
 
Other additional sensitivity analyses include repeating the above two statistical analyses on 
I-PP population and ITT population. 
 
 


 
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6.3.2. Exploratory Efficacy 
All exploratory efficacy endpoints will be summarized by the treatment group at each 
scheduled visit.  Descriptive statistics for continuous variables consists of mean, standard 
deviation (SD), median, minimum, and maximum. For categorical variables, numbers and 
percentages will be summarized. 
 
Additional analysis may be performed as appropriate for the following exploratory 
efficacy endpoints. 
 
Clinical Cure 
 
Clinical cure is defined as having all signs and symptoms completely resolved, including 
inflammatory/non-inflammatory lesions and pruritus. 
 
The number and percent of subjects who exhibit clinical cure (Yes or No) at Day 28 will be 
presented by treatment group.  A Cochran-Mantel-Haenszel test adjusted by study site 
stratification will be performed to compare the complete cure rates between the two 
treatment groups upon the same data imputation approach defined for primary endpoint.    
 
This analysis can be performed on the I-ITT population on both OC and LOCF data as 
needed.   
 
Microscopic Cure 
 
Microscopic cure is defined as microscopic or dermatoscopic demonstration of the absence 
of mites, eggs, and/or scybala, and negative for burrows. 
 
The number and percent of subjects who exhibit microscopic cure (Yes or No) at Day 28 
will be presented by treatment group.  A Cochran-Mantel-Haenszel general association test 
stratified by study site will be used to compare the two treatment groups upon the same 
data imputation approach defined for primary endpoint.   
 
Additional analyses can be performed on the I-ITT population by applying a logistic 
regression model adjusted for baseline factors if there is necessity to further analyze this 
component of the complete cure. 
 
CMH analysis can be performed on the I-ITT population on both OC and LOCF data as 
needed. 
 
Number of New Lesions 
 
The number of new lesions at Day 28 will be analyzed using a negative binomial 
regression model to compare the treatment difference. The model will include treatment 


 
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group and study site (small sites pooled) as fixed factors, and baseline total lesion count as 
a covariate.   
 
This analysis will be performed on the I-ITT population using LOCF approach. 
Total Lesion Counts 
Total lesion counts will be calculated as the sum of pre-existing lesions and new lesions. 
The baseline captures the total lesions on the day of first study drug administration.  
The change from baseline to Day 28 will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment and study site (small sites pooled) as factors and 
baseline total lesion counts as a covariate.  
 
This analysis will be performed on the I-ITT population using LOCF approach. In addition, 
descriptive statistics will be provided by visit based on OC data. 
 
Subset in ITT - subjects who were infested at baseline 
 
A subset of subjects in ITT population who were infested at baseline will be summarized to 
display the proportion of the completely cured subjects. 
 
The same analyses described for primary analysis will be performed for this subset of 
subjects using the similar data imputation approach described for primary analysis.   
 
6.4. 
Safety Analyses 
6.4.1. Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by System Organ Class (SOC) and Preferred Term (PT) for 
each treatment group. All AEs will be captured throughout the study period from the 
enrollment to the final visit (Visit 3) or the ET visit.  AEs that occur after the first dose of 
study treatment will be considered as treatment-emergent adverse events (TEAE).  
Within each SOC or PT, subjects will be counted only once if they had one or more than 
one event reported during the treatment period (the subject is counted for the event with 
the maximum severity).   
Adverse events will be summarized by presenting: 
 the number and percentage of subjects experiencing any TEAE 
 the number and percentage of subjects experiencing any TEAE grouped by 
SOC and PT 


 
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 the number and percentage of subjects experiencing any Serious Adverse Events 
(SAEs) 
 the number and percentage of subjects experiencing any TEAE grouped by 
SOC and PT and maximum severity 
 the number and percentage of subjects experiencing any TEAE grouped by 
SOC and PT and maximum relationship to IP 
 the number and percentage of subjects experiencing any TEAE leading to 
study medication discontinuation. 
 The number and percentages of subjects experiencing any unexpected 
life-threatening adverse reaction 
A listing will be produced for all subjects who reported SAEs or who discontinued study 
medication due to TEAEs. 
All AEs (ie, pretreatment AEs and TEAEs) will be listed by subject. However, only TEAEs 
will be included in the summary tables. 
 
6.4.2. General Skin and Eye Irritation Assessments 
Skin and eye irritation will be captured as adverse events, as defined in Section 9.1 of the 
protocol.  Eye irritation assessment ratings will be summarized descriptively for each 
treatment group by visit. 
6.4.3. Laboratory Evaluations 
Laboratory results will be summarized descriptively for each treatment group by visit for 
the observed value as well as for the change from baseline value.  In addition, laboratory 
shift tables will be provided for all laboratory parameters where low/normal/high or 
abnormal/normal status can be ascertained.    
6.4.4. Vital Signs 
Vital signs will be summarized descriptively for each treatment group by visit for the 
observed value as well as for the change from baseline value. 
 
6.4.5. Prior and Concomitant Medications 
The number and percent of subjects who took prior medications will be summarized 
descriptively by the Anatomical Therapeutic Chemistry (ATC) class and Preferred Term as 
coded in the WHO-Drug dictionary (WHO-DD) for each treatment group.  Prior 
medications include all medications that start prior to first dose of study medication.  
Concomitant medications will be summarized similarly.   
 
  


 
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Reference 
Goria, M.N. 1992. On the forth root transformation of chi-square. Australian Journal of 
Statistics, 34(1), 55-64. 
Li, K.-H., Meng, X.-L., Raghunathan, T.E., and Rubin, D.B. 1991. Significance levels 
from repeated p-values with multiply-imputed data. Statistica Sinica, 1(1), 65-92. 
Rubin D.B. 1987. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley 
and Sons. 
Wilson, E.B., Hilferty, M.M. 1931. The distribution of chi-squared. Proceedings of the 
National Academy of Sciences, Washington, 17, 684-688.