Trial Code: CT EP02
Amendment 2: 04 December 2007 CONFIDENTIAL
EctoPharma Ltd
Unit 2, Alpha Centre
Stirling University Innovation Park
Stirling FK9 4NF
Telephone number: 01786 440099
Fax number: 01786 440091
CLINICAL TRIAL PROTOCOL
A Multicentre Phase III trial of 1,2-octanediol at 5%(w/v) (KindaPed™) compared with malathion 0.5% (w/v) (DERBAC-M LIQUID) in the treatment of head lice
TRIAL CODE: CT EP02
CHIEF INVESTIGATOR: mr Ian Burgess, MEDICAL ENTOMOLOGY CENTRE,
HERTFORDSHIRE, UK
Draft 1 / 28 March 2007Draft 2 / 13 April 2007
Draft 3 / 18 April 2007
Final Draft / 25 April 2007
Final / 09 May 2007
Final / 21 June 2007
Amendment 1 / 16 July 2007
Amendment 2 / 04 December 2007
THIS IS A CONFIDENTIAL DOCUMENT
This document is the property of EctoPharma Limited. The information within it is confidential and is provided to you, for review by you and your staff. The document must be kept in a confidential manner and must be returned to EctoPharma upon request. No part of this document may be reproduced in any form without permission from EctoPharma. By accepting this document, you agree that the information contained therein will not be disclosed to a third party without written authorisation from EctoPharma.
1. TITLE PAGE, RESPONSIBLE PERSONNEL, PROTOCOL APPROVAL AND INVESTIGATOR SIGNATURES
1.1 TITLE PAGE
PROTOCOL TITLE:
A Multicentre Phase III trial of 1,2-octanediol at 5%(w/v) (KindaPed™) compared with malathion 0.5% (w/v) (DERBAC-M LIQUID) in the treatment of head lice
TRIAL CODE: CT EP02
PHASE: III
CHIEF INVESTIGATOR:
Mr Ian Burgess, Director
Medical Entomology Centre, Insect Research and Development Ltd,
Cambridge House, Barrington Road, Shepreth, Royston, Hertfordshire, SG8 6QZ
Telephone number: 01763 263011
Fax number: 01763 263022
E-mail:
:
PRINCIPAL INVESTIGATORS:
Geraldine Matlock, Senior Nurse
Medical Entomology Centre, Insect Research and Development Ltd
Cambridge House, Barrington Road, Shepreth, Royston, Hertfordshire SG8 6QZ
Telephone number: 01763 263011
Fax number: 01763 263022
E-mail: /
Ruth Jones, Senior Public Health Nurse
Fronallt, 2, Brondeg Lane, Alltwen, Pontardawe, Swansea, SA8 3AE Telephone number: 07772 780798
Fax number: 01792 862091
E-mail:
Katrina Kay, Infection Control Nurse - Ectoparasites
5 Wharfe Grange, Wetherby, Leeds LS22 6SS
Telephone: 07894 583 896 / 07957 378863
Fax number: 0113 2033426
E-mail:
1.2 OTHER RESPONSIBLE PERSONNEL
SPONSOR/CONTRACT PERSONNEL
Medical/Safety Monitoring
All Serious Adverse Events must be reported by phone and fax directly to:
Carol Markwell, Drug Safety Solutions Ltd., Silver Lining, Londonthorpe, Grantham NG31 9RU
Telephone number: 01476 570819
Fax number: 01476 570819
E-mail:
Medical Advisor: Dr Veronica Tebbs
Scientific
Dr D Magnus Nicolson, EctoPharma Ltd., Unit 2, Alpha Centre
Stirling University Innovation Park, Stirling FK9 4NF
Telephone number: 01786 440 099
Fax number: 01786 440 091
E-mail:
Regulatory
Mrs Fiona MacLeod
13 Liniclate, Isle of Benbecula, Western Isles HS7 5PJ
Telephone number: 01870 602226
Fax number: 0870 134 5343
E-mail:
Project Management
Dr Graeme Scott,
PSCR, 7 St Catherine’s Place, Edinburgh, EH9 1NU
Telephone number: 0131 668 2500
Fax number: 0870 120 6210
E-mail:
Clinical Trial Supplies
Penn Pharmaceuticals Ltd.,
Units 23-24, Tafarnaubach Industrial Estate, Tafarnaubach, Tredegar, Gwent NP22 3AA
Telephone number: 01495 711222
Fax number: 01495 711225
Data Management and Statistics
P.N. Lee Statistics and Computing Ltd
Hamilton House, 17 Cedar Road, Sutton, Surrey SM2 5DA
Telephone number: 0208 6428265
Fax number: 0208 6422135
E-mail:
Monitoring Organisations
Clinical Development & Support Services Limited
Suite 5, Silk House, Park Green, Macclesfield, Cheshire SK11 7QJ
Telephone number: 01625 617 447
Fax number: 0870 0940730
E-mail:
Mrs Mary Mumford
19 Charles Jarvis Court, Cupar, Fife KY15 5EJ
Telephone number: 01334 654282
E-mail:
1.3 PROTOCOL APPROVAL
PROTOCOL APPROVAL SHEETTRIAL CODE / CT EP02
PROTOCOL TITLE / A MULTICENTRE PHASE III TRIAL OF 1,2-OCTANEDIOL AT 5%(W/V) (KINDAPEDTM) COMPARED WITH MALATHION 0.5% (W/V) (DERBAC-M LIQUID) IN THE TREATMENT OF HEAD LICE
AUTHOR(S) / Author Graeme Scott, PSCR
(Signature) (Date)
Statistics Section Peter N Lee, P.N Lee Statistics and Computing Ltd.
(Signature) (Date)
APPROVAL / Medical Advisor Dr Veronica Tebbs
(Signature) (Date)
Sponsor Representative Dr Magnus Nicolson
(Signature) (Date)
Chief Investigator Mr Ian Burgess
(Signature) (Date)
1.4 INVESTIGATOR SIGNATURE SHEET
Investigator Signature Sheet
By signing below, I agree to the conditions relating to this trial as set out in this protocol (CT EP02 dated 04 December 2007).
I agree to conduct this clinical trial according to Good Clinical Practice (ICH GCP) and European Regulatory Requirements.
I fully understand that any changes instituted by me without previous discussion with EctoPharma Ltd. or their designated representative constitute a violation of the protocol.
I agree to adhere to the protocol in all circumstances other than where necessary to protect the well-being of the subject.
I will ensure that the trial products supplied by EctoPharma will be used only for administration to subjects included in this trial protocol and for no other purpose.
Principal Investigator’s
Name:______
Signature:______Date______
EUDRACT NO: 2007-001872-36 Page 1 of 45
Trial Code: CT EP02
Amendment 2: 04 December 2007 CONFIDENTIAL
1.5 TABLE OF CONTENTS
1. TITLE PAGE, RESPONSIBLE PERSONNEL, PROTOCOL APPROVAL AND INVESTIGATOR SIGNATURES...... 2
1.1 TITLE PAGE...... 2
1.2 OTHER RESPONSIBLE PERSONNEL...... 3
1.3 PROTOCOL APPROVAL...... 5
1.4 INVESTIGATOR SIGNATURE SHEET...... 6
1.5 TABLE OF CONTENTS...... 7
1.6 PROTOCOL SYNOPSIS...... 10
1.7 GLOSSARY OF TERMS...... 14
2. INTRODUCTION...... 15
3. OBJECTIVES...... 16
3.1 PRIMARY OBJECTIVE...... 16
3.2 SECONDARY OBJECTIVES...... 16
4. TRIAL DESIGN...... 16
4.1 OVERVIEW...... 16
4.2 DISCUSSION OF TRIAL DESIGN...... 18
4.3 STUDY CENTRES...... 18
4.4 SUBJECT NUMBERS……………………………………...... 18
4.5 SUBJECT INCLUSION CRITERIA...... 18
4.6 SUBJECT EXCLUSION CRITERIA...... 19
4.7 CONDUCT OF THE TRIAL...... 19
4.8 SCHEDULE OF TRIAL ACTIVITIES...... 24
5. TRIAL PRODUCTS...... 25
5.1 INVESTIGATIONAL product...... 25
5.2 Comparator...... 25
5.3 DOSAGE AND ADMINISTRATION...... 25
5.4 STORAGE...... 26
5.5 PACKAGING AND LABELLING...... 26
5.6 ASSIGNMENT OF TREATMENT...... 27
5.7 BLINDING...... 27
5.8 ACCOUNTABILITY OF DRUG AND SUBJECT COMPLIANCE...... 28
5.9 CONCOMITANT TREATMENT...... 28
5.10 WARNINGS AND PRECAUTIONS...... 29
5.11 AVAILABILITY OF TREATMENT AFTER THE TRIAL...... 29
6. TRIAL METHODS AND ASSESSMENTS...... 29
6.1 MEASURES OF OUTCOME...... 29
6.1.1 ASSESSMENT OF OUTCOME...... 30
6.1.2 PRIMARY OUTCOME...... 31
6.1.3 OTHER OUTCOMES...... 31
6.2 SAFETY ASSESSMENTS...... 31
6.2.1 ADVERSE EVENTS...... 31
6.2.2 SERIOUS ADVERSE EVENTS...... 32
6.3 PREMATURE DISCONTINUATION...... 33
6.4 REPLACEMENT POLICY FOR SUBJECTS WHO DISCONTINUE...... 34
7. STATISTICAL ANALYSIS...... 34
7.1 PRIMARY ENDPOINT...... 34
7.2 Secondary endpoints...... 34
7.3 Definition of Populations to be analysed...... 35
7.4 Statistical Methods...... 35
7.5 SAMPLE SIZE...... 35
8. ETHICAL AND REGULATORY CONSIDERATIONS...... 37
8.1 REGULATORY ISSUES...... 37
8.2 INDEMNITY, INSURANCE AND COMPENSATION...... 37
8.3 INFORMED CONSENT...... 37
8.4 APPROVALS...... 38
8.4.1 ETHICS COMMITTEE APPROVAL...... 38
8.4.2 MANAGEMENT APPROVAL...... 38
8.5 TRIAL DOCUMENTATION AND TRIAL CONFIDENTIALITY...... 39
8.5.1 TRIAL DOCUMENTATION, CRFS AND DOCUMENT KEEPING...... 39
8.5.2 DATA MANAGEMENT...... 41
8.5.3 CONFIDENTIALITY OF TRIAL DOCUMENTATION AND SUBJECT RECORDS..41
8.5.4 CONFIDENTIALITY OF PROPRIETARY INFORMATION...... 41
8.5.5 DATA PROTECTION...... 42
9. PUBLICATION OF DATA...... 42
10. ADMINISTRATIVE PROCEDURES...... 42
10.1 QUALITY ASSURANCE...... 42
10.2 MONITORING...... 42
10.3 PROTOCOL AMENDMENTS...... 43
10.4 ADMINISTRATIVE AND FINANCIAL AGREEMENT...... 43
10.5 TRIAL SCHEDULE...... 44
10.6 END OF TRIAL...... 44
10.7 INVESTIGATOR RESPONSIBILITIES...... 44
11. REFERENCES...... 44
EUDRACT NO: 2007-001872-36 Page 1 of 45
Trial Code: CT EP02
Amendment 2: 04 December 2007 CONFIDENTIAL
LIST OF APPENDICES
Appendix 1: Sample subject/guardian consent/assent forms
Appendix 2: Schedule of Trial Activities
Appendix 3: Serious Adverse Event Form
1.6 PROTOCOL SYNOPSIS
TITLE / A Multicentre Phase III trial of 1,2-octanediol at 5%(w/v) (KindaPed™) compared with malathion 0.5% (w/v) (DERBAC-M LIQUID) in the treatment of head liceTRIAL CODE / CT EP02
PHASE / Phase III
OBJECTIVE / The primary objective of the clinical trial is to compare the efficacy of each of two different application regimens (2-hour and 8-hour) of KindaPed™ with the standard regimen of Derbac-M Liquid in eliminating infestation (achieving cure or re-infestation) following two treatment applications.
The secondary objectives of the clinical trial include the comparison of each of two different application regimens of KindaPed™ with the standard regimen of Derbac-M Liquid in respect of the following:
· Efficacy in achieving ‘cure’, based only on the assessments at Days 2 and 6, following the first treatment application.
· Efficacy in killing head lice after two applications.
· Efficacy in killing louse eggs after two applications.
· Safety profile, as determined by the occurrence of adverse events.
· Ease of application.
· Subject assessment of acceptability.
TRIAL DURATION / Subjects will be in the clinical trial for approximately two weeks with treatment applied on Days 0 and 7.
TRIAL DESIGN / A phase III, randomised, assessor-blind, multicentre, parallel group trial of two treatment regimens of KindaPed™ and a comparator product (Derbac-M Liquid).
NUMBER OF SUBJECTS / A total of 510 subjects (170 in each of three treatment groups) will be recruited.
MAIN SELECTION CRITERIA
. / 1. Subjects aged four or over.
2. Subjects who upon examination are confirmed to have live head lice.
3. Subjects who have given written informed consent, or, if the subject is less than 16 years of age, whose parent/guardian has given written informed consent to participate in the study.
4. Subjects who will be available for home visits from research staff over the 15 days of the study.
TREATMENTS / KindaPed™ contains:
Active: 1, 2-octanediol at 5% (w/v).
Excipients:Propan-2-ol (IPA)/water 20% (v/v); Sodium Dodecyl Sulphate (SDS) 0.64%
The product will packed in 100 mL low density polyethylene (LDPE) plastic bottles with an applicator nozzle.
Derbac-M Liquid contains:
Active: Malathion at 0.5% (w/v)
Excipients:Methylhydroxybenzoate; Propylhydroxybenzoate; Lanette Wax SX; Potassium Citrate; Citric Acid; Perfume HT 52; Water.
The product is packed in 200 mL clear or amber glass bottles with polyethylene caps.
ADMINISTRATION / Treatment will be administered on Days 0 and 7 by research staff, who will not be involved in the assessment of the treated subjects.
KindaPed™
KindaPed™ will be applied directly to dry hair. Sufficient product will be applied to thoroughly moisten the hair and scalp. More than one bottle may be used if required (maximum of two bottles).
The period of time for which the product will be left in the hair prior to removal by shampooing will be determined by randomisation. This will be either:
1. At least two hours and no more than two and a half hours before being shampooed, using non-medicated, conditioner-free shampoo which will be supplied for the study, and rinsed off with water.
2. At least eight hours and no more than twelve hours before being shampooed, using non-medicated, conditioner-free shampoo which will be supplied for the study, and rinsed off with water.
Following application of KindaPed™ the hair will be left to dry naturally in a well-ventilated room. Once the treatment has been removed from the hair it can be styled as normal and a hair dryer can be used.
Derbac-M Liquid
Derbac-M Liquid will be rubbed into the scalp until all the hair and scalp are thoroughly moistened. The hair will be left to dry naturally in a well-ventilated room. After 12 hours (or the next day if preferred) the hair will be shampooed using a non-medicated, conditioner-free shampoo which will be supplied for the study, and rinsed off with water. Once the treatment has been removed from the hair it can be styled as normal and a hair dryer can be used.
A maximum of one bottle will be used for each treatment application.
PROCEDURE / At the recruitment visit (Day 0, Visit 1) verbal consent will be obtained to check for the presence of live head lice by dry combing the hair using a fine-toothed plastic louse detection comb. Lice found during the assessment will not be removed. Other family members who give their verbal permission can also be assessed for the presence of living lice. After the preliminary assessment, subjects can be enrolled to the study, provided they comply with the inclusion/exclusion criteria, and any further questions they may have are fully dealt with. Family members or other members of the household who have lice but are unable or unwilling to join the study will be offered an acceptable, commercially available alternative treatment (Hedrin 4% Lotion).
Subjects (or their parents/guardians if they are aged less than 16 years) will be asked to give written informed consent before participation in the trial. Baseline data will be recorded in the CRF and subjects will be randomised to determine which study treatment they will receive. Treatment will be applied on Day 0 and again on Day 7 (+/- 1 day) by a member of the study team not involved in the subjects’ follow up assessments. The subject will be asked to shampoo the treatment out, using a non-medicated, conditioner-free shampoo. Subjects will be assessed, at their home, for the presence of live head lice on Days 2, 6, 9 and 14 (+/- 1 day at each assessment) by a different assessor from the person who treated them. Any lice found at these assessments will be taped on to a sample form within the subject’s case report form (CRF). Shampoo to be used by the subjects will be supplied.
The study team member who applied the treatment will complete a questionnaire after the first treatment application. At the final visit (Day 14) the subject and/or parent/guardian will complete a questionnaire on the treatment that was applied at Day 0 and Day 7.
STATISTICS / For each regimen of KindaPed™, a test will be carried out of the superiority of the KindaPed™ rate of cure or re-infestation over that for Derbac-M Liquid.
Analyses will be conducted based on both the intention to treat (ITT) and the efficacy populations. 97.5% confidence intervals (CI) will be estimated for the primary and some secondary endpoints, 97.5% rather than 95% CI being used to take into account multiple comparisons (of two regimens of KindaPed™ each with Derbac-M Liquid). The distribution of baseline characteristics, safety and ease of use, acceptability and efficacy will be tabulated and analysed.
FOLLOW UP / The results of this phase III study will be used to support an application for Marketing Authorisation for KindaPed™.
1.7 GLOSSARY OF TERMS
ABPI / Association of British Pharmaceutical IndustryCI / Confidence interval
CRF / Case report form
CV / Curriculum vitae
GCP / Good clinical practice
GP / General Practitioner
ICH / International Conference on Harmonisation
IEC / Independent ethics committee
IPA / Isopropyl alcohol
ITT / Intention to treat
LDPE / Low density polyethylene
mL / Millilitre
MREC / Multicentre Research Ethics Committee
NHS / National Health Service
REC / Research Ethics Committee
SAE / Serious adverse event
SDS / Sodium dodecyl sulphate
SSI / Site specific information
SUSAR / Suspected, unexpected serious adverse reactions
v/v / Volume per unit volume
w/v / Weight per unit volume
2. INTRODUCTION
The incidence and prevalence of head lice is no longer monitored in the UK, but recent work commissioned by the Welsh National Assembly showed 8% of children in primary schools had head lice on the day of the check, indicating that almost 1 in 10 of primary school children within the Principality have the infection at any one time (1). Further work carried out in the former North Essex Health Authority gave a prevalence of 2.03% on the day of inspection whilst the results of a questionnaire showed an annual incidence of 37.4% (2).