Clinical Trial Results:
A randomised phase II multi-centre trial of topical treatment in women with vulval intraepithelial neoplasia
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Summary
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EudraCT number |
2006-004327-11 |
Trial protocol |
GB |
Global end of trial date |
28 Apr 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Nov 2018
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First version publication date |
09 Nov 2018
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Other versions |
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Summary report(s) |
2006-004327-11 Synopsis 2006-004327-11 Publication |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
SPON 245-06
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Additional study identifiers
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ISRCTN number |
ISRCTN34420460 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Cardiff University
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Sponsor organisation address |
30-36 Newport Road, Cardiff, United Kingdom, CF24 0DE
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Public contact |
Margherita Carucci, Centre for Trials Research, +44 02920687900, RT3VIN@cardiff.ac.uk
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Scientific contact |
Chris Hurt, Centre for Trials Research, +44 02920687471, HurtCN@cardiff.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Feb 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
18 Sep 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Apr 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To determine whether there is evidence that either (or both) of the topical treatments are active, safe and feasible to use, and would therefore warrant further investigation in a phase III setting.
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Protection of trial subjects |
The IDMC reviewed the interim data approximately 6 months after the date of randomisation of the first participant. These analyses was carried out to safeguard the interests of trial participants, monitor the main outcome measures including safety and efficacy, and monitor the overall conduct of the trial.
SAE reporting was done in real time according to regulatory requirements.
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Background therapy |
N/A | ||
Evidence for comparator |
Cidofovir is a nucleoside analogue with antiviral properties and proven activity in comparable disease (cervical intraepithelial neoplasia). In a pilot study of 15 women with cervical intraepithelial neoplasia type 3, seven (47%) of 15 women had a complete response after topical application of the drug. In a pilot study of cidofovir for vulval intraepithelial neoplasia grade 3, four (40%) of ten women had a complete response at the end of follow-up. Imiquimod is a drug that modifies the immune response. In previous small studies of topical imiquimod (n≤15), a complete response was reported in 28 (41%) of 67 women with vulval intraepithelial neoplasia, but with substantial variation among studies (0–73%). | ||
Actual start date of recruitment |
07 Oct 2009
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy, Scientific research | ||
Long term follow-up duration |
24 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 180
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Worldwide total number of subjects |
180
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EEA total number of subjects |
180
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
180
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
180 female participants were recruited from 32 UK sites between 21 Oct 2009 and 11 Jan 2013. | |||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Potential participants were given a copy of the PIS and signed a copy of the Consent Form before the screening assessments were carried out to confirm their eligibility. The screening assessments included: Medical history, Assessment of toxicities, Clinical assessment of lesions, Urinalysis, and Pregnancy test (in women with childbearing potential) | |||||||||||||||||||||||||||
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Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Imiquimod | |||||||||||||||||||||||||||
Arm description |
Imiquimod (5% concentration) was supplied in boxes of 12 individual sachets (one sachet per application). Imiquimod was applied three times a week for a period of 24 weeks, unless a complete response was observed earlier. A thin layer was spread over the whole affected area at night and the area was washed using aqueous cream and water the following day. Imiquimod was taken from commercial stock. However, as it was used outside of its licensed indication, separate labels were added to the boxes of imiquimod before being dispensed to the sites. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
Imiquimod
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Investigational medicinal product code |
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Other name |
Aldara 5% cream
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Pharmaceutical forms |
Cream
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Routes of administration |
Local use
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Dosage and administration details |
Imiquimod (5% concentration) was supplied in boxes of 12 individual sachets (one sachet per application). Imiquimod was applied three times a week for a period of 24 weeks, unless a complete response was observed earlier. A thin layer was spread over the whole affected area at night and the area was washed using aqueous cream and water the following day.
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Arm title
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Cidofovir | |||||||||||||||||||||||||||
Arm description |
Cidofovir was supplied in a 10g tube (1% concentration) containing a six week supply. It was manufactured in a topical formulation by St Marys Pharmaceutical Unit (SMPU), who dispensed the tubes of gel to the local pharmacies. Participants applied Cidofovir three times a week for a period of 24 weeks, unless a complete response was observed earlier. A thin layer was spread to cover the affected area at night and the area was washed using aqueous cream and water the following day. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
Cidofovir
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Investigational medicinal product code |
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Other name |
Vistide
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Pharmaceutical forms |
Gel
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Routes of administration |
Local use
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Dosage and administration details |
Participants applied Cidofovir three times a week for a period of 24 weeks, unless a complete response was observed earlier. A thin layer was spread to cover the affected area at night and the area was washed using aqueous cream and water the following day.
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Baseline characteristics reporting groups
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Reporting group title |
Imiquimod
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Reporting group description |
Imiquimod (5% concentration) was supplied in boxes of 12 individual sachets (one sachet per application). Imiquimod was applied three times a week for a period of 24 weeks, unless a complete response was observed earlier. A thin layer was spread over the whole affected area at night and the area was washed using aqueous cream and water the following day. Imiquimod was taken from commercial stock. However, as it was used outside of its licensed indication, separate labels were added to the boxes of imiquimod before being dispensed to the sites. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cidofovir
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Reporting group description |
Cidofovir was supplied in a 10g tube (1% concentration) containing a six week supply. It was manufactured in a topical formulation by St Marys Pharmaceutical Unit (SMPU), who dispensed the tubes of gel to the local pharmacies. Participants applied Cidofovir three times a week for a period of 24 weeks, unless a complete response was observed earlier. A thin layer was spread to cover the affected area at night and the area was washed using aqueous cream and water the following day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Imiquimod
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Reporting group description |
Imiquimod (5% concentration) was supplied in boxes of 12 individual sachets (one sachet per application). Imiquimod was applied three times a week for a period of 24 weeks, unless a complete response was observed earlier. A thin layer was spread over the whole affected area at night and the area was washed using aqueous cream and water the following day. Imiquimod was taken from commercial stock. However, as it was used outside of its licensed indication, separate labels were added to the boxes of imiquimod before being dispensed to the sites. | ||
Reporting group title |
Cidofovir
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Reporting group description |
Cidofovir was supplied in a 10g tube (1% concentration) containing a six week supply. It was manufactured in a topical formulation by St Marys Pharmaceutical Unit (SMPU), who dispensed the tubes of gel to the local pharmacies. Participants applied Cidofovir three times a week for a period of 24 weeks, unless a complete response was observed earlier. A thin layer was spread to cover the affected area at night and the area was washed using aqueous cream and water the following day. | ||
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End point title |
Histologically proven complete response [1] | |||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
6 weeks after stopping treatment (maximum 30 weeks after starting treatment)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical test was used in the analysis of the primary endpoint of this trial. Each arm used a Flemings single stage design (p0=0.3, p1=0.45, alpha=0.05, power=90%) . |
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| No statistical analyses for this end point | ||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Up to 6 weeks after end of treatment (maximum 30 weeks)
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Adverse event reporting additional description |
Adverse events are assessed by clinical examination every 6 weeks during treatment and 6 weeks after the end of treatment
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
3
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Reporting groups
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Reporting group title |
Imiquimod
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Reporting group description |
Imiquimod (5% concentration) was supplied in boxes of 12 individual sachets (one sachet per application). Imiquimod was applied three times a week for a period of 24 weeks, unless a complete response was observed earlier. A thin layer was spread over the whole affected area at night and the area was washed using aqueous cream and water the following day. Imiquimod was taken from commercial stock. However, as it was used outside of its licensed indication, separate labels were added to the boxes of imiquimod before being dispensed to the sites. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cidofovir
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Reporting group description |
Cidofovir was supplied in a 10g tube (1% concentration) containing a six week supply. It was manufactured in a topical formulation by St Marys Pharmaceutical Unit (SMPU), who dispensed the tubes of gel to the local pharmacies. Participants applied Cidofovir three times a week for a period of 24 weeks, unless a complete response was observed earlier. A thin layer was spread to cover the affected area at night and the area was washed using aqueous cream and water the following day. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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09 Dec 2008 |
Protocol Update Version 1.1 dated 30th September to Version 2.0 dated 23rd October 2008.
Addition of new PI’s/Research sites as follows:
• Mike Cohn-Hereford County Hospital
• Peter Baldwin-Addenbrookes Hospital
• Margaret Cruickshank-Aberdeen Royal Infirmary
• Allan MaClean –Royal Free Hospital
• Henry Kitchner-St. Marys Manchester
• John Tidy-Royal Hallamshire Hospital
• Paul Flyn-Singleton Hospital
• Pierre-Martin-Hirsch-Royal Preston Hospital
• Dirk Brinkmann-St. Marys Portsmouth
• Nick Johnson-Royal United Hospital
• Omer Devaja-Maidstone Hospital
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20 Mar 2009 |
Modification of Patient Information Sheets 2 and 3
PIS 2 Version 1.0 (05/02/09) changed to Version 1.2(05/02/09)
PIS 3 Version 1.0 (?)changed to Version 1.2(05/02/09)
Addition of new PI’s/Research sites as follows:
• Simon Leeson-Ysbyty Gwynedd
• Charles Redman-Uni Hospital of North Staffordshire
• Nick Johnson-Royal United Hospital Bath
• Elizabeth Derrick- Royal Sussex County Hospital
• Ghee-Kheng Chew-Northampton General Hospital
• Jill Adams-Torbay Hospital
• David Rowen-Royal South Hants Hospital
• Margaret Cruikshank-Aberdeen Royal Infirmary
• Nagindra Das-Royal Cornwall Hospital
• Rahul Nath-Guy’s Hospital
• Partha Sengupta-Uni Hospital of North Durham
• Nailah Nisar-Royal Surrey County Hospital
• Janet McLelland-Royal Victoria Infirmary
• Simon Leeson-Glan Glwd Hospital
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29 May 2009 |
Addition of new PI’s/Research sites as follows:
Shelia Pearson-Cumberland Royal Infirmary
Frank Lawton-Kings College Hospital
Change of PI:
Cathy Green-Ninewells Hospital
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25 Mar 2010 |
Protocol Update Version 2.0 (23/10/08) changed to Version 2.1(Feb 2010).
Addition of new PI’s/Research sites as follows:
• Farhana Ravat-Hillingdon Hospital
• Michael Rymer-Worthing Hospital
• Marcia Hall-Wexham Park Hospital
Change of PI:
Steven Attard Montalto-Musgrove Park Hospital
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09 Nov 2010 |
Protocol Update Version 2.1(Feb 2010) changed to Version 3.0(01-10-2010)
• Change of CI from Prof Alison Fiander to Dr Amanda Tristram
• Change of Trial Manager from Dr Jeanette Issac to Dr Tracie Madden
• Addition of Safety Officer contact details (Mrs Liz Merrifield)
PIS 2 Version 1.2 05-02-2009 changed to Version 2.0 01-10-2010
PIS 3 Version 1.2 05-02-2009 changed to Version 2.0 01-10-2010
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28 Sep 2011 |
Protocol Update Version 3.0 (01 Oct 2010) changed to version 4.0 (01 May 2011):
• To clarify the procedures for proteinuria testing
• To alter inclusion criteria 3 on lesion size
• To clarify the wording around contraception in inclusion criteria 4
• To clarify the instructions on how to take the post-treatment assessment visit biopsy
• To clarify rules pertaining to the crossover of patients from one trial arm to the other
• To clarify how new lesions should be treated and measured
• To update Appendix 1: Response Evaluation Criteria in Solid Tumours
• To update the expected adverse reactions with new information from the updated SPCs for imiquimod and cidofovir
• To simplify wording used to describe primary outcome measure
To alter the name of the Chief Investigator on the imiquimod IMP label
To seek approval for the use of Pregnancy Information Sheet and Consent Form Version 1.0 dated 24 Jun 2011
• To state the alternative topical analgesics that can be used in order of preference should there be another national shortage of 5% Lignocaine
To add 5 new research sites/Principal Investigators (PIs):
• Jonathan Frappell Derriford Hospital
• Brett Winter-Roach Salford FoundationTrust Hospital
• Usha Natarajan East Surrey Hospital
• Bruce Ramsay Peterborough City Hospital
• David Pickrell Worcester Royal Hospital
To change the PI at 3 existing research sites:
• Stephen Attard Montalto-Maidstone Hospital
• Kathryn Hillaby-Cheltenham General Hospital
• Kathryn Hillaby -Gloucester Royal Hospital
• To close Countess of Chester Hospital:
• Jeremy Hawe-Countess of Chester Hospital
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25 Jan 2012 |
To add 3 new research sites/Principal Investigators (PIs):
• Clive Gie- Kings Mill Hospital
• Tarang Majmudar-Hinchingbrooke Hospital
• Alaa Elghobashy-New Cross Hospital
To close 2 research sites:
• Marcia Hall-Wexham Park Hospital
• Charles Redman-University Hospital North Staffordshire
To change PI at 2 existing sites:
• Alastair Duncan-Northampton General Hospital
• Nicholas James Wood-Royal Preston Hospital |
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15 Aug 2012 |
To add 2new research sites/Principal Investigators (PIs):
• Karen Gibbon- Whipps Cross University Hospital
• Kyle Gilmour –Tameside NHS Foundation Trust
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Neither limitations nor caveats were applicable to this summary of the results. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/25304851 http://www.ncbi.nlm.nih.gov/pubmed/29336101 http://www.ncbi.nlm.nih.gov/pubmed/28600473 |
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