Clinical Trials Register

Summary
EudraCT Number:	2018-003507-19
Sponsor's Protocol Code Number:	HOPE9
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-05-24
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-003507-19

A.3

Full title of the trial

“Phase III, randomized, double-blind, placebo-controlled multicenter study to evaluate the efficacy of pre-surgical HPV 9-valent vaccination in women treated with electrosurgical excision with diathermic loop (LEEP) for high-grade cervical intraepithelial neoplasia (CIN2 +) up to initially invasive cervical cancer (FIGO IA1) - HOPE 9 STUDY”

“Studio di fase III, randomizzato, in doppio cieco, controllato con placebo multicentrico, per valutare l’efficacia della vaccinazione anti HPV 9-valente pre-chirurgica in donne trattate con escissione elettrochirurgica con ansa diatermica (LEEP) per neoplasia cervicale intraepiteliale di alto grado (CIN2+) fino a cancro cervicale inizialmente invasivo (FIGO IA1) - HOPE 9 STUDY”

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Impact on Disease Relapse of HPV Vaccination in Women Treated With electrosurgical excision with diathermic loop (LEEP) for Cervical Intraepithelial Neoplasia.

Impatto sulla recidiva di malattia della vaccinazione anti-HPV nelle donne trattate con escissione elettrochirurgica con ansa diatermica (LEEP) per neoplasia cervicale intraepiteliale.

A.3.2

Name or abbreviated title of the trial where available

HOPE9

A.4.1

Sponsor's protocol code number

HOPE9

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03848039

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AZIENDA USL TOSCANA NORD OVEST
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	MSD ITALIA
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AZIENDA USL TOSCANA NORD OVEST
B.5.2	Functional name of contact point	TASK FORCE SPERIMENTAZIONI
B.5.3	Address:
B.5.3.1	Street Address	VIA COCCHI 7/9
B.5.3.2	Town/ city	PISA
B.5.3.3	Post code	56121
B.5.3.4	Country	Italy
B.5.4	Telephone number	0586223031
B.5.5	Fax number	0586223217
B.5.6	E-mail	sperimentazioni.cliniche@uslnordovest.toscana.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	GARDASIL9 0,5 ml - sospensione iniettabile - uso intramuscolare – siringa pre-riempita (vetro) - 1 siringa preriempita + 2 aghi
D.2.1.1.2	Name of the Marketing Authorisation holder	MSD ITALIA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	GARDASIL9 0,5 ml - sospensione iniettabile - uso intramuscolare – siringa pre-riempita (vetro) - 1 s
D.3.2	Product code	[GARDASIL9 0, 5 ml - sospensione iniettabile - uso
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Papillomavirus (tipi umani 6,11,16,18,31,33, 45,52,58)
D.3.9.2	Current sponsor code	Proteina L1 tipi 6,11,16,18,31,33, 45,52,58 di Papillomavirus umano
D.3.10	Strength
D.3.10.1	Concentration unit	DF dosage form
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solvent for parenteral use
D.8.4	Route of administration of the placebo	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Prevention of recurrence after a first episode of high-grade cervical intraepithelial neoplasia (CIN2 +) up to initially invasive cervical cancer (FIGO IA1)

Prevenzione della recidiva dopo un primo episodio di neoplasia cervicale intraepiteliale di alto grado (CIN2+) fino a cancro cervicale inizialmente invasivo (FIGO IA1)

E.1.1.1

Medical condition in easily understood language

Prevention of recurrence after a first episode of high-grade cervical intraepithelial neoplasia up to initially invasive cervical cancer

Prevenzione della recidiva di malattia dopo un primo episodio di neoplasia cervicale intraepiteliale di alto grado fino a cancro della cervice inizialmente invasivo

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10008229
E.1.2	Term	Cervical cancer
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10056576
E.1.2	Term	Cervical intraepithelial neoplasia
E.1.2	System Organ Class	100000004872

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10064328
E.1.2	Term	Human papilloma virus test positive
E.1.2	System Organ Class	10022891 - Investigations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the impact of pre-surgical HPV 9-valent vaccination in patients subjected to conization for the management of high-grade cervical intraepithelial neoplasia (CIN2 +) and initially invasive cervical cancer in terms of possible reduction of recurrent post-surgical disease.

Valutare l'impatto della vaccinazione anti HPV 9-valente pre-chirurgica in pazienti sottoposte a conizzazione per la gestione della neoplasia cervicale intraepiteliale di alto grado (CIN2+) e del cancro cervicale inizialmente invasivo in termini di possibile riduzione di recidiva di malattia post chirurgica.

E.2.2

Secondary objectives of the trial

1. Analysis of the possible impact of the 9-valent vaccine on the post-surgical natural history of HPV infection.
2. Evaluation of 9-valent HPV vaccination in patients treated for CIN2 + in terms of possible reduction of the follow-up scheme in the cervical screening program (investigation on the possible temporal reduction of post-surgical surveillance).

1. Analisi del possibile impatto del vaccino 9-valente sulla storia naturale post-chirurgica dell'infezione da HPV.
2. Valutazione della vaccinazione anti HPV 9-valente nelle pazienti trattate per CIN2+ in termini di possibile riduzione dello schema di follow-up nel programma di screening cervicale (indagine sulla possibile riduzione temporale della sorveglianza post-chirurgica).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients = 18 years old and ecog performance status = 1
2. Patients diagnosed with high-grade cervical intraepithelial neoplasia or initially invasive cervical cancer (histological findings = CIN2 + and = Ia1 according to the FIGO staging of cervical cancer)
3. No fever at the time of vaccination
4. No previous HPV vaccination
5. Ability to understand and write in Italian
6. Signature of informed consent and consent to personal data

1. Pazienti di età =18 anni e con ecog performance status = 1
2. Pazienti con diagnosi di neoplasia intraepiteliale cervicale di alto grado o cancro cervicale inizialmente invasivo (risultati istologici = CIN2+ e = Ia1 secondo la stadiazione FIGO del cancro cervicale)
3. Assenza di febbre al momento della vaccinazione
4. Assenza di pregressa vaccinazione anti HPV
5. Capacità di comprendere e scrivere in italiano
6. Firma del consenso informato e del consenso al trattamento dei dati personali

E.4

Principal exclusion criteria

1. Patients enrolled in other clinical trials
2. History of allergic reaction or serious adverse events to previous vaccinations
3. Assessment of the state of pregnancy at the time of vaccination
4. Patients on immunosuppressive therapy
5. Subjects who received immunoglobulins or blood products in the 3 months prior to vaccination.
6. Thrombocytopenia or any other coagulation disorder that may lead to bleeding following intramuscular administration
7. Clinical criteria contraindicating the surgical act of conization
8. ECOG performance status =2

1. Pazienti arruolate in altri studi clinici
2. Storia di reazione allergica o gravi eventi avversi a precedenti vaccinazioni
3. Accertamento dello stato di gravidanza al momento della vaccinazione
4. Pazienti in terapia immunosoppressiva
5. Soggetti che hanno ricevuto immunoglobuline o emoderivati nei 3 mesi precedenti alla vaccinazione.
6. Trombocitopenia o ogni altro disturbo della coagulazione che possa portare al verificarsi di un sanguinamento a seguito della somministrazione per via intramuscolare
7. Criteri clinici controindicanti l’atto chirurgico di conizzazione
8. ECOG performance status =2

E.5 End points

E.5.1

Primary end point(s)

- evaluation of the reduction of disease recurrence (cervical intraepithelial neoplasia up to microinvasive cervical cancer) by comparing the number of recurrences in the two arms.

- valutazione riduzione delle recidive di malattia (neoplasia cervicale intraepiteliale fino cancro microinvasivo della cervice) mediante confronto della numerosità delle recidive nei due bracci.

E.5.1.1

Timepoint(s) of evaluation of this end point

During the entire duration of the study

Per tutta la durata dello studio

E.5.2

Secondary end point(s)

Analysis of the impact of the vaccine on prevalent post-surgery infections by comparing the prevalence of persistent HPV infections (duration greater than 12 months after surgery) in the two arms.; Analysis of the impact of the vaccine in the post-surgical surveillance times, comparison of the viral wash-out times (negativity of the HPV test), times of negativization of the pap test and of the colposcopic exam in the post-operative period: comparison of the overexposed times of negativization in the two arms.

Analisi dell’impatto del vaccino sulle infezioni prevalenti post chirurgia mediante confronto della prevalenza delle infezioni persistenti HPV (durata maggiore di 12 mesi dalla chirurgia) nei due bracci.; Analisi dell’impatto del vaccino nei tempi di sorveglianza post chirurgica, confronto dei tempi di wash-out virale (negativizzazione del test HPV), tempi di negativizzazione del pap test e del quadro colposcopico nel periodo post operatorio: confronto dei tempi di negativizzazione sovraesposti nei due bracci.

E.5.2.1

Timepoint(s) of evaluation of this end point

During the entire duration of the study; During the entire duration of the study

Per tutta la durata dello studio; Per tutta la durata dello studio

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS - Last Visit Last Subject

ultima visita dell'ultimo soggetto - LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

1200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2021-05-24.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

Yes

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

1220

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1220

F.4.2.2

In the whole clinical trial

1220

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

As a routine clinical practice

Come normale pratica clinica

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-09-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-09-10

P. End of Trial
P.	End of Trial Status	Ongoing

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