Clinical Trials Register

Summary
EudraCT Number:	2022-000082-41
Sponsor's Protocol Code Number:	2021-0486
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-01-18
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

Spain - AEMPS

A.2

EudraCT number

2022-000082-41

A.3

Full title of the trial

Impact of pitavastatin use in prostate cancer patients treated with new generation androgen therapy: multicenter clinical
trial

Impacto del uso de pitavastatina en pacientes con cáncer de próstata tratados con terapia androgénica de nueva
generación: ensayo clínico multicéntrico

A.3.1

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

A clinical trial is being conducted to see the benefit of a known lipid-lowering drug such as pitavastatin in patients with advanced prostate cancer who are being treated with the new anti-androgens.

Se realiza un ensayo clínico para ver el beneficio que puede tener un fármaco hipolipemiante conocido como es pitavastatina en pacientes con cáncer de próstata avanzado y que están siendo tratados con los nuevos antiandrógenos

A.4.1

Sponsor's protocol code number

2021-0486

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	Fundación para la Investigación en Urología
B.1.3.4	Country	Spain
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	Fundación para la Investigación en Urología (FIU)
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Asociación Española de Urología
B.5.2	Functional name of contact point	FIU
B.5.3	Address:
B.5.3.1	Street Address	Valenzuela 6, 1º derecha
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28014
B.5.3.4	Country	Spain
B.5.4	Telephone number	34913640849
B.5.6	E-mail	aeu@aeu.es

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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	Pitavastatin: Livazo 2 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	KOWA PHARMACEUTICAL EUROPE GMBH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Pitavastatin
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Buccal use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
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	Capsule
D.8.4	Route of administration of the placebo	Buccal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

We propose a multicenter, prospective, randomized, single-blind clinical trial, without conflict of interest, to determine the
clinical benefit of statins (Pitavastatin 2 mg) in prostate cancer patients being treated with ARTA (enzalutamide, apalutamide, darolutamide and
abiraterone). As primary objectives we will determine
whether in the experimental group an increase in metastasis-free survival and radiological progression-free survival is
achieved.

Proponemos un ensayo clínico, randomizado y simple ciego, sin conflicto de intereses, para determinar el beneficio
clínico de las estatinas en pacientes con cáncer de próstata que están siendo tratados con ARTA (enzalutamida, apalutamida, darolutamida y abiraterona). Como objetivos
primarios determinaremos si en el grupo experimental se consigue un aumento de la supervivencia libre de metástasis
y en la supervivencia libre de progresión radiológica.

E.1.1.1

Medical condition in easily understood language

To determine whether a widely used drug (pitavastatin) may be beneficial in patients with advanced prostate cancer; it will be investigated whether it can delay disease progression.

Determinar si un fármaco ampliamente utilizado (pitavastatina), puede ser beneficioso en pacientes con cancer de próstata avanzado; se investigará si puede retrasar la progresión de la enfermedad.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary objective: to determine whether in the pitavastatin treatment group there is an increase in metastasis-free survival and/or radiological progression-free survival (RFS).
free survival and/or radiological progression free survival (rPFS) in the pitavastatin treatment group. We evaluated metastasis-free survival in the group of patients
in the group of patients with high-risk non-metastatic castration-resistant prostate cancer (mCRPC) and defined it as the time to onset of metastasis.
defined as the time until the appearance of the first metastasis and thus change of clinical stage to metastatic CRPC.
metastatic. PrFS is assessed in the groups of patients who are already metastatic, i.e. in the group of hormone-sensitive and hormone-resistant patients.
and castration-resistant patients and is defined as the time to the appearance of a new metastasis.
metastasis.

Objetivo primario: determinar si en el grupo de tratamiento con pitavastatina existe un aumento en la supervivencia libre de
metástasis y/o en la supervivencia libre de progresión radiológica (SLPr). La supervivencia libre de metástasis la evaluamos
en el grupo de pacientes con cáncer de próstata resistente a la castración no metastásicos de alto riesgo (CPRCnm) y la
definimos como el tiempo hasta la aparición de la primera metástasis y por lo tanto cambian de estadio clínico a CPRC
metastásicos. La SLPr se evalúa en los grupos de pacientes que ya son metastásicos, es decir, en el grupo de pacientes
hormonosensibles y en los resistentes a la castración y se define como el tiempo hasta la aparición de una nueva
metástasis.

E.2.2

Secondary objectives of the trial

Secondary objectives: to determine whether the pitavastatin treatment group has an increase in overall survival and a decrease in the risk of cardiovascular events vs.
survival and a decrease in the risk of cardiovascular events compared to the control group (placebo) and if there are also changes in the biochemical parameters of testosterone, PSA and
modifications in the biochemical parameters of testosterone, PSA and a modulation of the inflammatory response through the modification of the
inflammatory response by modifying the following haematological parameters: neutrophil/lymphocyte ratio (NL/RN/L), platelet ratio
(NR/L), platelet/lymphocyte ratio (PL/L), systemic inflammatory index (SII).

Objetivos secundarios: conocer además si en el grupo de tratamiento con pitavastatina se produce un aumento en la
supervivencia global y una disminución del riesgo de eventos cardiovasculares frente al grupo control (placebo) y si
además se producen modificaciones en los parámetros bioquímicos de Testosterona, PSA y una modulación de la
respuesta inflamatoria mediante la modificación de los siguientes parámetros hematológicos: ratio neutrófilo/linfocito
(RN/L), ratio plaquetas/linfocito (RP/L), índice sistémico de inflamación (ISI).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients with a histological diagnosis of prostate cancer, who are in one of the clinical stages listed in the inclusion criteria.
listed in the inclusion criteria
a) Inclusion criteria:
Patients with hormone-sensitive metastatic prostate cancer (HSPCm), who have not received previous line
a.1. Patients with hormone-sensitive metastatic prostate cancer (HSPC), who have not received previous superantiandrogens or chemotherapy.
a.2. Patients with metastatic castration-resistant prostate cancer (mCRPC), who have not received previous
a.2. Patients with metastatic castration-resistant prostate cancer (mCRPC), who have not received previous superantiandrogens or chemotherapy.
The criteria defining castration-resistant prostate cancer are:
- Three consecutive PSA elevations, separated by at least one week, with two 50% increments
above nadir and provided that this increase results in a PSA greater than 2 ng/ml.
- Testosterone levels below 50 ng/dl or 1.7 nmol/l.
- Progression of bone lesions ≥ 2 on bone scan or progression of soft tissue lesions according to the RECIST criteria.
RECIST criteriaa.

3. Non-metastatic castration-resistant prostate cancer (CRPCnm) and high-risk prostate cancer patients
(PSA doubling time < 6 months).

Patients with PCa will be treated with one of these 4 active drugs for their disease: a.4.
disease:
-Abiraterone
-Enzalutamide
-Apalutamide
-Darolutamide
a.5 Drug to be studied (dependent variable): pitavastatin 2 mg.
It should be taken into account that enzalutamide is a potent inducer of cytochrome CYP3A4 and may interact with
statins. Differences in hepatic metabolism of statins are of great importance, as they are the main cause of the different interactions between statins and statins.
the main cause of the different interactions of these drugs. Thus, atorvastatin, lovastatin and simvastatin are metabolised by isoform 3.
metabolised by the 3A4 isoform of cytochrome P450 (CYP3A4), and some drugs can substantially increase the plasma levels of these statins.
plasma levels of these statins and, as a consequence, increase the risk of myopathies. Similarly, there are
enzyme inducers that will decrease their pharmacological effect (1-3) , such as enzalutamide. Therefore, the
statin chosen for the study is pitavastatin since its concentration according to in vitro and in vivo data indicates that it is not
is metabolised by the 3A4 isoform of cytochrome P450 in a clinically significant amount, making it the statin with the fewest interactions.
statin with the fewest interactions. On the other hand, due to its lipophilic structure it has a wide
bioavailability, and can be found in significant concentrations in prostate cells (4)
.
1.Franco D, Henao Y, Monsalve M, et al. Hypolipidemic agents drug interactions: approach to establish and assess its clinical significance.
its clinical significance. Structured review. Farm Hosp. 2013 Nov-Dec;37(6):539-57.
2. Ríos González E, Martínez-Piñeiro L. Enzalutamide in castration resistant prostate cancer. Arch Esp Urol. 2018
Sep;71(8):664-675.
Narayanan R, Hoffmann M, Kumar G, et al. Application of a "Fit for Purpose" PBPK Model to Investigate the CYP3A4 Induction Potential of CYP3A4.
CYP3A4 Induction Potential of Enzalutamide. Drug Metab Lett. 2016;10(3):172-179.
4. Ahmad H, Cheng-Lai A. Pitavastatin: a new HMG-CoA reductase inhibitor for the treatment of
hypercholesterolemia. Cardiol Rev. 2010 Sep-Oct;18(5):264-7.

Pacientes con diagnóstico histológico de cáncer de próstata, que se encuentren en uno de los estadios clínicos que se
enumeran en los criterios de inclusión
a) Criterios de inclusión:
a.1. Pacientes con cáncer de próstata metastásico hormonosensibles (CPHSm), que no hayan recibido línea
previa con superantiandrógenos ni quimioterapia.
a.2. Pacientes con cáncer de próstata metastásico resistente a la castración (CPRCm), que no hayan recibido
línea previa con superantiandrógenos ni quimioterapia.
Los criterios que definen el cáncer de próstata resistente a la castración son:
- Tres elevaciones consecutivas de PSA, separadas por al menos una semana, con dos incrementos del 50%
sobre el nadir y siempre que este incremento de lugar a un PSA mayor de 2 ng/ml.
- Niveles de testosterona inferiores a 50 ng/dl ó 1.7 nmol/l.
- Progresión de lesiones óseas ≥ 2 en gammagrafía ósea o progresión de lesiones de tejidos blandos según
los criterios RECIST
a.3. Pacientes con cáncer de próstata resistente a la castración no metastásicos (CRPCnm) y de alto riesgo
(tiempo de duplicación de PSA < 6 meses)
a.4. Los pacientes con CaP estarán bajo tratamiento con unos de estos 4 fármacos activos para su enfermedad:
-Abiraterona
-Enzalutamida
-Apalutamida
-Darolutamida
a.5 Fármaco a estudiar (variable dependiente): pitavastatina 2 mg.
Hay que tener en cuenta que enzalutamida es un potente inductor del citocromo CYP3A4 y puede interaccionar con
las estatinas. Las diferencias en el metabolismo hepático de las estatinas tienen gran importancia, debido a que son la
principal causa de las distintas interacciones de estos fármacos. Así, atorvastatina, lovastatina y simvastatina se
metabolizan por la isoforma 3A4 del citocromo P450 (CYP3A4), existiendo fármacos que pueden elevar sustancialmente
los niveles plasmáticos de estas estatinas y, como consecuencia, aumentar el riesgo de miopatías. Igualmente, hay
inductores enzimáticos que disminuirán su efecto farmacológico (1-3), tal es el caso de enzalutamida. Por lo tanto, la
estatina elegida para el estudio es la pitavastatina ya que su concentración según datos in vitro e in vivo indican que no
es metabolizada por la isoforma 3A4 del citocromo P450 en una cantidad clínicamente significativa, por lo que es la
estatina que menos interacciones presenta. Por otro lado, debido a su estructura lipofílica tiene una amplia
biodisponibilidad, pudiendo encontrarse en concentraciones significativas en las células prostáticas (4).

1. Franco D, Henao Y, Monsalve M, et al. Hypolipidemic agents drug interactions: approach to establish and assess
its clinical significance. Structured review. Farm Hosp. 2013 Nov-Dec;37(6):539-57.
2. Ríos González E, Martínez-Piñeiro L. Enzalutamide in castration resistant prostate cancer. Arch Esp Urol. 2018
Sep;71(8):664-675.
3. Narayanan R, Hoffmann M, Kumar G, et al. Application of a "Fit for Purpose" PBPK Model to Investigate the
CYP3A4 Induction Potential of Enzalutamide. Drug Metab Lett. 2016;10(3):172-179.
4. Ahmad H, Cheng-Lai A. Pitavastatin: a new HMG-CoA reductase inhibitor for the treatment of
hypercholesterolemia. Cardiol Rev. 2010 Sep-Oct;18(5):264-7.

E.4

Principal exclusion criteria

Exclusion criteria:
Patients with hyperlipidaemia at the time of diagnosis whether or not under pharmacological treatment; b.2.
b.2. Patients with transaminase levels twice the normal value.
b.3. Patients in whom information on the variables under study is not available.
b.4. Patients who refuse to take part in the study or do not sign the informed consent form.

Criterios de exclusión:
b.1. Pacientes con hiperlipidemia en el momento del diagnóstico estén o no bajo tratamiento farmacológico
b.2. Pacientes con niveles de transaminasas dos veces por encima del valor normal.
b.3. Pacientes en los que no se disponga de información sobre las variables a estudio.
b.4. Pacientes que rechacen formar parte del estudio o no firmen el consentimiento informado del estudio.

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

2-3 years

2-3 años

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

2-3 years

2-3 años

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

Yes

E.6.4

Safety

E.6.5

Efficacy

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

Yes

E.8.4

The trial involves multiple sites in the 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

E.8.7

Trial has a data monitoring committee

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

Completion of the study
b.1. Patient who has progressed. Progression is defined as either a significant clinical deterioration with a change in the patient's
with a change in the patient's performance status (change in a point on the ECOG scale) or when a new metastasis is detected by radiological
radiological examinations detect a new metastasis. The evaluation of response and/or progression of the disease shall be performed according to RECIST 1.1 criteria.
b.2. Exitus of the patient.

Finalización del estudio
b.1. Paciente que haya progresado. Se definirá progresión cuando exista bien un deterioro clínico importante
con cambio del performan status del enfermo (cambio en un punto de la escala ECOG) o bien cuando se detecten
mediante exploraciones radiológicas una nueva metástasis. La evaluación a la respuesta y/o progresión de la
enfermedad se realizará siguiendo los criterios RECIST 1.1 (Response Evaluation Criteria In SolidTumors).
b.2. Exitus del paciente.

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

110

F.2 Gender

F.2.1

Female

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

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

150

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)

When patients progress (end-of-study criteria), pitavastatin will be discontinued and a second line of treatment (switch to ARTA or chemotherapy) will be offered.

Cuando los pacientes progresen (criterio de finalización del estudio), se le suspenderá pitavastatina y se le ofrecerá un asegunda linea de tratamiento (cambio de ARTA ó quimioterapia).

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

2022-03-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-03-17

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

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