Clinical Trials Register

Summary
EudraCT Number:	2017-000402-38
Sponsor's Protocol Code Number:	GS-US-418-4279
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-07-25
Trial results	View 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

2017-000402-38

A.3

Full title of the trial

A Randomized, Double-blind, Placebo-controlled Phase 2 Study to Evaluate the Testicular Safety of Filgotinib in Adult Males with Moderately to Severely Active Ulcerative Colitis

Estudio en fase II aleatorizado, doble ciego y controlado con placebo para evaluar la seguridad a nivel testicular de filgotinib en varones adultos con colitis ulcerosa de actividad moderada a intensa

A.3.1

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

A clinical trial to evaluate the testicular safety of Filgotinib in adult males with Ulcerative Colitis

Ensayo clinico para evaluar la seguridad testicular de Filgotinib en hombres adultos con Colitis Ulcerosa

A.4.1

Sponsor's protocol code number

GS-US-418-4279

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	Gilead Sciences, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Gilead Sciences Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Gilead Sciences International Ltd.
B.5.2	Functional name of contact point	Clinical Trials Mailbox
B.5.3	Address:
B.5.3.1	Street Address	Flowers Building, Granta Park
B.5.3.2	Town/ city	Abington, Cambridge
B.5.3.3	Post code	CB21 6GT
B.5.3.4	Country	United Kingdom
B.5.5	Fax number	+441223897284
B.5.6	E-mail	clinical.trials@gilead.com

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	No
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.3.2	Product code	GS-6034
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FILGOTINIB
D.3.9.2	Current sponsor code	GS-6034
D.3.9.4	EV Substance Code	SUB182273
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

To evaluate the testicular safety of filgotinib in adult males with ulcerative colitis

Evaluar la seguridad testicular de Filgotinib en hombres adultos con colitis ulcerosa

E.1.1.1

Medical condition in easily understood language

Ulcerative Colitis

Colitis ulcerosa

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10045365
E.1.2	Term	Ulcerative colitis
E.1.2	System Organ Class	100000004856

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 effect of filgotinib on testicular function as defined by the proportion of subjects with a ≥ 50% decrease from baseline in sperm concentration at Week 13

E.2.2

Secondary objectives of the trial

To evaluate the effect of filgotinib on testicular function as defined by the proportion of subjects with a ≥ 50% decrease from baseline in sperm concentration at Week 26
To evaluate the effect of filgotinib on sperm total motility at Weeks 13 and 26
To evaluate the effect of filgotinib on total sperm count at Weeks 13 and 26
To evaluate the effect of filgotinib on the change from baseline in sperm concentration at Weeks 13 and 26
To evaluate the effect of filgotinib on ejaculate volume at Weeks 13 and 26
To evaluate the effect of filgotinib on sperm morphology at Weeks 13 and 26

Evaluar el efecto de filgotinib en la actividad testicular, determinado por la proporción de pacientes con una reducción del ≥50 % en la concentración de espermatozoides en la semana 26 con respecto al valor inicial
Evaluar el efecto de filgotinib en la movilidad total de los espermatozoides en las semanas 13 y 26
Evaluar el efecto de filgotinib en el número total de espermatozoides en las semanas 13 y 26
Evaluar el efecto de filgotinib en el cambio en la concentración de espermatozoides en las semanas 13 y 26 con respecto al valor inicial
Evaluar el efecto de filgotinib en el volumen de esperma en las semanas 13 y 26
Evaluar el efecto de filgotinib en la morfología de los espermatozoides en las semanas 13 y 26

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

For a full list please see the study protocol.

- Male subjects who are between the ages of 25 and 55 (inclusive) on the day of signing informed consent

- Documented diagnosis of UC of at least 4 months AND with a minimum disease extent of 15 cm from the anal verge. Documentation should include endoscopic and histopathologic evidence of UC as follows:
a) The criteria for documentation of UC based on endoscopy will be medical record documentation of, or an endoscopy report dated ≥ 4 months before enrollment, which shows features consistent with UC, determined by the procedure performing physician
b) The criteria for documentation of UC based on histopathology will be medical record documentation of or a histopathology report indicating features consistent with UC as determined by the pathologist

- Have moderately to severely active UC defined as a Mayo Clinic Score ≥ 6 with a physician global assessment (PGA) of moderately to severely active UC (PGA of 2 or 3) and local endoscopic subscore at screening or in the prior 60 days of ≥ 2

- Previously demonstrated an inadequate clinical response, loss of response to, or intolerance of at least one of the following agents (depending on current country treatment recommendations/guidelines):
a) corticosteroids, b) immunomodulators, c) TNFα antagonists, d) vedolizumab

- May be receiving the following drugs (subjects on these therapies must be willing to remain on stable doses for the noted times):
a) 5-aminosalicylate (5-ASA) compounds provided the dose prescribed has been stable for at least 4 weeks prior to
randomization; dose must remain stable for the first 13 weeks after randomization
b) Azathioprine, 6-MP, or MTX provided the dose prescribed has been stable for 4 weeks prior to randomization; dose of MTX must remain stable for 26 weeks and dose of AZA/6-MP must remain stable for first 13 weeks but can be adjusted if indicated between 13 and 26 weeks.
c) Corticosteroid therapy (prednisone prescribed at a stable dose ≤ 20 mg/day or budesonide prescribed at a stable dose of ≤ 9 mg/day) provided the dose prescribed has been stable for 2 weeks prior to randomization; dose should be stable for the first 13 weeks if possible, upon which a steroid taper may commence at the discretion of the investigator.

- Provide semen samples at Screening that meet the following minimum criteria:
a) Semen volume ≥ 1.5 mL, total sperm per ejaculate ≥ 39 million, sperm concentration ≥ 15 million per mL, sperm total motility ≥ 40%, and normal sperm morphology ≥ 4%

- LH, FSH, inhibin B, and total testosterone values within 20% of laboratory normal reference ranges at Screening

- Be up to date on colorectal cancer surveillance as per local guidelines prior to screening.

Para un listado completo por favor consultar el protocolo del estudio

- Varones adultos de entre 25 y 55 años de edad (ambas incluidas) el día de la firma del consentimiento informado

• Diagnóstico documentado de CU con una duración mínima de 4 meses Y con una extensión mínima de la enfermedad de 15 cm desde el margen anal. La documentación debe incluir signos endoscópicos e histopatológicos de CU, de la siguiente manera:
a) Los criterios para la documentación de la CU basados en la endoscopia serán la documentación en la historia clínica de o un informe de una endoscopia realizada en un plazo de ≥4 meses antes de la inscripción, que muestre características compatibles con CU determinadas por el médico que realizó la intervención.
b) Los criterios para la documentación de la CU basados en la histopatología serán la documentación en la historia clínica de un estudio histopatológico, o un informe de este, que muestre características compatibles con CU determinadas por el anatomopatólogo.
• Presentar CU de actividad moderada a intensa definida por una Puntuación de la clínica Mayo ≥6, una evaluación global por parte del médico (PGA) de CU de actividad moderada a intensa (PGA de 2 o 3) y una subpuntuación endoscópica local en la selección o en los 60 días anteriores ≥2.

• Respuesta clínica insuficiente, pérdida de la respuesta o intolerancia, ocurridas previamente con al menos uno de los siguientes fármacos (según las recomendaciones/directrices de tratamiento en vigor de cada país): a) Corticosteroides, b) Inmunomoduladores, c) Antagonistas del TNFα, d) Vedolizumab

• Pueden estar recibiendo los siguientes fármacos (pero deben estar dispuestos a seguir recibiendo dosis estables durante los tiempos señalados):
a) 5-aminosalicilatos (5-ASA), siempre la dosis prescrita se haya mantenido estable durante un mínimo de 4 semanas antes de la aleatorización; la dosis debe seguir siendo estable durante las primeras 13 semanas tras la aleatorización.
b) Azatioprina, 6-MP o MTX, siempre que la dosis prescrita se haya mantenido estable durante 4 semanas antes de la aleatorización; la dosis de MTX debe seguir siendo estable durante 26 semanas y la dosis de AZA/6-MP debe seguir siendo estable durante las primeras 13 semanas, pero puede ajustarse si así se indica entre las semanas 13 y 26.
c) Tratamiento con corticosteroides orales (prednisona prescrita a una dosis estable ≤20 mg/día o budesonida prescrita a una dosis estable ≤9 mg/día), siempre que la dosis prescrita se haya mantenido estable durante 2 semanas antes de la aleatorización; si es posible, la dosis debe permanecer estable durante las primeras 13 semanas, tras lo cual puede iniciarse la disminución gradual de la dosis de corticosteroides según criterio del investigador.

• Aportar muestras de semen para la selección que cumplan los siguientes criterios mínimos (basados en la media de las dos muestras según el apartado 6.14):
a) Volumen de semen ≥1,5 ml, espermatozoides totales por eyaculación ≥39 millones, concentración de espermatozoides ≥15 millones por ml, movilidad total de los espermatozoides ≥40 % y morfología normal de los espermatozoides ≥4%.

• Valores de LH, FSH, inhibina B y testosterona total con una variación máxima del 20 % con respecto a los intervalos normales de referencia de los análisis practicados en la selección.

• Estar al día de la supervisión de cáncer colorrectal de acuerdo con las directrices locales antes de la selección.

E.4

Principal exclusion criteria

For a full list please see the study protocol.

- Previously documented problems with male reproductive health including (but not limited to) known hypothalamic-pituitary disorders (eg, pituitary macroadenomas, pituitary infarction, hyperprolactinemia, panhypopituitarism), primary hypogonadism (eg, cryptorchidism, Klinefelter’s syndrome)

- Prior diagnosis of male infertility (including reduced fertility), or history of anti-sperm antibodies

- Clinically significant (per judgment of investigator) varicocele or spermatocele

- History of radiation to the testicles

- History of clinically significant trauma to, or surgery on, the testicles, including vasectomy

- Current treatment with antiandrogen therapy (including spironolactone or oral ketoconazole), or treatment within 4 weeks of Screening

- Current treatment with testosterone replacement therapy, or treatment within 12 weeks of Screening

- Presence of disorders of sperm transport (including but not limited to retrograde ejaculation and immotile cilia syndrome)

- Clinically significant urinary tract infection, prostatitis, epididymitis, including sexually transmitted infection within 4 weeks of Screening

- Current use of sulfasalazine or use of sulfasalazine within 26 weeks of Screening; sulfasalazine is not permitted at any point during the study

- Use of any TNFα antagonist or vedolizumab within 8 weeks prior to screening, ustekinumab 12 weeks prior to screening, or any other biologic agent within 8 weeks prior to Screening or within 5 half-lives of the biologic agent prior to screening, whichever is longer

- Diagnosis of UC that occurred > 20 years ago (eg, duration of disease must have been < 20 years)

Para un listado completo por favor consultar el protocolo del estudio

• Problemas documentados previamente del aparato reproductor masculino, como, por ejemplo, trastornos hipotálamo-hipofisarios (macroadenoma hipofisario, infarto hipofisario, hiperprolactinemia, panhipopituitarismo), hipogonadismo primario (criptorquidia, síndrome de Klinefelter).
• Diagnóstico previo de infertilidad masculina (incluida la fertilidad reducida) o antecedentes de anticuerpos antiespermatozoides.
• Varicocele o espermatocele de importancia clínica (a juicio del investigador).
• Antecedentes de radiación en los testículos.
• Antecedentes de traumatismo de importancia clínica o cirugía testicular, incluida la vasectomía.
• Tratamiento con antiandrógenos (incluidos espironolactona o ketoconazol por vía oral) actual o en el plazo de 4 semanas antes de la selección.
• Tratamiento sustitutivo de testosterona actual o en el plazo de 12 semanas antes de la selección.
• Presencia de trastornos en la emisión espermática (como, por ejemplo, la eyaculación retrógrada y la discinesia ciliar idiopática).
• Infección urinaria de importancia clínica, prostatitis, epididimitis, incluidas las infecciones de transmisión sexual en el plazo de 4 semanas antes de la selección.
• Administración de sulfasalazina actual o en el plazo de 26 semanas antes de la selección; la sulfasalazina no está permitida en ningún momento del estudio.
• Uso de algún antagonista del TNFα o vedolizumab en las 8 semanas antes de la selección, ustekinumab 12 semanas antes de la selección, o algún otro fármaco biológico en un plazo de 8 semanas antes de la selección o de 5 veces la semivida del fármaco biológico antes de la selección, lo que suponga más tiempo.
• Diagnóstico de la CU con una antigüedad >20 años (p. ej., la duración de la enfermedad debe haber sido <20 años).

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the proportion of subjects with a ≥ 50% decrease from baseline in sperm concentration at Week 13.

El criterio de valoración principal es la proporción de pacientes con una reducción de ≥50 % en la concentración de espermatozoides en la semana 13 con respecto al valor inicial.

E.5.1.1

Timepoint(s) of evaluation of this end point

End of week 13

Final de la semana 13

E.5.2

Secondary end point(s)

The proportion of subjects with a ≥ 50% decrease from baseline in sperm concentration at Week 26
Change from baseline in percent motile sperm at Weeks 13 and 26
Change from baseline in total sperm count at Weeks 13 and 26
Change from baseline in sperm concentration at Weeks 13 and 26
Change from baseline in ejaculate volume at Weeks 13 and 26
Change from baseline in percent normal sperm morphology at Weeks 13 and 26

la proporción de pacientes con una reducción del ≥50 % en la concentración de espermatozoides en la semana 26 con respecto al valor inicial.
Cambio en la movilidad total de los espermatozoides en las semanas 13 y 26 con respecto al valor inicial
Cambio en el número total de espermatozoides en las semanas 13 y 26 con respecto al valor inicial
Cambio en la concentración de espermatozoides en las semanas 13 y 26 con respecto al valor inicial
Cambio en el volumen de esperma en las semanas 13 y 26 con respecto al valor inicial
Cambio en la morfología de los espermatozoides en las semanas 13 y 26 con respecto al valor inicial

E.5.2.1

Timepoint(s) of evaluation of this end point

End of week 26

Final de la semana 26

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

E.6.6

Pharmacokinetic

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Austria

Belgium

Canada

Czech Republic

France

Germany

Hungary

India

Italy

Netherlands

New Zealand

Poland

Portugal

Romania

Russian Federation

Sri Lanka

Sweden

Ukraine

United Kingdom

United States

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

End of Study is defined as when the last subject has completed the Week 225 visit, or the last subject has completed their last visit, whichever is sooner.

El final del estudio se producira cuando el ultimo paciente haya compeltado la visita de la semana 225, o cuando el ultimo paciente haya completado su ultima visita, lo que ocurra antes

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:

250

F.1.3

Elderly (>=65 years)

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

124

F.4.2.2

In the whole clinical trial

250

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)

The long-term care of subjects who do not qualify for LTE or choose not to participate will remain the responsibility of their primary treating physician

Los cuidados a largo plazo de los sujetos que no puedan participar en el LTE o elijan no participar seguirán siendo responsabilidad de su medico de atencion primaria

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

2018-07-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-06-19

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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