Clinical Trials Register

Summary
EudraCT Number:	2016-002943-40
Sponsor's Protocol Code Number:	ALN-CC5-003
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:	2016-09-30
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

2016-002943-40

A.3

Full title of the trial

A Phase 2, Open-label, Single Dose, Study of Subcutaneously Administered ALN-CC5 in Patients with Paroxysmal Nocturnal Hemoglobinuria who are Inadequate Responders to Eculizumab

Estudio en fase II, sin enmascaramiento de una dosis única de ALN-CC5 administrado por vía subcutánea en pacientes con hemoglobinuria paroxística nocturna que presentan una respuesta insuficiente al eculizumab

A.3.1

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

A Clinical Study with Investigational Drug, ALN-CC5, in patients with Paroxysmal Nocturnal Hemoglobinuria who are Inadequate Responders to Eculizumab

Estudio clínico con fármaco en investigación, ALN-CC5, en pacientes con hemoglobinuria paroxística nocturna que presentan una respuesta insuficiente al eculizumab

A.4.1

Sponsor's protocol code number

ALN-CC5-003

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	Alnylam Pharmaceuticals 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	Alnylam Pharmaceuticals 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	Alnylam Pharmaceuticals Inc
B.5.2	Functional name of contact point	Clinical Trials Hotline
B.5.3	Address:
B.5.3.1	Street Address	300 Third Street
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	MA 021242
B.5.3.4	Country	United States
B.5.6	E-mail	clinicaltrials@alnylam.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	ALN-CC5
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ALN-62643
D.3.9.2	Current sponsor code	ALN-62643
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Paroxysmal nocturnal hemoglobinuria (PNH)

Hemoglobinuria paroxística nocturna (HPN)

E.1.1.1

Medical condition in easily understood language

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal hematopoietic stem cell disorder of the blood characterized by destruction of red blood cells by the complement system.

Hemoglobinuria paroxística nocturna es un raro trastorno clonal de células madre hematopoyéticas de la sangre caracterizado por destrucción de células rojas de sangre por el sistema del complemento.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10055629
E.1.2	Term	Paroxysmal nocturnal hemoglobinuria
E.1.2	System Organ Class	100000004857

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluate the effect of ALN-CC5 on red blood cell (RBC) hemolysis

Evaluar el efecto del ALN-CC5 en la hemólisis de eritrocitos (ERI)

E.2.2

Secondary objectives of the trial

Evaluate the safety and tolerability of ALN-CC5
Characterize the pharmacodynamic (PD) effect of ALN-CC5

Evaluar la seguridad y tolerabilidad del ALN-CC5
Caracterizar el efecto farmacodinámico (FD) del ALN-CC5

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age 18 years or older
2. History of PNH
3. Treatment with eculizumab at a stable dose for a minimum of 60 days before Screening
4. Inadequate response to eculizumab as defined by elevated LDH level before eculizumab infusion at Screening as follows:
• LDH≥3.0×ULN (with or without symptoms) attributable to hemolysis in the opinion of the Investigator; or,
• LDH ≥2.0×ULN, 1 or more of the following at Screening and while receiving eculizumab treatment, and which in the opinion of the Investigator is/are attributable to PNH disease: PNH symptoms (eg, fatigue, abdominal pain, dyspnea, dysphagia, or erectile dysfunction); Hemoglobin level ≤10 g/dL; Any blood transfusions within 90 days before Screening; and/or Spontaneous vascular thrombosis at any time since starting eculizumab treatment.
5. Women of child-bearing potential (WOCBP) must have a negative pregnancy test, cannot be breast feeding, and must be willing to use a highly effective method of contraception 14 days before ALN-CC5 administration, throughout study participation, and for 6 months after ALN-CC5 administration.
6. Willing and able to comply with the study requirements and to provide written informed consent
7. Vaccinated against Neisseria meningitides according to standard practice (patients may be rescreened if not previously vaccinated)

1. Edad igual o superior a 18 años.
2. Antecedentes de HPN.
3. Tratamiento con eculizumab en una dosis estable durante un mínimo de 60 días antes de la selección.
4. Respuesta insuficiente al eculizumab definida por una concentración elevada de LDH antes de la infusión de eculizumab en la selección como sigue:
• LDH ≥ 3,0 veces el LSN (con o sin síntomas) atribuible a hemólisis en opinión del investigador; o,
• LDH ≥ 2,0 veces el LSN, 1 o más de lo siguiente en la selección y durante el tratamiento con eculizumab, y que en opinión del investigador pueda atribuirse a la enfermedad de HPN:
• Síntomas de HPN (cansancio, dolor abdominal, disnea, disfagia o disfunción eréctil);
• Concentración de hemoglobina ≤ 10 g/dl;
• Alguna transfusión de sangre en los 90 días previos a la selección; y/o
• Trombosis vascular espontánea en cualquier momento desde el inicio del tratamiento con eculizumab.
5. Las mujeres en edad fértil (MEF) deberán obtener un resultado negativo en la prueba de embarazo, no podrán estar amamantando y tendrán que estar dispuestas a utilizar un método anticonceptivo muy eficaz desde 14 días antes de la administración de ALN-CC5, durante todo el tiempo que participen en el estudio y hasta 6 meses después de la administración de ALN-CC5.
6. Voluntad y capacidad de cumplir los requisitos del estudio y otorgar el consentimiento informado por escrito.
7. Vacunación contra Neisseria meningitides con arreglo a la práctica habitual (los pacientes tendrán que repetir la selección si no estaban ya vacunados).

E.4

Principal exclusion criteria

1. Alanine transaminase ≥2×ULN or total bilirubin ≥4×ULN (unless bilirubin elevation is due to Gilbert’s syndrome), which is considered clinically relevant in the opinion of the Investigator
2. Clinically significant bone marrow suppression as defined by 2 or more of the following:
• Absolute neutrophil count ≤1.0×10 to power of 9/L
• Platelet count ≤50×10 to power of 9/L
• Absolute reticulocyte count ≤60×10 to power of 9/L
3. Clinical laboratory test results considered clinically relevant and unacceptable in the opinion of the Investigator
4. Planned change in eculizumab dose within 60 days of administration of ALN-CC5 (patients may be re-Screened)
5. Spontaneous vascular thrombosis within 30 days of randomization (patients may be re Screened)
6. Known or suspected hereditary asymptomatic complement deficiency
7. Known clinical laboratory evidence or clinical diagnosis of human immunodeficiency virus infection (HIV), hepatitis C virus (HCV) infection, or chronic hepatitis B virus infection as shown by hepatitis B surface antigen positivity in blood
8. Suspicion of active viral, bacterial, fungal, or parasitic infection as a cause for breakthrough hemolysis and their presence within 14 days before ALN-CC5 administration (patients may be rescreened)
9. Travelled to Saudi Arabia or Africa within 90 days of Screening, or planning to do so during the study (patients may be rescreened)
10. Received an investigational agent within the last 90 days or are in follow-up of another clinical study before study enrollment
11. Active serious mental illness or psychiatric disorder, including, but not limited to, schizophrenia, bipolar disorder, or severe depression requiring current pharmacological intervention
12. Other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation
13. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc
14. History of intolerance to SC injection(s) at the proposed injection site(s) that could potentially hinder study drug administration or evaluation of local tolerability
15. History of meningococcal infection within 12 months before Screening
16. Known history of chronic liver disease or cirrhosis

1. Elevación de la alanina transaminasa ≥ 2 veces el LSN o bilirrubina total ≥4 veces el LSN (salvo que la elevación de la bilirrubina se deba al síndrome de Gilbert), que el investigador considere clínicamente relevante.
2. Supresión clínicamente significativa de la médula ósea definida por 2 o más de lo siguiente:
• Recuento absoluto de neutrófilos ≤ 1,0 × 109/l.
• Recuento de plaquetas ≤ 50 × 109/l.
• Recuento absoluto de reticulocitos ≤ 60 × 109/l.
3. Resultados de las evaluaciones analíticas que el investigador considere clínicamente relevantes e inaceptables.
4. Cambio previsto en la dosis de eculizumab en los 60 días previos a la administración de ALN-CC5 (los pacientes podrán repetir la selección).
5. Trombosis vascular espontánea en los 30 días previos a la aleatorización (los pacientes podrán repetir la selección).
6. Sospecha o confirmación de deficiencia hereditaria asintomática del complemento.
7. Signos analíticos conocidos o diagnóstico clínico de infección por el virus de la inmunodeficiencia humana (VIH), infección por el virus de la hepatitis C (VHC) o infección crónica por el virus de la hepatitis B, confirmada por un resultado positivo del antígeno de superficie del virus de la hepatitis B en sangre.
8. Sospecha de infección activa por virus, bacterias, hongos o parásitos como causa de hemólisis intercurrente y su presencia en los 14 días previos a la administración de ALN-CC5 (los pacientes podrán repetir la selección).
9. Haber viajado a Arabia Saudí o África en los 90 días previos a la selección, o tener previsto hacerlo durante el estudio (los pacientes podrán repetir la selección).
10. Haber recibido un fármaco en investigación en los últimos 90 días o ser objeto de seguimiento para otro estudio clínico antes del reclutamiento para este estudio.
11. Enfermedad mental o trastorno psiquiátrico grave y activo, como esquizofrenia, trastorno bipolar o depresión intensa que precise una intervención farmacológica en curso.
12. Otras afecciones médicas o enfermedades que, en opinión del investigador, podrían interferir con el cumplimiento del estudio o la interpretación de los datos.
13. Antecedentes de alergias múltiples a fármacos o antecedentes de reacción alérgica a un oligonucleótido o a GalNAc.
14. Antecedentes de intolerancia a inyecciones SC en el lugar de inyección propuesto que podría dificultar la administración del fármaco del estudio o la evaluación de la tolerabilidad local.
15. Antecedentes de infección meningocócica en los 12 meses previos a la selección.
16. Antecedentes conocidos de cirrosis o hepatopatía crónica.

E.5 End points

E.5.1

Primary end point(s)

Percent change from baseline in LDH

Cambio porcentual desde el inicio en la lactato deshidrogenasa (LDH)

E.5.1.1

Timepoint(s) of evaluation of this end point

At Week 12

En la semana 12

E.5.2

Secondary end point(s)

• Incidence of AEs
• Proportion of patients with LDH levels ≤1.5×ULN
• Change in complement activity levels (CAP and CCP)

• Incidencia de acontecimientos adversos (AA)
• Proporción de pacientes con niveles de LDH ≤ 1,5 × el límite superior de la normalidad (LSN)
• Cambio en los niveles de actividad del complemento (vía alternativa del complemento [VAC] y vía clásica del complemento [VCC])

E.5.2.1

Timepoint(s) of evaluation of this end point

• Incidence of AEs: throughout the study until the end of study visit
• Proportion of patients with LDH levels ≤1.5×ULN: at Week 12
• Change in complement activity levels (CAP and CCP): throughout the study until the end of study visit

• Incidencia de acontecimientos adversos (AA): durante todo el estudio hasta la visita de final de estudio
• Proporción de pacientes con niveles de LDH ≤ 1,5 × LSN a las 12 semanas
• Cambio en los niveles de actividad del complemento (VAC y VCC): durante todo el estudio hasta la visita de final de estudio

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

Yes

E.6.7

Pharmacodynamic

Yes

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

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

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

E.8.2.3

Other

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

Bulgaria

Canada

Czech Republic

Denmark

Finland

France

Germany

Israel

Korea, Republic of

Netherlands

Norway

Russian Federation

Spain

Sweden

Taiwan

Turkey

United Kingdom

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

LVLS

UVUP

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

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:

F.2 Gender

F.2.1

Female

Yes

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

F.4.2.2

In the whole clinical trial

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)

None

Ninguno

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

2016-11-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-11-14

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2016-11-23

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