Clinical Trials Register

Summary
EudraCT Number:	2020-005069-15
Sponsor's Protocol Code Number:	LIGHTHOUSEII
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:	2023-01-31
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

2020-005069-15

A.3

Full title of the trial

RANDOMISED DOUBLE-BLIND PLACEBO-CONTROLLED PHASE 3 TRIAL OF TRIUMEQ IN AMYOTROPHIC LATERAL SCLEROSIS

Ensayo de fase III aleatorio, doble ciego, controlado con placebo de Triumeq de esclerosis lateral amiotrófica

A.3.1

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

LIGHTHOUSE 2

A.3.2

Name or abbreviated title of the trial where available

Lighthouse 2

A.4.1

Sponsor's protocol code number

LIGHTHOUSEII

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	Stichting TRICALS Foundation
B.1.3.4	Country	Netherlands
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	ALS Stichting Nederland.
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Fight MND
B.4.2	Country	Australia
B.4.1	Name of organisation providing support	Ulla-Carin Lindquist Foundation
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Luzon Foundation
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	UICEC IDIBELL
B.5.2	Functional name of contact point	Unidad de Ensayos clíncos IDIBELL
B.5.3	Address:
B.5.3.1	Street Address	Feixa Llarga s/n (Edifici de Recerca)
B.5.3.2	Town/ city	L'Hospitalet de Llobregat/Barcelona
B.5.3.3	Post code	08907
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034932607107
B.5.6	E-mail	ucicecidibell@bellvitgehospital.cat

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	Triumeq
D.2.1.1.2	Name of the Marketing Authorisation holder	Viiv Healthcare BV
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Triumeq
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Gastroenteral use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Dolutegravir
D.3.9.1	CAS number	1051375/19/5
D.3.9.4	EV Substance Code	AS1
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	12.5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Abacavir
D.3.9.1	CAS number	188062/50/2
D.3.9.4	EV Substance Code	AS2
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	150
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lamivudine
D.3.9.1	CAS number	134678/1714
D.3.9.4	EV Substance Code	AS3
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	75
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	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Amyotrophic Lateral Sclerosis (ALS)

Esclerosis Lateral Amiotrófica (ELA)

E.1.1.1

Medical condition in easily understood language

ALS/ Motor Neuron Disease (MND)

Esclerosis lateral amiotrófica (ELA) / Enfermedad de la neurona motora

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

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	10002026
E.1.2	Term	Amyotrophic lateral sclerosis
E.1.2	System Organ Class	10029205 - Nervous system disorders

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 determine if Triumeq improves survival in patients with ALS

Determinar si Triumeq mejora la supervivencia en pacientes con ELA.

E.2.2

Secondary objectives of the trial

To determine if Triumeq improves secondary outcomes and selected biomarkers compared with placebo.

Determinar si Triumeq mejora los resultados secundarios y los biomarcadores seleccionados en comparación con el placebo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years at the time of screening
2. Diagnosis of ALS according to the Gold Coast Criteria (Please see Table 1 of Shefner et al Clinical Neurophysiology 2020, also available in Appendix 2)
3. Capable of providing informed consent and complying with trial procedures
4. TRICALS risk profile > -6.0 and < -2.0 (See Section 4.3.4)
5. Those taking Riluzole must be on a stable dose for at least 30 days prior to the baseline visit or must have stopped taking Riluzole at least 30 days prior to the baseline visit
6. Women must not become pregnant (e.g., post-menopausal, surgically sterile, using highly effective birth control methods or not having potentially reproductive sex) for the duration of the study plus five days. Highly effective methods of birth control are those with a failure rate of < 1% per year when employed consistently and correctly, e.g. Combined (oestrogen and progestogen containing) hormonal contraception or progestogen-only hormonal contraception. For more information, please refer to the HMA CTFG Guidelines: https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf?fbclid=IwAR3AY5Ha0ESDyqIBeUaYI9VTFWmx9bbt8NZ-80N-5ME6pkBb1UHvFsTwqlQ
7. Women of childbearing potential must have a negative serum pregnancy test at screening and baseline and be non-lactating. Patients will be advised regarding appropriate contraception. A menstruation history will be taken at each visit. Women of childbearing potential are defined as females who are fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy (https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf?fbclid=IwAR3AY5Ha0ESDyqIBeUaYI9VTFWmx9bbt8NZ-80N-5ME6pkBb1UHvFsTwqlQ).
8. For participants taking antacids (regularly or as required), participant is willing and able to avoid taking antacids for at least 2 hours before and 6 hours after Triumeq

1. Edad ≥ 18 años en el momento de la selección.
2. Diagnóstico de ELA según los Criterios de Gold Coast (Por favor, consulte la Tabla 1 de Shefner et al, en Neurofisiología Clínica 2020, también disponible en el Apéndice 2 del protocolo).
3. Capaces de otorgar su consentimiento informado y cumplir con los procedimientos del ensayo.
4. Perfil de riesgo TRICALS > -6,0 y < -2,0 (Ver Sección 4.3.4 protocolo)
5. Aquellos que tomen Riluzol deben estar en una dosis estable durante al menos 30 días antes de la visita basal o deben haber dejado de tomar Riluzol al menos 30 días antes de la visita basal.
6. Las mujeres no deben quedarse embarazadas (por ejemplo, posmenopáusicas, quirúrgicamente estériles, que utilicen métodos anticonceptivos altamente eficaces o que no tengan relaciones sexuales potencialmente reproductivas) durante la duración del estudio más cinco días. Los métodos anticonceptivos altamente eficaces son aquellos con una tasa de fracaso < 1% al año cuando se emplean de forma sistemática y correcta, por ejemplo, la anticoncepción hormonal combinada (que contiene estrógenos y progestágenos) o la anticoncepción hormonal sólo de progestágenos. Para más información, consulte las Directrices de la CTFG de la HMA: https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf?fbclid=IwAR3AY5Ha0ESDyqIBeUaYI9VTFWmx9bbt8NZ-80N-5ME6pkBb1UHvFsTwqlQ
7. Las mujeres en edad fértil deben tener una prueba de embarazo negativa en suero en el momento de la selección y visita basal del estudio y no estar lactando. Se aconsejará a las pacientes sobre los métodos anticonceptivos adecuados. Se realizará un historial menstrual en cada visita. Las mujeres en edad fértil se definen como fértiles tras la menarquia y hasta la posmenopausia, a menos que sean permanentemente estérilizadas. Los métodos de esterilización permanente incluyen la histerectomía, la salpingectomía bilateral y la ooforectomía bilateral (https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf?fbclid=IwAR3AY5Ha0ESDyqIBeUaYI9VTFWmx9bbt8NZ-80N-5ME6pkBb1UHvFsTwqlQ)
8. En el caso de participantes que tomen antiácidos (regularmente o cuando sea necesario), el participante está dispuesto y es capaz de evitar tomar antiácidos durante al menos 2 horas antes y 6 horas después de tomar Triumeq.

E.4

Principal exclusion criteria

1. People who are HLA-B*5701 positive
2. Known hypersensitivity to Dolutegravir, Abacavir or Lamivudine, or to any of the excipients
3. Safety Laboratory Criteria at screening:
ALT ≥ 5 times upper limit of normal (ULN)
AST ≥ 3 times ULN
Bilirubin ≥ 1.5 times ULN
Creatinine clearance < 30 mL / min
Platelet concentration of < 100 x109 per L
Absolute neutrophil count of < 1x109 per L
Haemoglobin < 100 g/L
Amylase & lipase ≥ 2 times ULN
Lactate ≥ 2 times ULN
4. Moderate to severe hepatic impairment, as defined by local clinical guidelines
5. Presence of HIV antibodies at screening
6. Presence of Hepatitis C antibodies at screening unless participants have had effective treatment for Hepatitis C
7. Presence of Hepatitis B core or surface antigen at screening
8. Participation in any other investigational drug trial or using investigational drug within 30 days prior to screening
9. Use of NIV ≥22 h per day or having a tracheostomy
10. Edaravone dose within 30 days prior to screening. Edaravone is approved by the FDA and in Japan, but remains an investigational product in Europe and Australia
11. Clinically significant history of unstable or severe cardiac, oncological, psychiatric, hepatic, or renal disease or other medically significant illness
12. Taking medication contraindicated with Triumeq: Dofetilideor Fampridine (dalfampridine)

1. Personas con HLA-B*5701 positivo
2. Hipersensibilidad conocida a Dolutegravir, Abacavir o Lamivudina, o a cualquiera de los excipientes.
3. Criterios de laboratorio de seguridad en el cribado:
ALT ≥ 5 veces el límite superior de la normalidad (ULN)
AST ≥ 3 veces el ULN
Bilirrubina ≥ 1,5 veces el ULN
Aclaramiento de creatinina < 30 mL / min
Concentración de plaquetas de < 100 x109 por L
Concentración absoluta de neutrófilos de < 1x109 por L
Hemoglobina < 100 g/L
Amilasa y lipasa ≥ 2 veces el ULN
Lactato ≥ 2 veces el ULN
4. Deterioro hepático de moderado a grave, según la definición de las guías clínicas locales.
5. Presencia de anticuerpos contra el VIH en el momento del screening.
6. Presencia de anticuerpos contra la hepatitis C en el momento del cribado, a menos que los participantes hayan recibido un tratamiento eficaz contra la hepatitis C.
7. Presencia de antígeno core o de superficie de la hepatitis B en el momento del cribado.
8. 8. Participación en cualquier otro ensayo clínico con fármacos en investigación o uso de fármacos en investigación en los 30 días anteriores al cribado.
9. Uso de VNI (ventilación no invasiva) ≥22 h al día o tener una traqueostomía.
10. Haber recibido dosis de Edaravona en los 30 días anteriores al cribado. La Edaravona está aprobada por la FDA y en Japón, pero sigue siendo un producto en investigación en Europa y Australia.
11. Antecedentes clínicamente significativos o de inestabilidad de enfermedad cardiaca grave, oncológica, psiquiátrica, hepática o grave u otra enfermedad médicamente significativa.
12. Toma de medicación contraindicada con Triumeq: Dofetilida o Fampridina (dalfampridina)

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is overall survival, defined as time to mortality from any cause

El criterio de valoración principal es la supervivencia global, definida como el tiempo transcurrido hasta la muerte por cualquier causa.

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to Month 24

Hasta el mes 24

E.5.2

Secondary end point(s)

1. To assess the effect of Triumeq versus placebo on a combined assessment of survival and measures of daily functioning (CAFS)
2. To assess the effect of Triumeq versus placebo on measures of daily functioning
3. To assess the effect of Triumeq versus placebo on respiratory function
4. To assess the effect of Triumeq versus placebo on plasma creatinine
5. To assess the effect of Triumeq versus placebo on the time to reach advanced disease stages
6. To evaluate the safety of Triumeq administered orally to participants with ALS
7. To evaluate the tolerability of Triumeq administered orally to participants with ALS
8. To assess the effect of Triumeq versus placebo on change in cognitive functioning
9. To assess the effect of Triumeq versus placebo on change in quality of life
10. To collect research blood and urine samples for post-trial explanatory analyses; markers will be included e.g. urinary P75ECD, plasma neurofilament light and heavy chain, HERV-K, and genotyping

Evaluar el efecto de Triumeq frente a placebo en una valoración combinada de supervivencia y medidas de funcionamiento diario (CAFS).
2. Evaluar el efecto de Triumeq frente a placebo en las medidas de funcionamiento diario.
3. Evaluar el efecto de Triumeq frente a placebo en la función respiratoria.
4. Evaluar el efecto de Triumeq frente a placebo sobre la creatinina plasmática.
5. Evaluar el efecto de Triumeq frente a placebo sobre el tiempo hasta alcanzar estadios avanzados de la enfermedad
6. Evaluar la seguridad de Triumeq administrado por vía oral a participantes con ELA.
7. Evaluar la tolerabilidad de Triumeq administrado por vía oral a participantes con ELA.
8. Evaluar el efecto de Triumeq frente a placebo en el cambio del funcionamiento cognitivo.
9. Evaluar el efecto de Triumeq frente a placebo en el cambio de la calidad de vida.
10. Recoger muestras de sangre y orina para anàlisis exploratorios: se analizaran marcadores como por ejemplo : P75ECD en orina, cadenas ligeras y pesadas de neurofilamentos en plasma, HERV-K y genotipado.

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to Month 24

Hasta el mes 24

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

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

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