Overview
Sponsor-declared trial summary
Phase
Phase I and Phase II (Integrated) - First administration to humans
Status
Ended
Participants planned
50
Countries
1
Sites
3
Primary Progressive Multiple Sclerosis
To assess the safety and efficacy of the combined administration of ocrelizumab and melatonin/placebo in patients with primary progressive multiple sclerosis
Key facts
- Sponsor
- Fundacion Publica Andaluza Para La Gestion De La Investigacion En Salud De Sevilla
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Nervous System Diseases [C10]
- Trial duration
- 15 Nov 2024 → 18 Feb 2026
- Decision date (initial)
- 2024-11-15
- Transition trial
- Yes
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- No
- Funding sources
- Ministry of Health of the Government of Andalusia, SPAIN (PC-0019-2017, P
External identifiers
- EU CT number
- 2023-508457-10-00
- EudraCT number
- 2018-001779-18
- ClinicalTrials.gov
- NCT03540485
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Efficacy, Safety
To assess the safety and efficacy of the combined administration of
ocrelizumab and melatonin/placebo in patients with primary progressive
multiple sclerosis
Secondary objectives 1
- To evaluate the efficacy on cerebral atrophy, inflammation, axonal damage, disruption of the blood-brain barrier and oxidative stress in blood and cerebrospinal fluid of patients with primary progressive multiple sclerosis, the expression of miRNA in cerebrospinal fluid and the composition of the microbiota. - Evaluate the effects on the symptoms of multiple sclerosis (fatigue, difficulty walking, spasticity, vision problems, pain, cognitive changes, quality of life and sleep disorders).
Conditions and MedDRA coding
Primary Progressive Multiple Sclerosis
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 21.1 | PT | 10063401 | Primary progressive multiple sclerosis | 100000004852 |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 1
- Patients who come to the Multiple Sclerosis Unit of the Department of Neurology of the Virgen Macarena University Hospital (Seville) or Vithas Nisa Seville Hospital or Virgen del Rocío University Hospital (Seville), AND who meet the following criteria: 1) Have progressive primary multiple sclerosis according to McDonald's diagnostic criteria modified in 2010; 2) Age between 18 and 65 years old; 3) Neurological impairment measured with the Expanded Disability Status Scale (EDSS) scale between 2 and 7 (both included, without disability or only clinical symptoms up to ambulatory capacity with bilateral support); 4) Not having received any immunomodulatory, except for ocrelizumab in stable doses for at least 9 months before inclusion in this study, or immunosuppressive treatment (including cytostatic agents) during the 3 months prior to participation in the trial; 5) If there is a possibility of pregnancy (in women of childbearing age (15 to 44 years)) or paternity, accept the use of a highly effective method of birth control recommended by the Clinical Trial Facilitation Group (CTFG) during the treatment phase of the trial; 6) Not having consumed melatonin or other dietary supplements (antioxidants or vitamins (tripling the recommended daily doses) during the month prior to participation in the trial; 7) Ability to give informed consent and comply with the visits scheduled in the study.
Exclusion criteria 1
- •Alternative diagnosis that explains both the neurological disability and the findings in nuclear magnetic resonance. •Clinically significant medical problems that, in the opinion of the investigators, may cause tissue damage in the central nervous system or limit its repair, or that may expose the patient to unjustified risks or damages, or cause the patient not to complete the study. •Clinical history of hypersensitivity reactions to melatonin. •Pregnancy or lactation, or planning to become pregnant or patients of childbearing age not subject to birth control methods (recommended by the Clinical Trial Facilitation Group (CTFG): http://www.hma.eu/fileadmin/dateien/Human_Medicines/ 01- About_HMA / Working_Groups / CTFG / 2014_09_HMA_CTFG_Contraception.pdf). •Abnormal results in basal blood tests, defined as: -Serum levels of alanine transaminase or aspartate transaminase greater than 1.5 times the upper limit of normal values. - Total leukocyte count less than 3,000 / mm3. - Platelet count less than 85,000 / mm3. - Serum creatinine level greater than 2.0 mg / dL or glomerular filtration rate less than 30 ml/min. •Neurological deterioration measured with the Expanded Disability Status Scale scale of less than 2 or greater than 7. •Be receiving any immunosuppressive therapy, except for ocrelizumab, including cytostatic agents.
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- Disease progression: rates of neurological impairment (Kurtzke Expanded Disability Status Scale) and rates of disability (Multiple Sclerosis Functional Composite - MSFC scale).
Secondary endpoints 1
- Number of participants with treatment-related adverse events, Cerebral atrophy, Fatigue, Quality of life, Sleep disorders, Spasticity, Efficacy of neuroinflammation, Axonal damage, Oxidative stress, Impact on microbiota
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 1
SCP136513 · ATC
- Active substance
- Benzyl Alcohol
- Substance synonyms
- BENZYLIC ALCOHOL, Phenylmethanol
- Route of administration
- ORAL USE
- Authorisation status
- Authorised
- ATC code
- N05CH01 — MELATONIN
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- Yes
- Modification description
- Dosage of 100, 50, 25 and 10 milligrams per day
Placebo 1
N/A · Product
- Other product name
- N/A
- Pharmaceutical form
- N/A
- ATC code
- N/A — N/A
- Marketing authorisation
- N/A
- MA holder
- N/A
- MA country
- Iceland
- Paediatric formulation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Fundacion Publica Andaluza Para La Gestion De La Investigacion En Salud De Sevilla
- Sponsor organisation
- Fundacion Publica Andaluza Para La Gestion De La Investigacion En Salud De Sevilla
- Address
- Avenida De Manuel Siurot S/n
- City
- Sevilla
- Postcode
- 41013
- Country
- Spain
Scientific contact point
- Organisation
- Fundacion Publica Andaluza Para La Gestion De La Investigacion En Salud De Sevilla
- Contact name
- Clinical Trial Unit IBIS/University Hospital Virgen del Rocío
Public contact point
- Organisation
- Fundacion Publica Andaluza Para La Gestion De La Investigacion En Salud De Sevilla
- Contact name
- Clinical Trial Unit IBIS/University Hospital Virgen del Rocío
Locations
1 EU/EEA country · 3 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Spain | Ended | 50 | 3 |
| Rest of world | — | 0 | — |
Investigational sites
Hospital Universitario Virgen De La Macarena
Neurology, Avenida Del Doctor Fedriani 3, 41009, Sevilla
University Hospital Virgen Del Rocio S.L.
Neurology, Avenida De Manuel Siurot S/n, 41013, Sevilla
Hospital Nisa Sevilla Aljarafe
Neurology, Avenida Placido Fernandez Viagas S/n, 41950, Castilleja De La Cuesta
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Spain | 2024-11-15 | 2024-11-15 | 2025-11-11 |
Oversight and notifications
Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77
Temporary halts 1 · Art. 38 CTR
Temporary halt TH-118133
- Halt date
- 2024-11-15
- Member states concerned
- Spain
- Publication date
- 2026-02-11
- Reason
- Medicinal Product related, Sponsor decision
- Explanation
- En el periodo de estudio (27 enero 2020 – 6 abril 2021) se han observado valores
anormales de laboratorio sugestivos de hepatoxicidad en tres de los ocho pacientes
incluidos entre las 4 y 12 semanas del inicio de tratamiento.
La unidad responsable de farmacovigilancia conjuntamente con los responsables de
proyecto global han realizado una revisión bibliográfica sobre aspectos de seguridad y
dosificación de la medicación de estudio así como una revisión exhaustiva de los datos
de los pacientes incluidos: antecedentes clínicos, medicación concomitante,
tratamiento recibido, pruebas realizadas. Los resultados se han consensuado con el
Servicio de Enfermedades Digestivas del Hospital Universitario Virgen del Rocío con el
fin de obtener la opinión de los expertos y valorar futura acciones.
A 6 de abril de 2021 se decide interrumpir en todos los pacientes incluidos la
administración de la medicación de estudio con la actual dosis así como las visitas de
seguimiento establecidas por protocolo no relacionadas seguimientos de seguridad
relacionados con la resolución de eventos adversos activos. Asimismo se interrumpirá
temporalmente el reclutamiento de nuevos pacientes en los dos centros participantes y
se valorará una posible bajada de dosis en un futuro cercano. - Follow-up measures
- • Cese de la medicación: Se interrumpió la administración de la melatonina (en su dosis inicial de 300 mg) o placebo en todos los pacientes.
• Cancelación de visitas rutinarias: Se detuvieron las visitas de seguimiento establecidas por protocolo que no estuvieran estrictamente relacionadas con la seguridad de eventos adversos activos.
• Seguimiento de seguridad intensivo: Los procedimientos continuaron únicamente para aquellos eventos de seguridad que permanecían abiertos, realizando un seguimiento hasta la resolución de los eventos adversos activos.
• Parada del reclutamiento: Se suspendió temporalmente la inclusión de nuevos pacientes en todos los centros participantes.
Medidas de manejo y seguimiento a largo plazo (Modificación Sustancial Nº 3)
Para permitir la reanudación del estudio (autorizada en febrero de 2022), se implementó la Modificación Sustancial Nº 3, que incluyó medidas de control mucho más estrictas para los pacientes:
• Reducción de la dosis: La dosis inicial para los pacientes se redujo de 300 mg a 100 mg diarios.
• Criterios de exclusión más estrictos: Se limitó la entrada al estudio a pacientes con niveles basales de transaminasas (ALT/AST) superiores a 1,5 veces el límite superior de la normalidad, siendo anteriormente de 3 veces.
• Esquema de seguimiento analítico tras interrupciones: Si se sospecha de hepatotoxicidad leve y se interrumpe la dosis, el paciente debe someterse a:
◦ Analíticas periódicas de seguridad: Bisemanales durante el primer mes y mensuales hasta completar tres meses.
◦ Pruebas exhaustivas: Incluyen hemogramas, serología viral y bioquímica con función hepática completa (AST, ALT, GGT, bilirrubina total, fosfatasa alcalina, creatinina y hPCR).
• Intervención de especialistas: Se estableció la necesidad de juicio clínico y manejo por parte de un especialista en aparato digestivo si procediera.
• Seguimiento telefónico: Implementación de llamadas para el control de acontecimientos adversos.
• Protocolo de reducción de dosis: Si las enzimas hepáticas se normalizan tras tres meses de interrupción, se aplican reducciones escalonadas de dosis (de 100 mg a 50 mg, 25 mg o incluso 10 mg) para minimizar el riesgo en caso de reexposición.
• Retirada definitiva: Se estipuló que si un paciente no normaliza sus niveles tras tres meses sin medicación, o si no tolera la dosis más baja (10 mg), debe ser retirado definitivamente del estudio. - Benefit-risk balance changed
- No
- Treatment stopped
- Yes
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 5 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Protocol 2023-508457-10-00 | 5 |
| Recruitment arrangements (for publication) | K1_ Recruitment arrangements | 1 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF adults | 5 |
| Summary of Product Characteristics (SmPC) (for publication) | E2_SmPC Circadin 2 mg | 1 |
| Synopsis of the protocol (for publication) | D1_Protocol synopsis ES 2023-508457-10-00 | 5 |
Application history
1 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-11-07 | Spain | Acceptable 2024-11-15
|
2024-11-15 |