A randomized, phase II/III trial on the biological and clinical effects of acetyl-L-carnitine in ALS

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Istituto Di Ricerche Farmacologiche Mario Negri

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

24 Feb 2025 → ongoing

Decision date (initial)

2025-02-07

Transition trial

No

Low-intervention

Yes

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

FightMND

External identifiers

EU CT number

2023-509853-29-00

ClinicalTrials.gov

NCT06126315

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Dose response

Assess the efficacy of acetyl-L-carnitine (ALCAR) (two different dosages will be tested: 1.5g/day and 3g/day) on the progression of functional disability (loss of self-sufficiency), as measured by the ALSFRS-R scale

Secondary objectives 3

1. The effect of ALCAR treatment on different clinical aspects: functional decline as measured by ALSFRS-R total score; the decline of forced vital capacity (FVC); quality of life as measured by ALSAQ-40 scale; cognitive function as measured by Edinburgh Cognitive and Behavioural ALS Screen (ECAS) scale; survival (being alive and without tracheostomy).
2. To measure the effects of ALCAR treatment on disease biomarkers potentially involved in the drug's mechanisms of action. These include PGC-1 alpha, 3-nitrotyrosine (3-NT), acetyl cyclophilin A (acetyl-PPIA), neurofilament light chain (NFL), creatine kinase (CK), Musclin/osteocrin, MyomiRNA (MiR-206), Uric acid, Matrix metalloproteinase-9 (MMP-9), Monocyte Chemoattractant Protein-1 (MCP-1), 4-Hydroxynonenal (HNE).
3. The tolerability and safety of ALCAR treatment by identifying unexpected adverse events.

Conditions and MedDRA coding

amyotrophic lateral sclerosis

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Age 18+;
2. ALS diagnosis according to the Gold Coast Criteria
3. Disease duration ≤ 24 months from symptom onset, as indicated by limb weakness or bulbar symptoms, at the randomization/baseline visit
4. Self-sufficiency [Satisfactory bulbar and spinal function (score 3+ on the ALSFRS-R for swallowing, cutting food and handling utensils, and walking)];
5. Satisfactory respiratory function (FVC ≥70% of predicted);
6. Documented progression of symptoms as measured by the ALSFRS-R scale. Disease progression rate (DFS) must be>= 0.33. DFS =(48- ALSFRS-R at screening)/months from onset to screening OR documented progression of symptoms in the last three months as measured by the ALSFRS-R scale (decrease of at least one point in the last three months)
7. Ability to understand and comply with the study requirements;
8. Ability to give written informed consent personally or, as an alternative, via a legally authorized representative;
9. Treatment with riluzole 50 mg twice/day for at least 4 weeks prior to randomization visit;
10. Intact cognitive function, again determined by the Principal Investigator.

Exclusion criteria 10

1. Antecedent polio infection or other active infection;
2. Motor neuron disease (MND) other than ALS;
3. Involvement of other systems possibly determining a functional impairment (as measured by the endpoints) for the entire duration of the study;
4. Other severe clinical conditions (e.g., cardiovascular disorders, neoplasms) with an impact on survival or functional disability in the next 12 months;
5. Previous use of ALCAR for more than 6 weeks. In case of previous use of ALCAR, 7 days of wash-out period must be performed before enrolling the participant;
6. Poor compliance with previous treatments;
7. Other experimental treatments in the three months prior to the screening visit (if a subject is receiving another experimental drug, a 3-month wash-out period before participating in the present clinical trial will be required);
8. Women who are lactating or able to become pregnant (e.g. who are not post-menopausal, surgically sterile, or using inadequate birth control) and men unable to practice contraception for the duration of the treatment and three months after its completion;
9. Inability to understand and comply with the study requirements;
10. Unwillingness or inability to take riluzole.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The proportion of participants remaining self-sufficient after 48 weeks in each treatment arm (those scoring three or higher in all the three ALSFRS-R items for swallowing, cutting food, handling utensils, and walking).

Secondary endpoints 11

1. Mean change of ALSFRS-R total score in each treatment arm from baseline to week 48.
2. Mean change of FVC% in each treatment arm from baseline to week 48.
3. Mean change in the five domains of ALSAQ-40 measuring different aspects of quality of life (physical mobility, ADL/independence, eating and drinking, emotional reactions, communication) in each treatment arm from baseline to week 48.
4. Mean change in ECAS total score in each treatment arm from baseline to week 48.
5. Cumulative probability of remaining self-sufficient in each treatment arm during 48 weeks.
6. Cumulative probability of remaining free from a 6-point or greater decline in ALSFRS-R total score in each treatment arm during 48 weeks.
7. Cumulative probability of remaining without gastrostomy in each treatment arm during 48 weeks.
8. Cumulative probability of remaining without non-invasive ventilation (NIV) support (≥12 hours a day in a 24-hour period) in each treatment arm during 48 weeks.
9. Cumulative survival probability (of being alive and without tracheostomy) in each treatment arm during 48 weeks
10. The mean change in the levels of PGC-1 alpha, 3-NT, acetyl-PPIA in the peripheral blood mononuclear cells (PBMCs) and of NFL, MMP-9, MCP-1, CK, MiR-206, Musclin/osteocrin, Uric acid, HNE in plasma in each treatment arm, during the entire treatment period (from baseline to 48 weeks).
11. Number of adverse events and serious adverse events in each treatment arm during 48 weeks of treatment.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Istituto Di Ricerche Farmacologiche Mario Negri

Sponsor organisation

Istituto Di Ricerche Farmacologiche Mario Negri

Address

Via Mario Negri 2

City

Milan

Postcode

20156

Country

Italy

Scientific contact point

Organisation

Istituto Di Ricerche Farmacologiche Mario Negri

Contact name

Elisabetta Pupillo

Public contact point

Organisation

Istituto Di Ricerche Farmacologiche Mario Negri

Contact name

Elisabetta Pupillo

Locations

1 EU/EEA country · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications