A study to investigate the safety and efficacy of AMX0035 in patients with Amyotrophic Lateral Sclerosis

• Register: EUCTR
• Last refreshed on: 3 November 2021
• Main ID: EUCTR2021-000250-26-DE
• Date of registration: 22/06/2021
• Prospective Registration: Yes
• Primary sponsor: Amylyx Pharmaceuticals Inc.
• Public title: A study to investigate the safety and efficacy of AMX0035 in patients with Amyotrophic Lateral Sclerosis
• Scientific title: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial to Evaluate the Safety and Efficacy of AMX0035 Versus Placebo for 48-week Treatment of Adult Patients with Amyotrophic Lateral Sclerosis (ALS) - Phoenix
• Date of first enrolment: 27/10/2021
• Target sample size: 600
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-000250-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, France, Germany, Ireland, Italy, Netherlands, Poland, Portugal, Spain, Sweden, United Kingdom, United States

Contacts

• Name: Project Manager
• Affiliation: Julius Clinical

• Name: Project Manager
• Affiliation: Julius Clinical

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female, at least 18 years of age.
2. Diagnosis of ALS (definite or clinically probable), made by a physician who is experienced with management of ALS, as defined by the World Federation of Neurology revised El Escorial criteria.
3. Time since onset of first symptom of ALS should be <24 months.
4. If the participant is to be treated with riluzole and/or edaravone during the course of the trial, then treatment with riluzole and/or edaravone was, at the time of the screening visit, started and maintained at a stable regimen for at least 14 days for riluzole and/or for a full treatment cycle for edaravone.
5. Capable of providing informed consent.
6. Capable and willing to follow trial procedures including visits to the trial clinic and visit requirements.
7. Women of childbearing potential (WOCBP; e.g., not post-menopausal for at least one year or surgically sterile*) must agree to use adequate birth control** for the duration of the trial and 3 months after the last dose of study drug.
8. Women must not be pregnant or planning to become pregnant for the duration of the trial and 3 months after last dose of study drug.
9. Men must agree to practice contraception for the duration of the trial and for at least 3 months after last dose of study drug;
10. Men must not plan to father a child or to provide sperm for donation for the duration of the trial and 3 months after the last dose of study drug.
* 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/ml or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
** Acceptable contraception for use in this trial are:
- Hormonal methods, such as birth control pills, patches, injections, vaginal ring, or implants;
- Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, cream, or gel that kills sperm);
- Intrauterine device (IUD);
- Abstinence (no heterosexual sex);
- Unique partner who is surgically sterile (men) or not of childbearing potential (female).
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 420
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 180

Exclusion criteria:
1. Presence of tracheostomy or PAV.
2. Slow Vital Capacity (SVC) less than 55%.
3. History of known allergy to PB or bile salts.
4. Abnormal liver function defined as bilirubin levels and/or aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 5 times the upper limit of the normal (obtained within 12 weeks from first dose).
5. Renal insufficiency as defined by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 (obtained within 12 weeks from first dose).
6. Pregnant women (confirmed by a pregnancy test within 7 days of first dose) or women currently breastfeeding.
7. Current severe biliary disease which may result in the Investigator medical judgment in biliary obstruction including for example active cholecystitis, primary biliary cirrhosis, sclerosing cholangitis, gallbladder cancer, gangrene of the gallbladder, abscess of the gallbladder.
8. History of Class III/IV heart failure (per New York Heart Association – NYHA).
9. Participant under severe salt restriction where the added salt intake due to treatment would put the participant at risk, in the Investigator clinical judgment.
10. Presence of unstable psychiatric disease, cognitive impairment, dementia or substance abuse that would impair ability of the participant to provide informed consent, according to Investigator judgment.
11. Clinically significant unstable medical condition (other than ALS) (e.g., cardiovascular instability, systemic infection, untreated thyroid dysfunction, clinically significant
laboratory test or ECG abnormality) that would pose a risk to the participant if he/she were to participate in the trial, according to Investigator judgment;
12. Previous treatment for ALS with cellular therapies or gene therapies;
13. Currently enrolled on another trial involving use of an investigational therapy;
14. Previous treatment with PB or taurursodiol within 30 days from Screening;
15. Implantation of Diaphragm Pacing System (DPS);
16. Currently or previously treated within the last 30 days or planned exposure to any prohibited medications listed in Section 6.8 of the protocol.




Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

ALS (amyotrophic lateral sclerosis)
MedDRA version: 21.1 Level: PT Classification code 10002026 Term: Amyotrophic lateral sclerosis System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Product Code: AMX0035
Pharmaceutical Form: Powder for oral suspension in sachet
INN or Proposed INN: phenylbutyrate
CAS Number: 1716-12-7
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 3-
INN or Proposed INN: Ursodoxicoltaurine
CAS Number: 14605-22-2
Other descriptive name: taurursodiol
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 1-
Pharmaceutical form of the placebo: Powder for oral suspension in sachet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: AEs and SAEs will be monitored continuously.
Clinical laboratory safety assessments will be performed at Screening and baseline, and 24 and 48 weeks after start of treatment.
ALSFRS-R will be assessed at baseline and every 4 weeks after start of treatment until 48 weeks after start of treatment.

Main Objective: 1. To assess the safety and tolerability of AMX0035 treatment over 48 weeks compared to placebo in adult patients with ALS.
2. To assess the impact of AMX0035 treatment compared to placebo on disease progression over 48 weeks based on change from baseline of ALSFRS-R and survival.

Secondary Objective: 1. To assess the impact of AMX0035 compared to placebo on Slow Vital Capacity (SVC) over 48 weeks.
2. To assess patient quality of life (QOL; using the 40-item ALS assessment questionnaire [ALSAQ-40] patient-reported outcome [PRO]) during treatment with AMX0035 compared to placebo over 48 weeks.
3. To assess AMX0035 compared to placebo on the time to any decline in King’s and MiToS stages as derived from ALSFRS-R data over 48 weeks.
4. To assess the impact of AMX0035 compared to placebo on ventilation free survival (defined as death, tracheostomy for respiratory distress or permanent non-invasive ventilation [>22 hours per day for 7 consecutive days]) over 48 weeks.
5. To assess AMX0035 compared to placebo on patient health status (using the EQ-5D descriptive system and the EQ visual analogue scale [EQ VAS] PRO during treatment with AMX0035 over 48 weeks.
Finally, a secondary objective of the trial is to assess the long-term survival of patients treated with AMX0035 or placebo.

Primary end point(s): Primary Safety Endpoints:
o Incidence and severity of AE and SAEs
o Incidence of abnormalities in clinical laboratory assessments
o Withdrawal from the trial
Primary Efficacy Endpoint
o Joint assessment of ALSFRS-R total score progression over 48 weeks adjusted for mortality

Secondary Outcome(s)

Secondary end point(s): o Change from baseline to Week 48 of the SVC as percentage of normalized values for gender, body weight, age, and ethnicity
o Change from baseline to Week 48 of the ALSAQ-40 total score
o Time from baseline to transition through a King’s stage or through a MiToS stages (derived from ALSFRS-R data)
o Time from baseline remaining ventilation free i.e., death, tracheostomy for respiratory distress, permanent non-invasive ventilation (PAV)
o Change from baseline of the EQ-5D score and visual analog scale (VAS) at Week 48
o Overall survival with all-cause mortality, assessed by independent confirmation of vitals status of all patients randomized into the trial extending after completion of the planned trial follow-up of 48 weeks

Timepoint(s) of evaluation of this end point: SVC will be assessed at Screening and baseline, and every 4 weeks after start of treatment until 48 weeks after start of treatment.
ALSAQ-40, King's stage, MiToS stage, EQ-5D-score and VAS scale will be assessed at baseline and every 12 weeks after start of treatment until 48 weeks after start of treatment.

Secondary ID(s)

A35-004

Source(s) of Monetary Support

Amylyx Pharmaceuticals Inc.

Ethics review

Status: Approved
Approval date: 11/10/2021
Contact: