E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
ALS (amyotrophic lateral sclerosis) |
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E.1.1.1 | Medical condition in easily understood language |
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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 |
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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 |
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. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives – Treatment Period 1. To assess the impact of AMX0035 compared to placebo on Slow Vital Capacity (SVC) in adult patients with ALS 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 in adult patients with ALS 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]) in adult patients with ALS 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 |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A sub-study is included in the main protocol. Matched evaluation will be performed of QTc interval prolongation (evaluated by digital ECG with central read) and blood sample for evaluation of systemic exposure (measurement in plasma using a validated assay for PB and its major metabolite PAA, and taurursodiol and its major metabolites ursodiol and glycine conjugated ursodiol). |
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E.3 | Principal inclusion criteria |
1. Male or female, at least 18 years of age; 2. Diagnosis of ALS (clinically 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 prior to randomization. Date of ALS symptom onset is defined as the onset of weakness (in the limbs, bulbar region, or trunk). Weakness in the bulbar region includes dysarthria and dysphagia; 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 Baseline Visit, previously 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, remote visits, and survival status reporting requirements; 7. Women of childbearing potential (WOCBP; e.g., not post-menopausal for at least one year or surgically sterile (a) must agree to use adequate birth control (b) 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; a. 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. b. 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). |
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E.4 | Principal exclusion criteria |
1. Presence of tracheostomy or PAV; defined as >22 hours daily of mechanical ventilation for more than 1 week (7 days); 2. Slow Vital Capacity (SVC) less than 55%; 3. History of known allergy to phenylbutyrate 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 (from a local laboratory within 12 weeks or central laboratory within 6 weeks from first dose at the Baseline Visit); 6. Pregnant women (confirmed by a pregnancy test within 7 days prior to 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, severe laboratory test anomaly or clinically significant ECG changes) 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 in another trial involving use of an investigational therapy (or within 5.5 plasma half-lives) prior to first dose at Baseline Visit; 14. Previous treatment with sodium phenylbutyrate (PB) or taurursodiol within 30 days from first dose at Baseline Visit; 15. Implantation of Diaphragm Pacing System (DPS); 16. Currently or previously treated within the last 30 days (or 5 half-lives, whichever is longer) from first dose at Baseline Visit or planned exposure during the treatment period to any prohibited medications listed in Section 6.7. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Joint assessment of ALSFRS-R total score progression over 48 weeks adjusted for mortality |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
ALSFRS-R will be assessed at baseline and every 4 weeks after start of treatment until 48 weeks after start of treatment. |
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E.5.2 | Secondary end point(s) |
• Change from Baseline to Week 48 of the SVC as percentage of normalized values for gender, body weight, age, and ethnicity • Change from Baseline to Week 48 of the ALSAQ-40 total score • Time from Baseline to transition through a King’s stage or through a MiToS stages (derived from ALSFRS-R data) • Time to ventilation free survival defined as the interval of time between randomization to the earliest of the date of tracheostomy for respiratory distress, the date of permanent non-invasive ventilation (PAV) and the date of death due to any causes • Change from Baseline of the EQ-5D score and visual analog scale (VAS) at Week 48 • Overall survival defined as the interval of time from randomization to the date of death due to any cause |
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E.5.2.1 | 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
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 | No |
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 |
Ireland |
Belgium |
France |
Germany |
Italy |
Netherlands |
Poland |
Portugal |
Spain |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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The end of the trial will correspond to the last participant last EOT visit/phone contact per the trial schedule. Participants will be followed up for the long-term survival status. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |