To assess safety and tolerability of AMX0035 for treatment of ALS.
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess the long-term safety and tolerability of treatment with AMX0035,
based on the incidence of all adverse events, adverse events leading to
discontinuation of treatment or withdrawal from the study, and all serious
adverse events in participants treated with AMX0035
Secondary outcome
To assess the impact of long-term treatment with AMX0035 on survival based on:
1. Overall survival of all-cause mortality 2. Ventilation free survival
(defined as death, tracheostomy for respiratory distress or permanent
non-invasive ventilation [>22 hours per day for 7 consecutive days]) To assess
the impact of long-term treatment with AMX0035 on measures of ALS function and
key events in disease progression based on: 1. Change from baseline in ALSFRS-R
score at Week 108 2. To assess the incidence rate of the following significant
ALS life-events over 108 weeks: a) Tracheostomy for assisted ventilation; b)
Tracheostomy for management of secretions; c) Permanent Assisted Ventilation
(PAV) [defined as >22 hours daily of mechanical ventilation for more than one
week (7 days)]. The date of onset of PAV is the first day of the 7 days; d)
Placement of feeding tube and clinically significant (i.e., requiring
hospitalization or emergency department [ED] visit) complication/intervention
(e.g., displacement, replacement, complications requiring surgical
intervention); e) Placement of infusion port (in the subset of participants
receiving concurrent IV edaravone) and clinically significant (i.e., requiring
hospitalization or ED visit) complication/intervention (e.g., thrombosis,
bleeding, infection, replacement); f) Incidence and duration of
hospitalizations lasting more than 24 hours.
Background summary
ALS is a very serious and fatal condition characterized by progressive
degeneration of the upper and lower motor neurons. There
are limited pharmacological options in the treatment of ALS and they focus on
symptom treatment. The only existing authorized
medicine for treating ALS in the European Union is Riluzole.
In a randomized, Phase II, placebo-controlled trial, AMX0035 administered
orally for 24 weeks as add-on treatment to Investigator
selected standard of care showed statistical significant and clinically
meaningful benefit on a validated functional outcome (ALS
Functional Rating Scale-Revised [ALSFRS-R]), allowing participants to maintain
their independence longer. Secondary endpoints
measuring breathing and muscle strength showed effects in the same direction
and with similar magnitude as the primary endpoint
although not statistically significant. AMX0035 did not demonstrate significant
safety concerns and the most notable drug-related
adverse events were diarrhea and nausea
Study objective
To assess safety and tolerability of AMX0035 for treatment of ALS.
Study design
This is a phase IIIb open label extension study. Adults with clinically
definite or clinically probable ALS diagnosis, who meet all inclusion and
exclusion criteria, will receive AMX0035. All participants will receive
open-label treatment with AMX0035, starting on day 1 with an oral dose twice
daily (once in the morning and once in the evening) for the duration of the
study. After the baseline visit (day 1), enrolled participants will visit every
12 weeks (± 2 weeks) until week 108 or the end-of-treatment (EOT) visit,
followed by a safety follow-up approximately 28 days after the last dose. A
follow-up assessment for survival is done every 12 weeks after the EOT visit
until the time of death or end of study (EOS).
Intervention
All participants will receive oral (or by feeding tube) treatment with AMX0035
(a fixed dose combination of phenylbutyrate and taurursodiol). All participants
will take 2 sachets per day (one dose in the morning and one dose in the
evening) starting on day 1, throughout the study (in case twice a day is poorly
tolerated, more information on dose interruptions and reductions is in section
6.3).
AMX0035 is supplied by Amylyx in the form of a cardboard box containing
single-use sachets for approximately 1 month. Each bag of AMX0035 contains
active ingredients in a powder formulation containing 3 g phenylbutyrate and 1
g taurursodiol. The powder AMX0035 is mixed with water and taken orally (or by
feeding tube).
Study burden and risks
Side effects may occur following the use of AMX0035. It cannot be ruled out
that side effects may occur that are serious, long-lasting or permanent. All
possibilities will be used to minimize discomfort. The following side effects
have been found in patients using AMX0035 in previous studies (occurrence in 1
out of 10, or more):
- Diarrhea
- Constipation
- Nausea
- Muscle weakness
- Falls
- Headaches
- Dizziness
- Viral infection of the upper respiratory system
The most common side effects of AMX0035 in ALS patients are diarrhea and nausea
(about 1 in 5 people).
The study drug may also cause side effects that are currently unknown.
Thorndike St. 43
Cambridge MA 02141
US
Thorndike St. 43
Cambridge MA 02141
US
Listed location countries
Age
Inclusion criteria
1. Previous participation in Study A35-004 (PHOENIX), including completion of
the randomized-controlled phase through Week 48 (this timepoint may be upcoming
at the time of screening). Participants who do not complete
randomized-controlled phase through Week 48 for medical reasons may be included
on a case-by-case basis, in consultation with the sponsor; 2. Capable of
providing informed consent; 3. Capable and willing to follow trial procedures
including visits to the trial clinic, remote visits, and survival status
reporting requirements; 4. Women of childbearing potential (WOCBP; e.g., not
post-menopausal for at least one year or surgically sterilea must agree to use
adequate birth controlb for the duration of the trial and 3 months after the
last dose of AMX0035; a. 12 months of spontaneous amenorrhea or 6 months of
spontaneous amenorrhea with serum FSH levels > 40 mIU/ml or 6 weeks
postsurgical bilateral oophorectomy with or without hysterectomy. b. Acceptable
contraception methods for use in this trial are: - Hormonal methods, such as
birth control pills, patches, injections, vaginal ring, or implants; Barier
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). 5. Women must not be pregnant or planning to
become pregnant for the duration of the trial and 3 months after last dose of
AMX0035; 6. Men must agree to practice contraception for the duration of the
trial and for at least 3 months after last dose of AMX0035; 7. 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 AMX0035.
Exclusion criteria
1. History of known allergy to phenyl butyrate or bile salts; 2. 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); 3. Renal insufficiency as defined
by eGFR <60 mL/min/1.73m2 normal (obtained within 12 weeks from first dose); 4.
Pregnant women or women currently breastfeeding; 5. Current severe biliary
disease which may result in the Investigator medical judgement in biliary
obstruction including for example active cholecystitis, primary biliary
cirrhosis, sclerosing cholangitis, gallbladder cancer, gangrene of the
gallbladder, abscess of the gallbladder; 6. History of Class III/IV heart
failure (per New York Heart Association - NYHA); 7. Participant under severe
salt restriction where the added salt intake due to treatment would put the
participant at risk, in the Investigator clinical judgment; 8. 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; 9. Clinically significant unstable medical
condition (other than ALS) (e.g., cardiovascular instability, systemic
infection, untreated thyroid dysfunction, severe laboratory test anomaly or
clinically significant electrocardiogram [ECG] changes) that would pose a risk
to the participant if he/she were to participate in the trial, according to
Investigator judgment; 10. Currently enrolled in another trial (excluding Study
A35-004 (PHOENIX)) involving use of an investigational therapy (or within 5
plasma half-lives) prior to first dose at Baseline Visit; 11. Implantation of
Diaphragm Pacing System (DPS); 12. Currently or previously treated within the
last 30 days (or 5 half-lives, whichever is longer) from first dose at the
Baseline Visit or planned exposure during the treatment period to any
prohibited medications listed in Section 6.7 of the protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2022-002348-33-NL |
| ClinicalTrials.gov | NCT03488524 |
| CCMO | NL82383.100.22 |