Open Label Extension Study of AMX0035 in Patients With ALS

The Centaur Open Label Extension Study (CENTAUR-OLE) is an extension study for patients with ALS who participated in the CENTAUR study (Study AMX3500). During the OLE, all participants received active treatment (AMX0035), and the investigators, evaluators, and participants remained blinded to the randomized treatment assigned at the beginning of the double-blind main study. The study was designed to assess the longer term safety and therapeutic potential of AMX0035.

• AMX0035 (Drug), also known as Sodium Phenylbutyrate (PB) and Taurursodiol (TURSO, also known as Ursodoxicoltaurine or Tauroursodeoxycholic Acid [TUDCA]): Combination therapy of PB and TURSO

Primary outcomes

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [From the Baseline Visit in the OLE study through Week 132 or the Early Discontinuation (Final Safety) Visit for each participant (for up to approximately 132 weeks)]: Number of participants with TEAEs from baseline in the OLE study through the last participant's last visit in the OLE

Secondary outcomes

• Amyotrophic Lateral Sclerosis Rating Scale Revised Total Score (ALSFRS-R) Change in Slope [From baseline in the Main Study through Week 24 of the OLE (48 weeks overall)]: Comparison of the difference in change in slope of Amyotrophic Lateral Sclerosis Rating Scale Revised (ALSFRS-R) total score from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). The slope is measured as a change in score divided by a change in time. ALSFRS-R consists of 12 items across 4 subdomains of function (bulbar, fine motor, gross motor, and breathing) with each item scored on a scale from 0 (total loss of function) to 4 (no loss of function). Total scores range from 0 to 48, with higher scores indicating better function.
• Survival - Time to Death [From date of first dose in the Main Study (each participant's Baseline Visit) through up to approximately 42 months (approximately 182 weeks)]: Median survival in months
• Composite of Time to Hospitalization, Death or Death Equivalent [From date of first dose in the Main Study (each participant's Baseline Visit) through up to approximately 42 months (approximately 182 weeks)]: The composite endpoint of time to hospitalization, death or death equivalent was defined as hospitalization, death, tracheostomy or PAV. PAV is defined as more than 22 hours daily of non-invasive mechanical ventilation for more than 1 week (7 days).
• Accurate Testing of Limb Isometric Strength (ATLIS) Change in Slope - Upper Extremities [From baseline in the Main Study through Week 24 of the OLE (48 weeks overall)]: Comparison of the difference in change in slope of Accurate Testing of Limb Isometric Strength (ATLIS) upper extremity score from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). The ATLIS device measures isometric strength in 6 upper extremity muscle groups. Raw values were standardized to percent predicted normal values for strength based on sex, age, weight, and height.
• Accurate Testing of Limb Isometric Strength (ATLIS) Change in Slope - Lower Extremities [From baseline in the Main Study through Week 24 of the OLE (48 weeks overall)]: Comparison of the difference in change in slope of Accurate Testing of Limb Isometric Strength (ATLIS) lower extremity score from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). The ATLIS device measures isometric strength in 6 lower extremity muscle groups. Raw values were standardized to percent predicted normal values for strength based on sex, age, weight, and height.
• Slow Vital Capacity Change in Slope [From baseline in the Main Study through Week 24 of the OLE (48 weeks overall)]: Comparison of the difference in change in slope of Slow Vital Capacity (SVC) from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). SVC volumes were standardized to predicted percent normalized values for respiratory muscle function based on age, sex, and height.
• Accurate Testing of Limb Isometric Strength (ATLIS) Total Score Change in Slope [From Baseline in the Main Study through Week 24 in the OLE (48 weeks overall)]: Comparison of the difference in change in slope of Accurate Testing of Limb Isometric Strength (ATLIS) total score from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). The ATLIS device measures isometric strength in 6 upper and 6 lower extremity muscle groups. Raw values were standardized to percent predicted normal values for strength based on sex, age, weight, and height.

Sex: All

Inclusion Criteria:

1. Completion of all visits in the randomized, double blind AMX3500 study. Participants who received tracheostomy or permanent assisted ventilation (PAV) during the course of the main study could enroll in the OLE if they completed all visits in the main study.
2. Must enroll in the OLE within 28 days of the Week 24 visit of the main study.
3. Signed informed consent to enter the OLE phase.

Exclusion Criteria:

1. Discontinued study drug prematurely in the double-blind phase of the study for reasons other than tracheostomy or PAV.
2. Exposure to or anticipated requirement for any disallowed medication listed in the protocol.
3. Any ongoing adverse events that in the opinion of the Site Investigator are clear contraindications to the study drug.
4. Unstable cardiac or other life-threatening disease emergent during the randomized, double blind study
5. Any major medical condition that in the opinion of the Site Investigator would interfere with the study and place the subject at increased risk.

Participant flow

Outcome results

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Primary), Count of participants, Participants: AMX0035 in OLE 81
• Amyotrophic Lateral Sclerosis Rating Scale Revised Total Score (ALSFRS-R) Change in Slope (Secondary), Least squares mean, Change in ALSFRS-R Total Score per Month: Randomized to Placebo in Main Study and Did or Did Not Participate in OLE 17.38 +/- 1.545; Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE 21.61 +/- 1.178 (p 0.0239)
• Survival - Time to Death (Secondary), Median, Months: Randomized to Placebo in Main Study and Did or Did Not Participate in OLE 18.7 (13.5 to 24.4); Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE 23.5 (19.5 to 26.2) (p 0.0475)
• Composite of Time to Hospitalization, Death or Death Equivalent (Secondary), Median, Months: Randomized to Placebo in Main Study and Did or Did Not Participate in OLE 10.0 (6.1 to 12.7); Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE 14.8 (10.7 to 18.2) (p 0.0308)
• Accurate Testing of Limb Isometric Strength (ATLIS) Change in Slope - Upper Extremities (Secondary), Least squares mean, % of Predicted Normal Change per Month: Randomized to Placebo in Main Study and Did or Did Not Participate in OLE 12.06 +/- 3.283; Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE 19.83 +/- 2.591 (p 0.0291)
• Accurate Testing of Limb Isometric Strength (ATLIS) Change in Slope - Lower Extremities (Secondary), Least squares mean, % of Predicted Normal Change per Month: Randomized to Placebo in Main Study and Did or Did Not Participate in OLE 20.48 +/- 3.653; Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE 25.24 +/- 2.893 (p 0.2261)
• Slow Vital Capacity Change in Slope (Secondary), Least squares mean, % of Predicted Normal Change per Month: Randomized to Placebo in Main Study and Did or Did Not Participate in OLE 37.85 +/- 4.427; Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE 48.52 +/- 3.356 (p 0.0372)
• Accurate Testing of Limb Isometric Strength (ATLIS) Total Score Change in Slope (Secondary), Least squares mean, % of Predicted normal change per month: Randomized to Placebo in Main Study and Did or Did Not Participate in OLE 16.65 +/- 2.973; Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE 22.84 +/- 2.371 (p 0.0503)

Adverse events

Time frame: Adverse event data were collected from baseline in the OLE study through study completion (generally about 2.5 years). Vital status was collected from date of first dose in the Main Study (each participant's Baseline Visit) through up to approximately 42 months (approximately 182 weeks)

Serious adverse events by term

Other adverse events by term

• Results publication: Paganoni S, Watkins C, Cawson M, Hendrix S, Dickson SP, Knowlton N, Timmons J, Manuel M, Cudkowicz M. Survival analyses from the CENTAUR trial in amyotrophic lateral sclerosis: Evaluating the impact of treatment crossover on outcomes. Muscle Nerve. 2022 Aug;66(2):136-141. doi: 10.1002/mus.27569. Epub 2022 May 31. PMID 35508892
• Results publication: Paganoni S, Hendrix S, Dickson SP, Knowlton N, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA, Heitzman D, Heiman-Patterson TD, Jackson C, Quinn C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha SS, Miller TM, Scelsa SN, Vu TH, Fournier C, Johnson KM, Swenson A, Goyal N, Pattee GL, Babu S, Chase M, Dagostino D, Hall M, Kittle G, Eydinov M, Ostrow J, Pothier L, Randall R, Shefner JM, Sherman AV, Tustison E, Vigneswaran P, Yu H, Cohen J, Klee J, Tanzi R, Gilbert W, Yeramian P, Cudkowicz M. Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial. J Neurol Neurosurg Psychiatry. 2022 May 16;93(8):871-5. doi: 10.1136/jnnp-2022-329024. Online ahead of print. PMID 35577511
• Results publication: Paganoni S, Hendrix S, Dickson SP, Knowlton N, Macklin EA, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA, Heitzman D, Heiman-Patterson TD, Jackson CE, Quinn C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha S, Miller TM, Scelsa SN, Vu TH, Fournier CN, Glass JD, Johnson KM, Swenson A, Goyal NA, Pattee GL, Andres PL, Babu S, Chase M, Dagostino D, Hall M, Kittle G, Eydinov M, McGovern M, Ostrow J, Pothier L, Randall R, Shefner JM, Sherman AV, St Pierre ME, Tustison E, Vigneswaran P, Walker J, Yu H, Chan J, Wittes J, Yu ZF, Cohen J, Klee J, Leslie K, Tanzi RE, Gilbert W, Yeramian PD, Schoenfeld D, Cudkowicz ME. Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis. Muscle Nerve. 2021 Jan;63(1):31-39. doi: 10.1002/mus.27091. Epub 2020 Oct 30. PMID 33063909

• Study Protocol (PDF, 2020-03-30)
• Statistical Analysis Plan: Primary SAP (PDF, 2019-10-31)
• Statistical Analysis Plan: Integrated Survival Analysis SAP (PDF, 2020-03-27)
• Statistical Analysis Plan: Addendum to Integrated Survival Analysis SAP (PDF, 2020-08-26)

• Sabrina Paganoni, MD, PhD, Principal investigator, Massachusetts General Hospital