Trial Outcomes & Findings for Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial (NCT NCT03836716)

NCT ID: NCT03836716

Last Updated: 2023-08-24

Results Overview

Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. No participant was treated for 76 weeks. Participants with on-treatment TEAEs are reported. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A participant may have several on-treatment periods separated by interruption intervals.

• Recruitment status: TERMINATED
• Study phase: PHASE3
• Target enrollment: 120 participants
• Primary outcome timeframe: From Day 1 in ORARIALS-02 to Early Termination, an average of approximately 28 weeks
• Results posted on: 2023-08-24

Participant Flow

Participant milestones

Measure	Arimoclomol (Open-label) 248 mg arimoclomol base 3 times daily (planned duration 152 weeks; actual duration after early termination of the trial approx. 28 weeks \[range 2-71 weeks\]).
Overall Study STARTED	120
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	120

Reasons for withdrawal

Measure	Arimoclomol (Open-label) 248 mg arimoclomol base 3 times daily (planned duration 152 weeks; actual duration after early termination of the trial approx. 28 weeks \[range 2-71 weeks\]).
Overall Study Adverse Event	3
Overall Study Death	22
Overall Study Withdrawal by Subject	8
Overall Study Study terminated by sponsor	87

Baseline Characteristics

Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial

Baseline characteristics by cohort

Measure	Arimoclomol (Open-label) n=120 Participants 248 mg arimoclomol base 3 times daily
Age, Continuous	57.6 years STANDARD_DEVIATION 10.30 • n=5 Participants
Sex: Female, Male Female	36 Participants n=5 Participants
Sex: Female, Male Male	84 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	79 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	38 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants
Race (NIH/OMB) White	80 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	39 Participants n=5 Participants
Region of Enrollment Canada	2 participants n=5 Participants
Region of Enrollment Netherlands	10 participants n=5 Participants
Region of Enrollment Sweden	5 participants n=5 Participants
Region of Enrollment Belgium	5 participants n=5 Participants
Region of Enrollment United States	28 participants n=5 Participants
Region of Enrollment Poland	15 participants n=5 Participants
Region of Enrollment Italy	14 participants n=5 Participants
Region of Enrollment United Kingdom	2 participants n=5 Participants
Region of Enrollment France	17 participants n=5 Participants
Region of Enrollment Germany	7 participants n=5 Participants
Region of Enrollment Spain	15 participants n=5 Participants
ALS Functional Rating Scale - Revised (ALSFRS-R)	26.0 units on a scale STANDARD_DEVIATION 10.38 • n=5 Participants

PRIMARY outcome

Timeframe: From Day 1 in ORARIALS-02 to Early Termination, an average of approximately 28 weeks

Population: Safety analysis set: All enrolled patients who received at least one dose of arimoclomol.

Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. No participant was treated for 76 weeks.

Participants with on-treatment TEAEs are reported. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration >14 days or the last dose at the end of trial). A participant may have several on-treatment periods separated by interruption intervals.

Outcome measures

Measure	Arimoclomol (Open-label) n=120 Participants 248 mg arimoclomol base 3 times daily
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period TEAEs leading to IMP interruption	12 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period Possibly related TEAEs	22 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period Not related TEAEs	62 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period Serious TEAEs (SAEs)	21 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period Treatment-related serious TEAEs	1 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period TEAEs leading to IMP withdrawal	9 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period Treatment-emergent adverse events (TEAEs)	93 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period Mild TEAEs	34 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period Moderate TEAEs	44 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period Severe TEAEs	15 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period Treatment-related TEAEs	31 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Over the Open-label Treatment Period Probably related TEAEs	9 Participants

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 2 participants at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Standard hematology parameters. White blood cell differential count for basophils, eosinophils, leukocytes, lymphocytes, monocytes, and neutrophils, and platelet count.

Outcome measures

Measure	Arimoclomol (Open-label) n=2 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Eosinophils, change from baseline to Week 76	-0.070 10^9 cells/L Standard Deviation 0.0424
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Leukocytes, Week 76	9.120 10^9 cells/L Standard Deviation 3.1537
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Basophils, Week 76	0.030 10^9 cells/L Standard Deviation 0.0000
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Basophils, change from baseline to Week 76	-0.015 10^9 cells/L Standard Deviation 0.0071
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Eosinophils, Week 76	0.150 10^9 cells/L Standard Deviation 0.0141
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Leukocytes, change from baseline to Week 76	-0.565 10^9 cells/L Standard Deviation 2.4395
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Lymphocytes, Week 76	1.445 10^9 cells/L Standard Deviation 0.4738
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Lymphocytes, change from baseline to Week 76	-0.365 10^9 cells/L Standard Deviation 0.3041
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Monocytes, Week 76	0.460 10^9 cells/L Standard Deviation 0.1414
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Monocytes, change from baseline to Week 76	-0.055 10^9 cells/L Standard Deviation 0.0212
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Neutrophils, Segmented, Week 76	7.030 10^9 cells/L Standard Deviation 3.4648
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Neutrophils, Segmented, change from baseline to Week 76	-0.070 10^9 cells/L Standard Deviation 2.8001
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Platelets, Week 76	334.0 10^9 cells/L Standard Deviation 114.55
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (1) Platelets, change from baseline to Week 76	62.5 10^9 cells/L Standard Deviation 103.94

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 2 participants at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Standard hematology parameters. Percentage of leukocytes were determined for basophils, eosinophils, lymphocytes, monocytes, and neutrophils

Outcome measures

Measure	Arimoclomol (Open-label) n=2 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (2) Basophils/Leukocytes, Week 76	0.40 percentage of leukocytes Standard Deviation 0.141
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (2) Basophils/Leukocytes, change from baseline to Week 76	-0.05 percentage of leukocytes Standard Deviation 0.212
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (2) Eosinophils/Leukocytes, Week 76	1.70 percentage of leukocytes Standard Deviation 0.424
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (2) Eosinophils/Leukocytes, change from baseline to Week 76	-0.50 percentage of leukocytes Standard Deviation 0.849
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (2) Lymphocytes/Leukocytes, Week 76	17.85 percentage of leukocytes Standard Deviation 11.384
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (2) Lymphocytes/Leukocytes, change from baseline to Week 76	-0.95 percentage of leukocytes Standard Deviation 8.132
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (2) Monocytes/Leukocytes, Week 76	5.05 percentage of leukocytes Standard Deviation 0.212
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (2) Monocytes/Leukocytes, change from baseline to Week 76	-0.20 percentage of leukocytes Standard Deviation 1.556
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (2) Neutrophils/Leukocytes, Week 76	74.95 percentage of leukocytes Standard Deviation 12.092
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematology (2) Neutrophils/Leukocytes, change from baseline to Week 76	1.70 percentage of leukocytes Standard Deviation 10.607

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 2 participants at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Standard hematology parameter.

Outcome measures

Measure	Arimoclomol (Open-label) n=2 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Erythrocytes Erythrocytes, Week 76	3.70 10^12 cells/L Standard Deviation 0.000
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Erythrocytes Erythrocytes, change from baseline to Week 76	-0.40 10^12 cells/L Standard Deviation 0.707

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 2 participants at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Standard hematology parameter.

Outcome measures

Measure	Arimoclomol (Open-label) n=2 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematocrit Hematocrit, Week 76	0.345 L of cells / L of blood Standard Deviation 0.0071
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hematocrit Hematocrit, change from baseline to Week 76	-0.025 L of cells / L of blood Standard Deviation 0.0636

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 2 participants at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Standard hematology parameter.

Outcome measures

Measure	Arimoclomol (Open-label) n=2 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hemoglobin Hemoglobin, Week 76	115.5 g/L Standard Deviation 3.54
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Hemoglobin Hemoglobin, change from baseline to Week 76	-14.0 g/L Standard Deviation 21.21

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 1 participant at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints

Standard clinical chemistry parameters. Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Creatine Kinase, Gamma Glutamyl Transferase, and Lactate Dehydrogenase.

Outcome measures

Measure	Arimoclomol (Open-label) n=1 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (1) Alanine Aminotransferase, Week 76	14.0 U/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (1) Alanine Aminotransferase, change from baseline to Week 76	-31.0 U/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (1) Alkaline Phosphatase, Week 76	97.0 U/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (1) Alkaline Phosphatase, change from baseline to Week 76	16.0 U/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (1) Aspartate Aminotransferase, Week 76	11.0 U/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (1) Aspartate Aminotransferase, change from baseline to Week 76	-15.0 U/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (1) Creatine Kinase, Week 76	39.0 U/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (1) Creatine Kinase, change from baseline to Week 76	-118.0 U/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (1) Gamma Glutamyl Transferase, Week 76	13.0 U/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (1) Gamma Glutamyl Transferase, change from baseline to Week 76	-15.0 U/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (1) Lactate Dehydrogenase, Week 76	151.0 U/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (1) Lactate Dehydrogenase, change from baseline to Week 76	-42.0 U/L Standard Deviation NA Standard deviation not applicable as N=1

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 1 participant at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Standard clinical chemistry parameters. Calcium, Calcium Corrected, Cholesterol, Glucose, HDL Cholesterol, LDL Cholesterol, Potassium, Sodium, Triglycerides, and Urea Nitrogen.

Outcome measures

Measure	Arimoclomol (Open-label) n=1 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Calcium, Week 76	2.220 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Calcium, change from baseline to Week 76	-0.350 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Calcium Corrected, Week 76	2.270 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Calcium Corrected, change from baseline to Week 76	-0.080 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Cholesterol, Week 76	3.050 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Cholesterol, change from baseline to Week 76	-1.060 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Glucose, Week 76	8.50 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Glucose, change from baseline to Week 76	1.60 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) HDL Cholesterol, Week 76	0.830 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) HDL Cholesterol, change from baseline to Week 76	-0.770 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) LDL Cholesterol, Week 76	1.760 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) LDL Cholesterol, change from baseline to Week 76	-0.540 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Potassium, Week 76	3.90 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Potassium, change from baseline to Week 76	-0.50 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Sodium, Week 76	138.0 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Sodium, change from baseline to Week 76	-6.0 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Triglycerides, Week 76	1.100 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Triglycerides, change from baseline to Week 76	0.320 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Urea Nitrogen, Week 76	4.60 mmol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (2) Urea Nitrogen, change from baseline to Week 76	-0.40 mmol/L Standard Deviation NA Standard deviation not applicable as N=1

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 1 participant at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Standard clinical chemistry parameters. Bilirubin, Creatinine, Direct Bilirubin, and Indirect Bilirubin.

Outcome measures

Measure	Arimoclomol (Open-label) n=1 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (3) Bilirubin, Week 76	5.0 micromol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (3) Bilirubin, change from baseline to Week 76	-7.0 micromol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (3) Creatinine, Week 76	18.0 micromol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (3) Creatinine, change from baseline to Week 76	-35.0 micromol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (3) Direct Bilirubin, Week 76	2.0 micromol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (3) Direct Bilirubin, change from baseline to Week 76	-1.0 micromol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (3) Indirect Bilirubin, Week 76	3.0 micromol/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Clinical Chemistry (3) Indirect Bilirubin, change from baseline to Week 76	-6.0 micromol/L Standard Deviation NA Standard deviation not applicable as N=1

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 1 participant at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Standard clinical chemistry parameters.

Outcome measures

Measure	Arimoclomol (Open-label) n=1 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Albumin and Protein Albumin, Week 76	38.0 g/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Albumin and Protein Albumin, change from baseline to Week 76	-13.0 g/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Albumin and Protein Protein, Week 76	64.0 g/L Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Albumin and Protein Protein, change from baseline to Week 76	-16.0 g/L Standard Deviation NA Standard deviation not applicable as N=1

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 2 participants at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Standard clinical chemistry parameter.

Outcome measures

Measure	Arimoclomol (Open-label) n=2 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Cystatin C Cystatin C, Week 76	1.310 mg/L Standard Deviation 0.7495
Mean and Change From Baseline in Clinical Safety Laboratory Tests - Cystatin C Cystatin C, change from baseline to Week 76	0.350 mg/L Standard Deviation 0.6364

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 1 participant at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Standard vital signs. Systolic and diastolic blood pressure.

Outcome measures

Measure	Arimoclomol (Open-label) n=1 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Vital Signs - Blood Pressure Systolic Blood Pressure, Week 76	112.0 mmHg Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Vital Signs - Blood Pressure Systolic Blood Pressure, change from baseline to Week 76	-10.0 mmHg Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Vital Signs - Blood Pressure Diastolic Blood Pressure, Week 76	76.0 mmHg Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Vital Signs - Blood Pressure Diastolic Blood Pressure, change from baseline to Week 76	-1.0 mmHg Standard Deviation NA Standard deviation not applicable as N=1

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 1 participant at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Standard vital signs measurement.

Outcome measures

Measure	Arimoclomol (Open-label) n=1 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Vital Signs - Pulse Rate Pulse Rate, Week 76	86.0 beats/min Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Vital Signs - Pulse Rate Pulse Rate, change from baseline to Week 76	-3.0 beats/min Standard Deviation NA Standard deviation not applicable as N=1

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 1 participant at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Standard vital signs measurement.

Outcome measures

Measure	Arimoclomol (Open-label) n=1 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Vital Signs - Respiratory Rate Respiratory Rate, Week 76	12.0 breaths/min Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Vital Signs - Respiratory Rate Respiratory Rate, change from baseline to Week 76	-4.0 breaths/min Standard Deviation NA Standard deviation not applicable as N=1

PRIMARY outcome

Timeframe: Week 76

Population: Data only available for 1 participant at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Standard vital signs measurement.

Outcome measures

Measure	Arimoclomol (Open-label) n=1 Participants 248 mg arimoclomol base 3 times daily
Mean and Change From Baseline in Vital Signs - Temperature Temperature, change from baseline to Week 76	0.80 Degrees Celsius Standard Deviation NA Standard deviation not applicable as N=1
Mean and Change From Baseline in Vital Signs - Temperature Temperature, Week 76	36.40 Degrees Celsius Standard Deviation NA Standard deviation not applicable as N=1

PRIMARY outcome

Timeframe: From Day 1 in ORARIALS-02 to Early Termination, an average of approximately 28 weeks

Population: Safety analysis set: All enrolled patients that received at least one dose of arimoclomol.

Clinical safety laboratory data and vital signs were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. No patient was treated for 76 weeks.

Outcome measures

Measure	Arimoclomol (Open-label) n=120 Participants 248 mg arimoclomol base 3 times daily
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Hemoglobin (g/L) <= 95 (Females) <= 115 (Males)	10 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Hemoglobin (g/L) >= 165 (Females), >= 185 (Males)	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Cholesterol (mmol/L) >= 6.2 (Fasting=Yes)	15 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Erythrocytes (10^12/L) <= 3.5 (Females), <= 3.8 (Males)	16 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Erythrocytes (10^12/L) >= 6.0 (Females), >= 7.0 (Males)	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Hematocrit <= 0.32 (Females), <= 0.37 (Males)	21 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Hematocrit >= 0.5 (Females), >= 0.55 (Males)	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Leukocytes (10^9/L) <= 2.8	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Leukocytes (10^9/L) >= 16	3 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Neutrophils/Leukocytes (%) <= 20	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Neutrophils/Leukocytes (%) >= 85	3 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Eosinophils/Leukocytes (%) >= 10	1 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Basophils/Leukocytes (%) >= 10	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Lymphocytes/Leukocytes (%) <= 10	6 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Lymphocytes/Leukocytes (%) >= 75	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Monocytes/Leukocytes (%) >= 15	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Platelets (10^9/L) <= 75	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Platelets (10^9/L) >= 600	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Aspartate Aminotransferase (U/L) >= 3 x Upper Limit of Normal (ULN)	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Alanine Aminotransferase (U/L) >= 3 x ULN	7 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Bilirubin (umol/L) >= 34	2 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Direct Bilirubin (umol/L) >= 12	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Indirect Bilirubin (umol/L) >= 22	4 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Alkaline Phosphatase (U/L) >= 3 x ULN	1 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Gamma Glutamyl Transferase (U/L) >= 200	4 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Creatinine (umol/L) >= 1.5 x ULN	1 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Urea Nitrogen (mmol/L) >= 11	7 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Sodium (mmol/L) <= 125	2 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Sodium (mmol/L) >= 155	1 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Potassium (mmol/L) <= 3.0	4 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Potassium (mmol/L) >= 6.0	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Calcium (mmol/L) <= 1.8	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Calcium (mmol/L) >= 3.0	2 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Glucose (mmol/L) <= 3.9 (Fasting=No or blank)	8 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Glucose (mmol/L) >= 11.1 (Fasting=No or blank)	7 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Glucose (mmol/L) <= 3.5 (Fasting=Yes)	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Glucose (mmol/L) >= 7.0 (Fasting=Yes)	7 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Protein (g/L) <= 45	1 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Protein (g/L) >= 95	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Albumin (g/L) <= 27	2 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Cholesterol (mmol/L) >= 7.8 (Fasting=No or blank)	15 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Triglycerides (mmol/L) >= 5.65 (Fasting=No or blank)	6 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Triglycerides (mmol/L) >= 4.2 (Fasting=Yes)	3 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period LDL Cholesterol (mmol/L) >= 5.3 (Fasting=No or blank)	13 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period LDL Cholesterol (mmol/L) >= 4.9 (Fasting=Yes)	7 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period HDL Cholesterol (mmol/L) <= 0.8 (Fasting=No or blank)	11 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period HDL Cholesterol (mmol/L) <= 0.9 (Fasting=Yes)	2 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Creatine Kinase (U/L) >= 400 (Females) >= 750 (Males)	20 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Lactate Dehydrogenase (U/L) >= 750	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Pulse Rate <50 and decrease from baseline of >= 15 beats/min	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Pulse Rate >120 and increase from baseline of >= 15 beats/min	0 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Diastolic Blood Pressure <=50 and decrease from baseline of >= 15 mmHg	1 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Diastolic Blood Pressure >105 and increase from baseline of >= 15 mmHg	6 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Systolic Blood Pressure <=90 and decrease from baseline of >= 20 mmHg	3 Participants
Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Safety Laboratory Tests and Vital Signs Over the Open-label Treatment Period Systolic Blood Pressure >180 and increase from baseline of >= 20 mmHg	0 Participants

PRIMARY outcome

Timeframe: From Day 1 in ORARIALS-02 to Early Termination, an average of approximately 28 weeks

Population: Safety analysis set: All enrolled patients who received at least one dose of arimoclomol.

The C-SSRS is a detailed questionnaire assessing both suicidal behavior and suicidal ideation through a series of simple, plain-language questions administered as an interview by a qualified investigator or delegate.

Outcome measures

Measure	Arimoclomol (Open-label) n=120 Participants 248 mg arimoclomol base 3 times daily
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Preparatory acts or behavior	0 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Suicidal ideation (yes on any 1 of the following 5 items)	16 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Wish to be Dead	15 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Non-specific active suicidal thoughts	10 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Active Suicidal ideation with any methods (not Plan) without intent to Act	5 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Active suicidal ideation with some intent, without Specific Plan	1 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Active Suicidal ideation with specific Plan and Intent	0 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Suicidal Behavior (yes on any 1 of the following 5 items)	0 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Aborted Attempt	0 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Interrupted Attempt	0 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Actual Attempt (non-fatal)	0 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Completed Suicide	0 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Suicidal ideation or Behavior (yes to any of the above 10 items)	16 Participants
Columbia-Suicide Severity Rating Scale (C-SSRS) Over the Open-label Treatment Period Self-injurious Behavior without suicidal intent	0 Participants

SECONDARY outcome

Timeframe: Week 76

Population: Data were not collected at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

The ALSFRS-R is an ordinal rating scale used to determine subjects' subjective assessment of their capability and independence with 12 functional activities ('speech', 'salivation', 'swallowing', handwriting', 'cutting food and handling utensils', 'dressing and hygiene', 'turning in bed and adjusting bed clothes', 'walking', 'dyspnoea', 'orthopnoea' and 'respiratory insufficiency'). Each activity is rated on a 5-point scale (from 0 [no ability] to 4 [normal]), giving a maximal ALSFRS-R score of 48. A lower score corresponds to a lower capability and independence.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 76 weeks

Population: Data only available for 1 patient at Week 76 since the trial was terminated early by the sponsor as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints.

Slow vital capacity (SVC) measures the volume that can be exhaled from a full inhalation after exhaling to a maximum as slowly as possible. Predicted SVC was derived per European Community of Coal and Steel (ECCS) reference equations:

• If male: Predicted SVC = 0.061 x height (cm) - 0.028 x age (years) - 4.65
• If female: Predicted SVC = 0.0466 x height (cm) - 0.024 x age (years) - 3.28

Outcome measures

Measure	Arimoclomol (Open-label) n=1 Participants 248 mg arimoclomol base 3 times daily
Change in Percentage (%) Predicted Slow Vital Capacity (SVC) From Baseline to Week 76 (for Subjects Who Did Not Meet the Survival Endpoint in the ORARIALS-01 Trial)	-21.6 percentage of predicted SVC Standard Deviation NA Standard deviation not applicable as N=1

Adverse Events

Arimoclomol (Open-label)

Serious events: 21 serious events

Other events: 91 other events

Deaths: 23 deaths

Serious adverse events

Measure	Arimoclomol (Open-label) n=120 participants at risk 248 mg arimoclomol base 3 times daily
Infections and infestations Pneumonia	5.8% 7/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Infections and infestations Clostridium difficile infection	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Infections and infestations Corona virus infection	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Infections and infestations Respiratory tract infection	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	2.5% 3/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	1.7% 2/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	1.7% 2/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Cardiac disorders Cardiac arrest	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Cardiac disorders Cardiac failure	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Cardiac disorders Coronary artery disease	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Renal and urinary disorders Acute kidney injury	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Renal and urinary disorders Urinary incontinence	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Gastrointestinal disorders Ileus	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Injury, poisoning and procedural complications Rib fracture	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Investigations False positive investigation result	0.83% 1/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.

Other adverse events

Measure	Arimoclomol (Open-label) n=120 participants at risk 248 mg arimoclomol base 3 times daily
Infections and infestations Urinary tract infection	5.8% 7/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Infections and infestations Corona virus infection	5.0% 6/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Gastrointestinal disorders Constipation	6.7% 8/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Injury, poisoning and procedural complications Fall	6.7% 8/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Investigations Cystatin C increased	5.8% 7/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Blood and lymphatic system disorders Anaemia	5.0% 6/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Infections and infestations Fungal skin infection	2.5% 3/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Gastrointestinal disorders Flatulence	2.5% 3/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Gastrointestinal disorders Gastrooesophageal reflux disease	2.5% 3/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Gastrointestinal disorders Diarrhoea	3.3% 4/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Gastrointestinal disorders Nausea	4.2% 5/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Injury, poisoning and procedural complications Head injury	2.5% 3/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Investigations Alanine aminotransferase increased	3.3% 4/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Investigations Gamma-glutamyltransferase increased	2.5% 3/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Musculoskeletal and connective tissue disorders Muscle spasms	2.5% 3/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Metabolism and nutrition disorders Type 2 diabetes mellitus	3.3% 4/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Metabolism and nutrition disorders Decreased appetite	3.3% 4/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Metabolism and nutrition disorders Hypokalaemia	2.5% 3/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Psychiatric disorders Anxiety	3.3% 4/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Psychiatric disorders Depression	2.5% 3/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Blood and lymphatic system disorders Leukocytosis	2.5% 3/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Cardiac disorders Tachycardia	2.5% 3/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Vascular disorders Hypertension	2.5% 3/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.
Musculoskeletal and connective tissue disorders Pain in extremity	2.5% 3/120 • Adverse event (AE) data were collected throughout the trial until early termination. The average duration of exposure was 198.7 days (approximately 28 weeks; standard deviation 99.57 days; minimum 16 days, maximum 494 days). 58 participants (48.3%) were exposed less than 6 months; 55 participants (45.8%) were exposed 6 to less than 12 months; 7 participants (5.8%) were exposed 12 to less than 18 months. A treatment-emergent AE (TEAE) is defined as an AE with onset, or a pre-existing AE that worsened in severity, on or after the first dose of IMP. An on-treatment TEAE is any TEAE in the on-treatment period defined as the time from first dose of IMP until 14 days since the last preceding administration of IMP (either before a temporary IMP interruption with duration \>14 days or the last dose at the end of trial). A patient may have several on-treatment periods separated by interruption intervals.

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