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Clinical Trial Results:
An open-label multi-part first-in-human study of oral LMI070 in infants with Type 1 spinal muscular atrophy.

Summary
EudraCT number	2014-002053-19
Trial protocol	DK IT DE BE NL CZ PL HU BG
Global end of trial date	29 Dec 2022

Results information
Results version number	v1(current)
This version publication date	14 Jul 2023
First version publication date	14 Jul 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CLMI070X2201

ISRCTN number

US NCT number

NCT02268552

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

Novartis Campus, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

29 Dec 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Dec 2022

Was the trial ended prematurely?

Main objective of the trial

Part 1: Determine the safety and tolerability of ascending weekly doses and estimate the maximum tolerated dose (MTD) of branaplam in infants with Type 1 SMA. Part 2: Evaluate the safety and tolerability of 2 doses of branaplam administered weekly for 52 weeks in subjects with Type 1 SMA. Part 3: Assess long term safety and tolerability of extended, once a week branaplam treatment in subjects with Type 1 SMA who have had at least 52 weeks of treatment in either Part 1 or 2 of this protocol.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Apr 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 5

Country: Number of subjects enrolled

Bulgaria: 1

Country: Number of subjects enrolled

Denmark: 3

Country: Number of subjects enrolled

Germany: 1

Country: Number of subjects enrolled

Italy: 2

Country: Number of subjects enrolled

Poland: 9

Country: Number of subjects enrolled

Russian Federation: 17

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

There was a screening period of 1 week to assess eligibility and a baseline period of 1 week to review baseline safety evaluation results prior to dosing.

Period 1 title

Overall (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Part 1 LMI070 Overall

Arm description

Enteral route via feeding tube or oral. There were 5 cohorts: 0.3125, 0.625, 1.25, 2.5, 3.125 mg/kg weekly doses for 2 weeks

Arm type

Experimental

Investigational medicinal product name

branaplam

Investigational medicinal product code

LMI070

Other name

Pharmaceutical forms

Gastroenteral solution, Oral solution

Routes of administration

Enteral use , Oral use

Dosage and administration details

Branaplam in a dose strength of 3.5 mg/mL administered by the enteral route or orally depending ability to swallow

Part 2 LMI070 0.625 mg/kg

Arm description

LMI070 0.625 mg/kg by enteral route via feeding tube or oral

Arm type

Experimental

Investigational medicinal product name

branaplam

Investigational medicinal product code

LMI070

Other name

Pharmaceutical forms

Gastroenteral solution, Oral solution

Routes of administration

Enteral use , Oral use

Dosage and administration details

Branaplam in a dose strength of 3.5 mg/mL administered by the enteral route or orally depending ability to swallow

Part 2 LMI070 2.5 mg/kg

Arm description

LMI070 2.5 mg/kg by enteral route via feeding tube or oral

Arm type

Experimental

Investigational medicinal product name

branaplam

Investigational medicinal product code

LMI070

Other name

Pharmaceutical forms

Gastroenteral solution, Oral solution

Routes of administration

Enteral use , Oral use

Dosage and administration details

Branaplam in a dose strength of 3.5 mg/mL administered by the enteral route or orally depending ability to swallow

Parts 1 & 3 Overall

Arm description

Participants who completed 52 weeks of treatment in Part 1 could have continued on same dose or moved to optimal dose (2.5 mg/kg) in Part 3

Arm type

Experimental

Investigational medicinal product name

branaplam

Investigational medicinal product code

LMI070

Other name

Pharmaceutical forms

Gastroenteral solution, Oral solution

Routes of administration

Enteral use , Oral use

Dosage and administration details

Branaplam in a dose strength of 3.5 mg/mL administered by the enteral route or orally depending ability to swallow

Parts 2 & 3 Overall

Arm description

Participants who completed 52 weeks of treatment in Part 2 could have continued on same dose or could have moved to optimal dose (2.5 mg/kg) in Part 3

Arm type

Experimental

Investigational medicinal product name

branaplam

Investigational medicinal product code

LMI070

Other name

Pharmaceutical forms

Gastroenteral solution, Oral solution

Routes of administration

Enteral use , Oral use

Dosage and administration details

Branaplam in a dose strength of 3.5 mg/mL administered by the enteral route or orally depending ability to swallow

Number of subjects in period 1	Part 1 LMI070 Overall	Part 2 LMI070 0.625 mg/kg	Part 2 LMI070 2.5 mg/kg	Parts 1 & 3 Overall	Parts 2 & 3 Overall
Started	13	10	15	13	25
Completed	7	10	12	0	0
Not completed	6	0	3	13	25
Adverse event, serious fatal	5	-	2	5	7
Early termination of trial	-	-	-	7	15
Did not complete, reason not stated	-	-	-	-	1
Subject/guardian decision	1	-	1	1	2

Baseline characteristics

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Reporting group title

Overall

Reporting group description

Reporting group values	Overall	Total
Number of subjects	38	38
Age categorical
Units: Subjects
Infants and toddlers (28 days-23 months)	38	38
Age Continuous
Units: months
arithmetic mean (standard deviation)	4.04 ( 1.331 )	-
Sex: Female, Male
Units: participants
Female	22	22
Male	16	16
Race/Ethnicity, Customized
Units: Subjects
Asian	1	1
Caucasian	35	35
Other	2	2

Subject analysis set title

Part 1 LMI070 Overall BL

Subject analysis set type

Full analysis

Subject analysis set description

Enteral route via feeding tube or oral. There were 5 cohorts: 0.3125, 0.625, 1.25, 2.5, 3.125 mg/kg weekly doses for 2 weeks for Baseline

Subject analysis set title

Part 2 LMI070 0.625 BL

Subject analysis set type

Full analysis

Subject analysis set description

LMI070 0.625 mg/kg by enteral route via feeding tube or oral for Baseline

Subject analysis set title

Part 2 LMI070 2.5 mg/kg BL

Subject analysis set type

Full analysis

Subject analysis set description

LMI070 2.5 mg/kg by enteral route via feeding tube or oral for Baseline

Subject analysis sets values	Part 1 LMI070 Overall BL	Part 2 LMI070 0.625 BL	Part 2 LMI070 2.5 mg/kg BL
Number of subjects	13	10	15
Age categorical
Units: Subjects
Infants and toddlers (28 days-23 months)	13	10	15
Age Continuous
Units: months
arithmetic mean (standard deviation)	( )	( )	( )
Sex: Female, Male
Units: participants
Female	8	5	9
Male	5	5	6
Race/Ethnicity, Customized
Units: Subjects
Asian	0	0	1
Caucasian	11	10	14
Other	2	0	0

End points

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Reporting group title

Part 1 LMI070 Overall

Reporting group description

Enteral route via feeding tube or oral. There were 5 cohorts: 0.3125, 0.625, 1.25, 2.5, 3.125 mg/kg weekly doses for 2 weeks

Reporting group title

Part 2 LMI070 0.625 mg/kg

Reporting group description

LMI070 0.625 mg/kg by enteral route via feeding tube or oral

Reporting group title

Part 2 LMI070 2.5 mg/kg

Reporting group description

LMI070 2.5 mg/kg by enteral route via feeding tube or oral

Reporting group title

Parts 1 & 3 Overall

Reporting group description

Participants who completed 52 weeks of treatment in Part 1 could have continued on same dose or moved to optimal dose (2.5 mg/kg) in Part 3

Reporting group title

Parts 2 & 3 Overall

Reporting group description

Participants who completed 52 weeks of treatment in Part 2 could have continued on same dose or could have moved to optimal dose (2.5 mg/kg) in Part 3

Subject analysis set title

Part 1 LMI070 Overall BL

Subject analysis set type

Full analysis

Subject analysis set description

Enteral route via feeding tube or oral. There were 5 cohorts: 0.3125, 0.625, 1.25, 2.5, 3.125 mg/kg weekly doses for 2 weeks for Baseline

Subject analysis set title

Part 2 LMI070 0.625 BL

Subject analysis set type

Full analysis

Subject analysis set description

LMI070 0.625 mg/kg by enteral route via feeding tube or oral for Baseline

Subject analysis set title

Part 2 LMI070 2.5 mg/kg BL

Subject analysis set type

Full analysis

Subject analysis set description

LMI070 2.5 mg/kg by enteral route via feeding tube or oral for Baseline

Primary: Number of participants with dose limiting toxicities (DLT) in Part 1 - Safety analysis set (SAS)

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End point title

Number of participants with dose limiting toxicities (DLT) in Part 1 - Safety analysis set (SAS) ^[1] ^[2]

End point description

A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant therapies that occurs within the first 14 days of treatment with LMI070 and meets any of the criteria for blood and lymphatic system disorders, gastrointestinal disorders, investigations and other toxicities considered clinically significant.

End point type

Primary

End point timeframe

Baseline up to 2 weeks for Part 1

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No analysis was done
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Part 1 LMI070 Overall
Number of subjects analysed	13
Units: Participants	0

No statistical analyses for this end point

Primary: Number of participants with treatment emergent adverse events (TEAEs) and serious adverse events -SAS

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End point title

Number of participants with treatment emergent adverse events (TEAEs) and serious adverse events -SAS ^[3] ^[4]

End point description

TEAEs are defined as adverse events starting on or after the first dose of study treatment that were absent pre-treatment, or events present prior to the first dose but increased in severity after the first dose. Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post last treatment.

End point type

Primary

End point timeframe

Baseline up to approximately 83 months

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No analysis was done
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Parts 1 & 3 Overall	Parts 2 & 3 Overall
Number of subjects analysed	13	25
Units: participants
Participants with adverse events (AEs)	13	25
Participants with AEs causing study drug discont	1	2
Participants with serious adverse events (SAEs)	13	19
Participants with SAEs causing study drug discont	1	2
Deaths	9	3

No statistical analyses for this end point

Secondary: Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) after a single dose - Part 1 - Pharmacokinetics analysis set (PAS)

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End point title

Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) after a single dose - Part 1 - Pharmacokinetics analysis set (PAS) ^[5]

End point description

The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity [mass x time / volume)

End point type

Secondary

End point timeframe

Post single dose

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Part 1 LMI070 Overall
Number of subjects analysed	12
Units: h*ng/mL
arithmetic mean (standard deviation)
0.321 mg/kg - Actual	378 ( 31.9 )
0.654 mg/kg - Actual	892 ( 12.3 )
1.39 mg/kg - Actual	1820 ( 999 )
2.49 mg/kg - Actual	3310 ( 1340 )
2.94 mg/kg - Actual	3800 ( 1590 )

No statistical analyses for this end point

Secondary: Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) for all observation periods - Part 1 - PAS

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End point title

Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) for all observation periods - Part 1 - PAS ^[6]

End point description

AUC is the area under the curve for branaplan in plasma after a single dose. AUC values used for comparison are combined from AUCinf values after single dose and AUC 0–168-hour values after repeated administration.

End point type

Secondary

End point timeframe

Post single dose, hours 1,2,4,8,24,48,96,168

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Part 1 LMI070 Overall
Number of subjects analysed	12
Units: h*ng/mL
arithmetic mean (standard deviation)
0.299 mg/kg - Actual	413 ( 98.3 )
0.644 mg/kg - Actual	761 ( 170 )
1.30 mg/kg - Actual	1340 ( 381 )
2.52 mg/kg - Actual	3310 ( 850 )
2.99 mg/kg - Actual	4280 ( 1030 )

No statistical analyses for this end point

Secondary: Summary of plasma pharmacokinetic (PK) parameter Cmax after a single dose - Part 1 - PAS

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End point title

Summary of plasma pharmacokinetic (PK) parameter Cmax after a single dose - Part 1 - PAS ^[7]

End point description

The observed maximum plasma (or serum or blood) concentration following drug administration [mass / volume)

End point type

Secondary

End point timeframe

Post single dose

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Part 1 LMI070 Overall
Number of subjects analysed	11
Units: ng/mL
arithmetic mean (standard deviation)
0.321 mg/kg - Actual	9.10 ( 1.22 )
0.654 mg/kg - Actual	18.6 ( 1.63 )
1.39 mg/kg - Actual	55.6 ( 999 )
2.49 mg/kg - Actual	53.2 ( 9.50 )
2.94 mg/kg - Actual	72.4 ( 16.7 )

No statistical analyses for this end point

Secondary: Summary of plasma pharmacokinetic (PK) parameter Cmax for all observation periods - Part 1 - PAS

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End point title

Summary of plasma pharmacokinetic (PK) parameter Cmax for all observation periods - Part 1 - PAS ^[8]

End point description

The observed maximum plasma (or serum or blood) concentration following drug administration [mass / volume

End point type

Secondary

End point timeframe

Post single dose, hours 1,2,4,8,24,48,96,168

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Part 1 LMI070 Overall
Number of subjects analysed	12
Units: ng/mL
arithmetic mean (standard deviation)
0.299 mg/kg - Actual	8.84 ( 3.58 )
0.644 mg/kg - Actual	15.3 ( 4.10 )
1.30 mg/kg - Actual	37.8 ( 12.8 )
2.51 mg/kg - Actual	69.1 ( 15.7 )
2.99 mg/kg - Actual	96.5 ( 32.7 )

No statistical analyses for this end point

Secondary: Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) after a single dose - Part 2 - PAS

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End point title

Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) after a single dose - Part 2 - PAS ^[9]

End point description

The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity [mass x time / volume)

End point type

Secondary

End point timeframe

Post single dose

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Part 2 LMI070 0.625 mg/kg	Part 2 LMI070 2.5 mg/kg
Number of subjects analysed	10	10
Units: h*ng/mL
arithmetic mean (standard deviation)	1150 ( 357 )	4060 ( 734 )

No statistical analyses for this end point

Secondary: Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) for all observation periods - Part 2 - PAS

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End point title

Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) for all observation periods - Part 2 - PAS ^[10]

End point description

The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity [mass x time / volume). AUC values used for comparison are combined from AUCinf values after single dose and AUC 0–168-hour values after repeated administration.

End point type

Secondary

End point timeframe

Post single dose, hours 1,2,4,8,24,48,96,168

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Part 2 LMI070 0.625 mg/kg	Part 2 LMI070 2.5 mg/kg
Number of subjects analysed	10 ^[11]	15 ^[12]
Units: h*ng/mL
arithmetic mean (standard deviation)	1020 ( 278 )	3470 ( 909 )

Notes
[11] - The number of subjects analyzed was 10 and number of observations was 28
[12] - The number of subjects analyzed was 15 and number of observations was 29

No statistical analyses for this end point

Secondary: Summary of plasma pharmacokinetic (PK) parameter Cmax for a single dose - Part 2 - PAS

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End point title

Summary of plasma pharmacokinetic (PK) parameter Cmax for a single dose - Part 2 - PAS ^[13]

End point description

The observed maximum plasma (or serum or blood) concentration following drug administration [mass / volume)

End point type

Secondary

End point timeframe

Post single dose

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Part 2 LMI070 0.625 mg/kg	Part 2 LMI070 2.5 mg/kg
Number of subjects analysed	10	15
Units: ng/mL
arithmetic mean (standard deviation)	22.0 ( 5.70 )	82.0 ( 22.5 )

No statistical analyses for this end point

Secondary: Summary of plasma pharmacokinetic (PK) parameter Cmax for all observation periods - Part 2 - PAS

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End point title

Summary of plasma pharmacokinetic (PK) parameter Cmax for all observation periods - Part 2 - PAS ^[14]

End point description

The observed maximum plasma (or serum or blood) concentration following drug administration [mass / volume)

End point type

Secondary

End point timeframe

Post single dose, hours 1,2,4,8,24,48,96,168

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Part 2 LMI070 0.625 mg/kg	Part 2 LMI070 2.5 mg/kg
Number of subjects analysed	10 ^[15]	15 ^[16]
Units: ng/mL
arithmetic mean (standard deviation)	21.7 ( 5.71 )	77.4 ( 27.5 )

Notes
[15] - The number of subjects analyzed was 10 and number of observations was 29
[16] - The number of subjects analyzed was 15 and number of observations was 38

No statistical analyses for this end point

Secondary: Change from baseline in growth parameters: chest circumference, body length and chest circumference - FAS

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End point title

Change from baseline in growth parameters: chest circumference, body length and chest circumference - FAS ^[17]

End point description

To evaluate the effect of branaplam on length, head circumference and chest circumference

End point type

Secondary

End point timeframe

Baseline up to Part 3, Month 6

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Parts 1 & 3 Overall	Parts 2 & 3 Overall
Number of subjects analysed	13	25
Units: cm
arithmetic mean (standard deviation)
Chest - Week 52	4.68 ( 2.4769 )	5.656 ( 3.0167 )
Chest - P3 Month 6	14.750 ( 5.0548 )	8.582 ( 2.7423 )
Head -Week 52	5.030 ( 1.1235 )	5.111 ( 1.3407 )
Head - P3 Month 6	9.717 ( 1.8766 )	6.359 ( 1.2971 )
Length - Week 52	16.950 ( 3.7825 )	16.942 ( 4.5806 )
Length - P3 Month 6	52.140 ( 9.8766 )	22.944 ( 3.7686 )

No statistical analyses for this end point

Secondary: Change from baseline in growth parameter: body weight - FAS

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End point title

Change from baseline in growth parameter: body weight - FAS ^[18]

End point description

To evaluate the effect of branaplam on weight

End point type

Secondary

End point timeframe

Baseline up to Part 3, Month 6

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Parts 1 & 3 Overall	Parts 2 & 3 Overall
Number of subjects analysed	13	25
Units: kg
arithmetic mean (standard deviation)
Week 52	2.739 ( 1.3545 )	3.145 ( 1.5089 )
P3 Month 6	9.546 ( 3.5069 )	4.402 ( 1.3250 )

No statistical analyses for this end point

Secondary: Change from baseline in respiratory function: Pulse oximetry - FAS

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End point title

Change from baseline in respiratory function: Pulse oximetry - FAS ^[19]

End point description

To evaluate the effect of branaplam on pulse oximetry in percentage (%) of oxygen saturation.

End point type

Secondary

End point timeframe

Baseline up to Part 3, Month 6

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Parts 1 & 3 Overall	Parts 2 & 3 Overall
Number of subjects analysed	13	25
Units: percentage
arithmetic mean (standard deviation)
Week 52	-0.8 ( 2.59 )	-0.1 ( 1.56 )
P3 Month 6	-0.7 ( 2.58 )	0.0 ( 1.83 )

No statistical analyses for this end point

Secondary: Change from baseline in respiratory function: Respiratory rate - FAS

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End point title

Change from baseline in respiratory function: Respiratory rate - FAS ^[20]

End point description

To evaluate the effect of branaplam on respiratory rate

End point type

Secondary

End point timeframe

Baseline up to Part 3, Month 6

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Parts 1 & 3 Overall	Parts 2 & 3 Overall
Number of subjects analysed	12	25
Units: breaths per minute
arithmetic mean (standard deviation)
Week 52	41.3 ( 7.57 )	40.5 ( 13.46 )
P3 Month 6	29.2 ( 6.59 )	37.2 ( 8.95 )

No statistical analyses for this end point

Secondary: Change from baseline in respiratory function: Chest circumference during quiet breathing - end of inspiration and expiration - FAS

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End point title

Change from baseline in respiratory function: Chest circumference during quiet breathing - end of inspiration and expiration - FAS ^[21]

End point description

To evaluate the effect of branaplam on chest circumference during quiet breathing or sleep at the end of inspiration.

End point type

Secondary

End point timeframe

Baseline, Week 52 and Part 3 Month 6

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Parts 1 & 3 Overall	Parts 2 & 3 Overall
Number of subjects analysed	1	18
Units: cm
arithmetic mean (standard deviation)
Week 52 - end of inspiration	999 ( 999 )	5.964 ( 3.6345 )
P3 Month 6 - end of inspiration	999 ( 999 )	8.535 ( 3.3083 )
Week 52 - end of expiration	999 ( 999 )	6.033 ( 3.9466 )
P3 Month 6 - end of expiration	999 ( 999 )	9.147 ( 3.5755 )

No statistical analyses for this end point

Secondary: Number of participants with presence of paradoxical breathing - FAS

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End point title

Number of participants with presence of paradoxical breathing - FAS ^[22]

End point description

A paradoxical breathing occurs when one compartment moves out of phase compared to another one. In SMA type I, paradoxical breathing is often a sign of breathing problems where the pulmonary ribcage moves inward during inspiration rather than outward while the abdomen expands.

End point type

Secondary

End point timeframe

Baseline up to Part 3, Month 6

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Parts 1 & 3 Overall	Parts 2 & 3 Overall
Number of subjects analysed	13	25
Units: participants
Week 52	5	15
P3 Month 6	4	14

No statistical analyses for this end point

Secondary: Summary of CHOP INTEND total score - Parts 1 and 3 and Parts 2 and 3 - FAS

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End point title

Summary of CHOP INTEND total score - Parts 1 and 3 and Parts 2 and 3 - FAS ^[23]

End point description

CHOP INTEND is a motor test measure for SMA Type 1 and similarly weak infants with neuromuscular disease. The CHOP INTEND provides a useful measure of motor skills and strength in this population. It is a 16 item, 64 point scale. Each item (motor skill) is given a score from zero to 4: zero indicates can't complete the movement, 1 to 3 indicates partial performance and a 4 indicates person can complete the movement on their own without assistance. These scores are added up to a possible total score of 64 and higher scores indicate better outcomes.

End point type

Secondary

End point timeframe

Baseline up to Part 3, Month 6

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Parts 1 & 3 Overall	Parts 2 & 3 Overall
Number of subjects analysed	8	18
Units: scores on a scale
arithmetic mean (standard deviation)
Week 52	38.1 ( 8.69 )	43.6 ( 6.79 )
Part 3, Month 6	26.0 ( 999 )	44.7 ( 8.73 )

No statistical analyses for this end point

Secondary: Number of participants fed orally or by feeding tube for Parts 1 and 3 and Parts 2 and 3 - FAS

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End point title

Number of participants fed orally or by feeding tube for Parts 1 and 3 and Parts 2 and 3 - FAS ^[24]

End point description

To evaluate the efficacy of branaplam on preservation of oral feeding

End point type

Secondary

End point timeframe

Baseline up to Part 3, Month 6

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Parts 1 & 3 Overall	Parts 2 & 3 Overall
Number of subjects analysed	13	25
Units: participants
Only exclusively orally fed	3	18
Only exclusively tube fed	0	0
Started on orally fed, switched to tube fed	0	2
Started on tube fed, switched to orally fed	0	0
Other (mixture of both tube and oral feeding)	8	5

No statistical analyses for this end point

Secondary: Number of participants and HINE Motor subscale milestones (ability to sit, stand or walk without support) - FAS

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End point title

Number of participants and HINE Motor subscale milestones (ability to sit, stand or walk without support) - FAS ^[25]

End point description

HINE Section 2 is a standardized evaluation of motor function. It evaluates 8 items; grasp, head control, kicking, rolling over, sitting up, crawling, standing and walking. Motor skills are assigned a score of 0 to 3 to 5 points and zero means the child lacks that motor skill. The maximum score is 26 which is dependent on age, level of development and severity of disease. A higher score is a better outcome. This assessment was added with amendment 6, therefore no baseline was available.

End point type

Secondary

End point timeframe

Baseline up to Part 3, Month 6

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Parts 1 & 3 Overall	Parts 2 & 3 Overall
Number of subjects analysed	13	25
Units: participants
Week 52 Sitting	1	1
Week 52 Standing	0	2
Week 52: Walking	0	1
Part 3, Month 6: Sitting	0	4
Part 3, Month 6: Standing	0	5
Part 3, Month 6: Walking	0	2

No statistical analyses for this end point

Secondary: Ventilation use for Parts 1 and 3 and Parts 2 and 3 - FAS

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End point title

Ventilation use for Parts 1 and 3 and Parts 2 and 3 - FAS ^[26]

End point description

BiBAP (bilevel positive airway pressure) ventilation is a 2 level breathing support which has a tube that connects to a mask. It provides a different level of air pressure for inhalation vs. exhalation, whereas a CPAP (continuous positive airway pressure) only pumps one level of air pressure but is also non-invasiive. Invasive ventilation is delivered via an endotracheal or tracheostomy tube.

End point type

Secondary

End point timeframe

Baselline up 168 weeks

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Parts 1 & 3 Overall	Parts 2 & 3 Overall
Number of subjects analysed	11	25
Units: participants
Non-invasive ventilation - BiPAP	9	18
Non-invasive ventilation - CPAP	3	2
Invasive ventilation	4	5

No statistical analyses for this end point

Secondary: Summary of Hammersmith Infant Neurologic Examination Section 2 (HINE-2) - FAS

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End point title

Summary of Hammersmith Infant Neurologic Examination Section 2 (HINE-2) - FAS ^[27]

End point description

End point type

Secondary

End point timeframe

Baseline up to Week 52

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No analysis was done

End point values	Parts 1 & 3 Overall	Parts 2 & 3 Overall
Number of subjects analysed	8	25
Units: total scores
arithmetic mean (standard deviation)
Week 52	3.3 ( 2.31 )	4.9 ( 3.44 )
Part 3 Month 6	3.0 ( 2.12 )	7.7 ( 4.82 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post last treatment up a maximum of 83 months.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Parts 1 and 3

Reporting group description

Parts 1 and 3

Reporting group title

Parts 2 and 3 LMI070 2.5

Reporting group description

Parts 2 and 3 LMI070 2.5

Reporting group title

Parts 2 and 3 LMI070 0.625

Reporting group description

Parts 2 and 3 LMI070 0.625

Serious adverse events	Parts 1 and 3	Parts 2 and 3 LMI070 2.5	Parts 2 and 3 LMI070 0.625
Total subjects affected by serious adverse events
subjects affected / exposed	13 / 13 (100.00%)	11 / 15 (73.33%)	8 / 10 (80.00%)
number of deaths (all causes)	9	2	1
number of deaths resulting from adverse events	0	0	0
Vascular disorders
Circulatory collapse
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	5 / 13 (38.46%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	2 / 13 (15.38%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Apnoea
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	5 / 13 (38.46%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 8	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchostenosis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laryngospasm
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstructive airways disorder
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pneumomediastinum
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	5 / 13 (38.46%)	2 / 15 (13.33%)	2 / 10 (20.00%)
occurrences causally related to treatment / all	0 / 8	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 4	0 / 0	0 / 0
Tachypnoea
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Ejection fraction decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
N-terminal prohormone brain natriuretic peptide increased
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oxygen saturation decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus test positive
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Rotavirus test positive
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Salmonella test positive
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ultrasound kidney abnormal
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	4 / 13 (30.77%)	0 / 15 (0.00%)	2 / 10 (20.00%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foreign body in gastrointestinal tract
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shunt malfunction
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Left ventricular hypertrophy
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Tachycardia
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Epilepsy
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic cerebral infarction
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastric ulcer
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peptic ulcer haemorrhage
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatomegaly
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Hypercalciuria
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal tubular disorder
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchiolitis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 13 (0.00%)	2 / 15 (13.33%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterovirus infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis bacterial
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Otitis media
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Parainfluenzae virus infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumococcal sepsis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	3 / 13 (23.08%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pseudomonas infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 13 (0.00%)	2 / 15 (13.33%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	2 / 13 (15.38%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	9 / 13 (69.23%)	7 / 15 (46.67%)	4 / 10 (40.00%)
occurrences causally related to treatment / all	0 / 18	0 / 13	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rhinovirus infection
subjects affected / exposed	3 / 13 (23.08%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	2 / 10 (20.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	2 / 13 (15.38%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypophagia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Parts 1 and 3	Parts 2 and 3 LMI070 2.5	Parts 2 and 3 LMI070 0.625
Total subjects affected by non serious adverse events
subjects affected / exposed	13 / 13 (100.00%)	15 / 15 (100.00%)	10 / 10 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Vascular disorders
Thrombosis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Cyanosis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Diastolic hypertension
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Hypertension
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	3 / 10 (30.00%)
occurrences all number	0	0	5
Hypotension
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Surgical and medical procedures
Therapy cessation
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Tracheostomy
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Asthenia
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Catheter site haemorrhage
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Discomfort
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Granuloma
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Hyperthermia
subjects affected / exposed	1 / 13 (7.69%)	4 / 15 (26.67%)	0 / 10 (0.00%)
occurrences all number	2	7	0
Malaise
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Medical device pain
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Medical device site granuloma
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Non-cardiac chest pain
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Pain
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Pyrexia
subjects affected / exposed	11 / 13 (84.62%)	6 / 15 (40.00%)	7 / 10 (70.00%)
occurrences all number	58	16	19
Hyperpyrexia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0
Immune system disorders
Allergy to arthropod bite
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Drug hypersensitivity
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Immunisation reaction
subjects affected / exposed	6 / 13 (46.15%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	7	0	0
Multiple allergies
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Reproductive system and breast disorders
Genital rash
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Vulvovaginal dryness
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Vulvovaginal rash
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Respiratory, thoracic and mediastinal disorders
Bronchiectasis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Aspiration
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Asthma
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Atelectasis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	1
Bronchospasm
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Respiratory distress
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Chronic respiratory failure
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Cough
subjects affected / exposed	3 / 13 (23.08%)	4 / 15 (26.67%)	3 / 10 (30.00%)
occurrences all number	10	6	3
Dysphonia
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Dyspnoea
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Epistaxis
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Hypoxia
subjects affected / exposed	1 / 13 (7.69%)	2 / 15 (13.33%)	0 / 10 (0.00%)
occurrences all number	2	2	0
Increased bronchial secretion
subjects affected / exposed	3 / 13 (23.08%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0
Increased upper airway secretion
subjects affected / exposed	4 / 13 (30.77%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	10	0	0
Lung disorder
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Nasal congestion
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Nasal discomfort
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Nasal obstruction
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Obstructive airways disorder
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Productive cough
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	2	1	0
Pulmonary fibrosis
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Respiratory depression
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Respiratory disorder
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Choking
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	0	1	1
Respiratory failure
subjects affected / exposed	2 / 13 (15.38%)	1 / 15 (6.67%)	2 / 10 (20.00%)
occurrences all number	3	1	2
Rhinorrhoea
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Sputum discoloured
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Tachypnoea
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	0	1	2
Vasomotor rhinitis
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Respiratory tract inflammation
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Psychiatric disorders
Behaviour disorder
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Agitation
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Anxiety
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Irritability
subjects affected / exposed	3 / 13 (23.08%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0
Restlessness
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Investigations
Fungal test positive
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Aspartate aminotransferase increased
subjects affected / exposed	3 / 13 (23.08%)	0 / 15 (0.00%)	5 / 10 (50.00%)
occurrences all number	4	0	9
Blood albumin decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Blood alkaline phosphatase decreased
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 13 (0.00%)	2 / 15 (13.33%)	1 / 10 (10.00%)
occurrences all number	0	2	1
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Blood creatinine decreased
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	3 / 10 (30.00%)
occurrences all number	0	1	3
Blood iron decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	2 / 10 (20.00%)
occurrences all number	1	1	2
Blood parathyroid hormone decreased
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Blood potassium decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Blood potassium increased
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	0	2
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	0	1	1
Body temperature increased
subjects affected / exposed	3 / 13 (23.08%)	2 / 15 (13.33%)	0 / 10 (0.00%)
occurrences all number	3	5	0
Brain natriuretic peptide increased
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
C-reactive protein increased
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	2	0	1
Crystal urine present
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	0	2
Electrocardiogram P pulmonale
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Alanine aminotransferase increased
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	5 / 10 (50.00%)
occurrences all number	2	0	5
Gamma-glutamyltransferase increased
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	2	0	1
White blood cell count decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Haemoglobin decreased
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	4	2	1
Heart rate decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Heart rate increased
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
N-terminal prohormone brain natriuretic peptide increased
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	1	1	1
Nerve conduction studies abnormal
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Neutrophil count decreased
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Oxygen saturation decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	1
Platelet count increased
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Red blood cell count decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	4	0	0
Reticulocyte count decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Transaminases increased
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	0	1	1
Troponin T increased
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Troponin increased
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	2	0
Ultrasound kidney abnormal
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Urine phosphorus increased
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Urine uric acid increased
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	0	1	1
Vitamin D decreased
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Weight decreased
subjects affected / exposed	4 / 13 (30.77%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	6	0	1
Haematocrit decreased
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	4	0	0
White blood cells urine positive
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	4
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	1
Exposure to SARS-CoV-2
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Femur fracture
subjects affected / exposed	2 / 13 (15.38%)	3 / 15 (20.00%)	1 / 10 (10.00%)
occurrences all number	2	3	1
Fibula fracture
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Foot fracture
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Humerus fracture
subjects affected / exposed	3 / 13 (23.08%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	3	0	1
Joint dislocation
subjects affected / exposed	3 / 13 (23.08%)	2 / 15 (13.33%)	1 / 10 (10.00%)
occurrences all number	3	2	1
Lower limb fracture
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Subdural haematoma
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	2
Subdural haemorrhage
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Sunburn
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Tibia fracture
subjects affected / exposed	4 / 13 (30.77%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	4	1	0
Tracheostomy malfunction
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0
Upper limb fracture
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Congenital, familial and genetic disorders
Cryptorchism
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Dacryostenosis congenital
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Developmental hip dysplasia
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Hypertrophic cardiomyopathy
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Phimosis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Plagiocephaly
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Atrial tachycardia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Bradycardia
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Cardiac failure
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Myocarditis
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Pericardial effusion
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Right ventricular hypertrophy
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Sinus node dysfunction
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Sinus tachycardia
subjects affected / exposed	1 / 13 (7.69%)	2 / 15 (13.33%)	1 / 10 (10.00%)
occurrences all number	1	2	1
Supraventricular extrasystoles
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	2	0
Supraventricular tachycardia
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Tachycardia
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	2 / 10 (20.00%)
occurrences all number	0	1	2
Sinus bradycardia
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Nervous system disorders
Brain injury
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Cerebral atrophy
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Complex regional pain syndrome
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Facial paresis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Glossopharyngeal nerve disorder
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Headache
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0
Hydrocephalus
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Motor dysfunction
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Blood and lymphatic system disorders
Monocytosis
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	2 / 10 (20.00%)
occurrences all number	0	1	2
Lymphopenia
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Leukopenia
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	2 / 10 (20.00%)
occurrences all number	0	1	3
Leukocytosis
subjects affected / exposed	0 / 13 (0.00%)	2 / 15 (13.33%)	1 / 10 (10.00%)
occurrences all number	0	2	1
Iron deficiency anaemia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	1
Anaemia
subjects affected / exposed	2 / 13 (15.38%)	3 / 15 (20.00%)	0 / 10 (0.00%)
occurrences all number	3	5	0
White blood cell disorder
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Thrombocytosis
subjects affected / exposed	1 / 13 (7.69%)	3 / 15 (20.00%)	4 / 10 (40.00%)
occurrences all number	2	8	8
Thrombocytopenia
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	2 / 10 (20.00%)
occurrences all number	1	1	2
Polycythaemia
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Pancytopenia
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Neutropenia
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	3 / 10 (30.00%)
occurrences all number	1	3	10
Reticulocytopenia
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	9	0	0
Tympanic membrane hyperaemia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Eye disorders
Heterophoria
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Astigmatism
subjects affected / exposed	3 / 13 (23.08%)	3 / 15 (20.00%)	1 / 10 (10.00%)
occurrences all number	3	3	1
Blepharitis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Chalazion
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Hypermetropia
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Ocular hyperaemia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Optic atrophy
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Strabismus
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Myopia
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Gastrointestinal disorders
Functional gastrointestinal disorder
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Abdominal distension
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Abdominal pain
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Abdominal pain upper
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	2	0	1
Anal fissure
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Aphthous ulcer
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Constipation
subjects affected / exposed	6 / 13 (46.15%)	3 / 15 (20.00%)	7 / 10 (70.00%)
occurrences all number	19	5	7
Dental cyst
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Diarrhoea
subjects affected / exposed	7 / 13 (53.85%)	2 / 15 (13.33%)	2 / 10 (20.00%)
occurrences all number	19	3	3
Dyspepsia
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	0	1	2
Dysphagia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Erosive oesophagitis
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Faecaloma
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Flatulence
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	3	0	1
Food poisoning
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Gastrointestinal pain
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0
Gingival pain
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0
Gingival swelling
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Haematochezia
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Hiatus hernia
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Inguinal hernia
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Malocclusion
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Nausea
subjects affected / exposed	2 / 13 (15.38%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	2	1	0
Oesophagitis
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Oesophagitis haemorrhagic
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Regurgitation
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Salivary hypersecretion
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Teething
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	4	0	1
Tongue disorder
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Toothache
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Vomiting
subjects affected / exposed	10 / 13 (76.92%)	2 / 15 (13.33%)	2 / 10 (20.00%)
occurrences all number	40	10	3
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	1	2	1
Hepatobiliary disorders
Hepatomegaly
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Hypertransaminasaemia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	4 / 13 (30.77%)	3 / 15 (20.00%)	1 / 10 (10.00%)
occurrences all number	7	8	1
Blister
subjects affected / exposed	3 / 13 (23.08%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0
Decubitus ulcer
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Dermatitis
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	1	1	1
Dermatitis atopic
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	1	1	1
Dermatitis diaper
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Drug eruption
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Eczema
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	1	1	2
Hyperhidrosis
subjects affected / exposed	2 / 13 (15.38%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	2	1	0
Keratosis pilaris
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Papule
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Perioral dermatitis
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Pruritus
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Rash erythematous
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Rash maculo-papular
subjects affected / exposed	3 / 13 (23.08%)	1 / 15 (6.67%)	2 / 10 (20.00%)
occurrences all number	4	1	2
Urticaria
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Renal and urinary disorders
Calculus urinary
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Dysuria
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Hypercalciuria
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Ketonuria
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	3 / 10 (30.00%)
occurrences all number	0	2	7
Leukocyturia
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	0	2	2
Nephrocalcinosis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Nephrolithiasis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Nephroptosis
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Proteinuria
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Pyelocaliectasis
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Urinary retention
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Musculoskeletal and connective tissue disorders
Joint swelling
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Arthralgia
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Deformity thorax
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Flank pain
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Foot deformity
subjects affected / exposed	3 / 13 (23.08%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	3	1	1
Fracture pain
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Joint contracture
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Muscular weakness
subjects affected / exposed	4 / 13 (30.77%)	0 / 15 (0.00%)	2 / 10 (20.00%)
occurrences all number	10	0	2
Osteolysis
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Osteopenia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Osteoporosis
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Pain in extremity
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Rib deformity
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Scoliosis
subjects affected / exposed	5 / 13 (38.46%)	3 / 15 (20.00%)	4 / 10 (40.00%)
occurrences all number	5	3	4
Musculoskeletal chest pain
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 13 (7.69%)	8 / 15 (53.33%)	5 / 10 (50.00%)
occurrences all number	6	10	9
Asymptomatic COVID-19
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Bacterial disease carrier
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Bacterial rhinitis
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Gastroenteritis norovirus
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Gastroenteritis viral
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Gastrointestinal infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	1
Hordeolum
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Infected bite
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	4	0	0
Infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Klebsiella infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Bronchitis bacterial
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
COVID-19
subjects affected / exposed	1 / 13 (7.69%)	2 / 15 (13.33%)	0 / 10 (0.00%)
occurrences all number	1	2	0
Candida infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Cellulitis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Conjunctivitis
subjects affected / exposed	2 / 13 (15.38%)	3 / 15 (20.00%)	2 / 10 (20.00%)
occurrences all number	2	5	2
Cystitis
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Cytomegalovirus infection
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Dermatitis infected
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Ear infection
subjects affected / exposed	3 / 13 (23.08%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	8	1	1
Ear infection viral
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Eye infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Folliculitis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Fungal skin infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Gastroenteritis
subjects affected / exposed	5 / 13 (38.46%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	6	0	0
Medical device site infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Staphylococcal infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Oral candidiasis
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Oral fungal infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Otitis externa
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	2	1	0
Otitis media
subjects affected / exposed	4 / 13 (30.77%)	1 / 15 (6.67%)	1 / 10 (10.00%)
occurrences all number	6	1	1
Otitis media acute
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Pharyngitis
subjects affected / exposed	0 / 13 (0.00%)	2 / 15 (13.33%)	0 / 10 (0.00%)
occurrences all number	0	2	0
Pneumonia
subjects affected / exposed	5 / 13 (38.46%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	8	2	0
Pseudomonas infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Pyuria
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Rash pustular
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Respiratory syncytial virus infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Respiratory tract infection
subjects affected / exposed	4 / 13 (30.77%)	3 / 15 (20.00%)	3 / 10 (30.00%)
occurrences all number	17	3	3
Respiratory tract infection viral
subjects affected / exposed	2 / 13 (15.38%)	1 / 15 (6.67%)	2 / 10 (20.00%)
occurrences all number	2	1	2
Rhinitis
subjects affected / exposed	6 / 13 (46.15%)	4 / 15 (26.67%)	2 / 10 (20.00%)
occurrences all number	13	12	2
Rhinovirus infection
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	4	0	0
Roseola
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Skin bacterial infection
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Skin infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Nasopharyngitis
subjects affected / exposed	5 / 13 (38.46%)	6 / 15 (40.00%)	0 / 10 (0.00%)
occurrences all number	9	8	0
Tonsillitis
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	1
Upper respiratory tract infection
subjects affected / exposed	7 / 13 (53.85%)	3 / 15 (20.00%)	4 / 10 (40.00%)
occurrences all number	34	5	11
Urethritis
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Urinary tract infection
subjects affected / exposed	6 / 13 (46.15%)	2 / 15 (13.33%)	2 / 10 (20.00%)
occurrences all number	20	2	6
Varicella
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Viral infection
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Viral upper respiratory tract infection
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	2 / 10 (20.00%)
occurrences all number	1	0	2
Vulvitis
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Metabolism and nutrition disorders
Feeding disorder
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Failure to thrive
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	2 / 10 (20.00%)
occurrences all number	0	1	2
Feeding intolerance
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Fluid intake reduced
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Hyperglycaemia
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Hypoalbuminaemia
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	0	1	0
Hypoglycaemia
subjects affected / exposed	1 / 13 (7.69%)	1 / 15 (6.67%)	0 / 10 (0.00%)
occurrences all number	1	4	0
Hyponatraemia
subjects affected / exposed	1 / 13 (7.69%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	0	0
Hypophagia
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	0 / 10 (0.00%)
occurrences all number	3	0	0
Iron deficiency
subjects affected / exposed	0 / 13 (0.00%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Malnutrition
subjects affected / exposed	0 / 13 (0.00%)	1 / 15 (6.67%)	2 / 10 (20.00%)
occurrences all number	0	1	2
Decreased appetite
subjects affected / exposed	2 / 13 (15.38%)	0 / 15 (0.00%)	1 / 10 (10.00%)
occurrences all number	4	0	1

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Were there any global substantial amendments to the protocol? Yes

28 Nov 2014

Clarified the phases of the study, the sequential enrollment of subjects into the cohorts. Provided clariication on the safety monitoring of the subjects after they received their first dose of study treatment. Correction of the study phase from Phase II to Phase I/II

27 Feb 2015

Clarifed the exclusion criteria, the dose limiting toxicities and the provisional dose levels. Revised the criteria for interruption and re-initiation of branaplam treatment based on the revision of the dose limiting toxicity (DLT) criteria.

30 Nov 2015

Iimplemented additional safety measures following an urgent safety measures (USM). Ophthalmologic monitoring was added as part of the safety monitoring plan. Implemented requests for modification from the independent data monitoring committee (DMC) following their review of the clinical safety data. Added a different and much less burdensome assessment to evaluate respiratory function, measurement of chest circumference during quiet breathing. Plans to increase the total number of subjects to be enrolled in Part 1 of the study up to approximately 30.

31 Mar 2016

Implemented additional cardiac monitoring following a second USM. Exclusion criterion #10 was expanded to exclude a broader range of cardiac disease. Dose modification rules were added for cardiac disorders and hypertension. Two higher dose levels (120 mg/m2 and 240 mg/m2), which exceeded the available preclinical toxicology exposure were removed. Measurement of quadriceps muscle thickness by ultrasound and the evaluation of exploratory biomarkers in hair and in urine were removed.

31 Aug 2016

Implemented additional safety monitoring following a third USM. Reduction of the Weekly dose of branaplam administered to all subjects having completed the initial 13 Weeks of treatment to 6 mg/m2. Addition of two following safety endpoints: neurologic examination and neurophysiologic examination to the primary objective. Correction of a discrepancy in secondary objective which indicated that branaplam pharmacokinetics were evaluated in serum instead of plasma samples. The CMAP which used to be optional was amended as mandatory for all subjects enrolled in the study.

28 Apr 2017

Implemented to allow resumption of enrollment in the ongoing study as agreed by the independent DMC. Part 2 of the study was modified to obtain additional safety and efficacy data with oral administration of up to 3 dose levels of branaplam, already tested in Part 1. Part 2 was to enroll approximately 30 subjects. The age of subjects at screening was restricted to 180 days of age. A minimum CHOP INTEND score of 15 was required at baseline and subjects were required to be able to feed orally for all nutritional needs and be greater than the 2nd percentile for weight on the standard growth curves for the country of origin.

29 Dec 2017

Implemented in all countries where the study was being conducted the changes made based on the request of the German Health Authority during their review of the Amended Protocol version v06.Added criteria used to decide interrupting and re-initiating treatment with branaplam in the event of thrombocytosis. The name of the Novartis department where serious adverse events (SAEs) need to be sent was changed. Updated Appendix 16.1.1-Protocol-Table 6-2 to include the dose conversion from BSA to weight for doses in Part 1 of the study.

31 Oct 2018

Ensured that the studied doses were clinically distinguishable and more efficiently investigated the branaplam dose-response relationship in conjunction with the data generated in Part 1. Several modifications to the inclusion and exclusion criteria. Clarified that Part 1 subjects followed the Extended treatment Schedule of Assessment and subjects enrolled in Part 2 could receive study treatment in a separate protocol.

30 Apr 2019

Provided subjects from Part 1 and Part 2 of this protocol the possibility for continuous treatment and long-term safety and efficacy follow up in the newly added Part 3 of the study. Study description for Part 3 provided. Eliminated assessments that were present in Parts 1 and 2 and which were not necessary for Part 3. Revised efficacy endpoints (CHOP INTEND to be collected up to 3 years of age, i.e. 36 months). Clarified and simplified the process of branaplam administration at home.

28 Feb 2020

Clarified the frequency of ophthalmology assessments in Part 3 of the study. Updated the possibility to have a dose increase to 2.5 mg/kg in Part 3 for subjects treated with 0.625 mg/kg dose from Part 2, if no further improvement becomes evident, or in case of disease progression at the discretion of investigator and after consultation with the sponsor.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results.

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Clinical trials

Clinical Trial Results: An open-label multi-part first-in-human study of oral LMI070 in infants with Type 1 spinal muscular atrophy.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of participants with dose limiting toxicities (DLT) in Part 1 - Safety analysis set (SAS)

Primary: Number of participants with dose limiting toxicities (DLT) in Part 1 - Safety analysis set (SAS)

Primary: Number of participants with treatment emergent adverse events (TEAEs) and serious adverse events -SAS

Primary: Number of participants with treatment emergent adverse events (TEAEs) and serious adverse events -SAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) after a single dose - Part 1 - Pharmacokinetics analysis set (PAS)

Secondary: Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) after a single dose - Part 1 - Pharmacokinetics analysis set (PAS)

Secondary: Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) for all observation periods - Part 1 - PAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) for all observation periods - Part 1 - PAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter Cmax after a single dose - Part 1 - PAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter Cmax after a single dose - Part 1 - PAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter Cmax for all observation periods - Part 1 - PAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter Cmax for all observation periods - Part 1 - PAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) after a single dose - Part 2 - PAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) after a single dose - Part 2 - PAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) for all observation periods - Part 2 - PAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter area under the curve (AUC) for all observation periods - Part 2 - PAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter Cmax for a single dose - Part 2 - PAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter Cmax for a single dose - Part 2 - PAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter Cmax for all observation periods - Part 2 - PAS

Secondary: Summary of plasma pharmacokinetic (PK) parameter Cmax for all observation periods - Part 2 - PAS

Secondary: Change from baseline in growth parameters: chest circumference, body length and chest circumference - FAS

Secondary: Change from baseline in growth parameters: chest circumference, body length and chest circumference - FAS

Secondary: Change from baseline in growth parameter: body weight - FAS

Secondary: Change from baseline in growth parameter: body weight - FAS

Secondary: Change from baseline in respiratory function: Pulse oximetry - FAS

Secondary: Change from baseline in respiratory function: Pulse oximetry - FAS

Secondary: Change from baseline in respiratory function: Respiratory rate - FAS

Secondary: Change from baseline in respiratory function: Respiratory rate - FAS

Secondary: Change from baseline in respiratory function: Chest circumference during quiet breathing - end of inspiration and expiration - FAS

Secondary: Change from baseline in respiratory function: Chest circumference during quiet breathing - end of inspiration and expiration - FAS

Secondary: Number of participants with presence of paradoxical breathing - FAS

Secondary: Number of participants with presence of paradoxical breathing - FAS

Secondary: Summary of CHOP INTEND total score - Parts 1 and 3 and Parts 2 and 3 - FAS

Secondary: Summary of CHOP INTEND total score - Parts 1 and 3 and Parts 2 and 3 - FAS

Secondary: Number of participants fed orally or by feeding tube for Parts 1 and 3 and Parts 2 and 3 - FAS

Secondary: Number of participants fed orally or by feeding tube for Parts 1 and 3 and Parts 2 and 3 - FAS

Secondary: Number of participants and HINE Motor subscale milestones (ability to sit, stand or walk without support) - FAS

Secondary: Number of participants and HINE Motor subscale milestones (ability to sit, stand or walk without support) - FAS

Secondary: Ventilation use for Parts 1 and 3 and Parts 2 and 3 - FAS

Secondary: Ventilation use for Parts 1 and 3 and Parts 2 and 3 - FAS

Secondary: Summary of Hammersmith Infant Neurologic Examination Section 2 (HINE-2) - FAS

Secondary: Summary of Hammersmith Infant Neurologic Examination Section 2 (HINE-2) - FAS

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
An open-label multi-part first-in-human study of oral LMI070 in infants with Type 1 spinal muscular atrophy.