Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT02851797

Recruitment Status : Completed

First Posted : August 2, 2016

Results First Posted : February 2, 2023

Last Update Posted : February 2, 2023

View this study on the modernized ClinicalTrials.gov

Sponsor:

Collaborator:

Syneos Health

Information provided by (Responsible Party):

Italfarmaco

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Duchenne Muscular Dystrophy
Interventions	Drug: givinostat Drug: placebo
Enrollment	179

Participant Flow

Recruitment Details	Within the overall population, a total of 118 subjects were enrolled in the givinostat group. A total of 61 subjects were enrolled in the placebo group.
Pre-assignment Details


Arm/Group Title	Givinostat	Placebo
Arm/Group Description	Givinostat oral suspension (10 mg/m...	Placebo oral suspension (10 mg/mL) ...
Arm/Group Description	Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid	Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.
Period Title: Overall Study
Started	118	61
All Enrolled Subjects	118	61
ITT Population	118	61
Safety Set	118	61
PK Analysis Set	117	0
Target Population	81	39
MR Cohort	77	37
Completed	111	59
Not Completed	7	2
Reason Not Completed
Withdrawal by Subject	4	2
Adverse Event	3	0

Baseline Characteristics

Arm/Group Title		Givinostat	Placebo	Total
Arm/Group Description		Givinostat oral suspension (10 mg/m...	Placebo oral suspension (10 mg/mL) ...	Total of all reporting groups
Arm/Group Description		Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid	Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.	Total of all reporting groups
Overall Number of Baseline Participants		118	61	179
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Number of Subjects Enrolled in Each Country (Overall Population).The all-enrolled subjects set included all subjects who were randomised to study treatment. The overall all-enrolled subjects set included all subjects in both the target and off-target populations (Group A + Group B) who were randomised to study treatment.
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	118 participants	61 participants	179 participants
	<=18 years	118 100.0%	61 100.0%	179 100.0%
	Between 18 and 65 years	0 0.0%	0 0.0%	0 0.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	118 participants	61 participants	179 participants
		9.78 (2.022)	9.97 (2.082)	9.84 (2.039)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	118 participants	61 participants	179 participants
	Female	0 0.0%	0 0.0%	0 0.0%
	Male	118 100.0%	61 100.0%	179 100.0%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	118 participants	61 participants	179 participants
	Hispanic or Latino	9 7.6%	3 4.9%	12 6.7%
	Not Hispanic or Latino	109 92.4%	58 95.1%	167 93.3%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	118 participants	61 participants	179 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	4 3.4%	2 3.3%	6 3.4%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	3 2.5%	0 0.0%	3 1.7%
	White	106 89.8%	57 93.4%	163 91.1%
	More than one race	5 4.2%	2 3.3%	7 3.9%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	118 participants	61 participants	179 participants
Canada		9	6	15
Netherlands		5	3	8
Belgium		6	3	9
United States		24	19	43
Italy		24	13	37
United Kingdom		10	3	13
Israel		1	0	1
France		9	5	14
Serbia		0	1	1
Germany		13	2	15
Spain		17	6	23

Outcome Measures

1.Primary Outcome


Title	Mean Change From Baseline in 4 Standard Stairs (4SC) Climb After 18 Months of Treatment
Description	The time (in seconds) to climb 4 standard-sized stairs is a TFT that r...
Description	The time (in seconds) to climb 4 standard-sized stairs is a TFT that represents stair-climbing ability. The test was evaluated by qualified functional evaluators (ie, physiotherapists) who were different from the site personnel who reviewed subjects' safety results. The test was performed in a standardised manner described in a specific site manual. Baseline 4SC was the measurement taken at the randomization assessment, unless this was missing, in which case baseline was taken as the last non missing value recorded prior to or on the date of first study treatment. The shorter the time, the better the outcome.
Time Frame	Baseline and 18 months

Outcome Measure Data

Analysis Population Description

ITT analysis set: the intent-to-treat (ITT) analysis set included all subjects who were randomised, received at least one dose of study drug, and had at least 1 non-missing post-baseline 4SC measure or missing post-baseline 4SC measure due to being either non-ambulatory or otherwise physically unable to perform the assessment, irrespective of any deviation from the protocol or premature discontinuation.


Arm/Group Title	Givinostat	Placebo
Arm/Group Description:	Givinostat oral suspension (10 mg/m...	Placebo oral suspension (10 mg/mL) ...
Arm/Group Description:	Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid	Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.
Overall Number of Participants Analyzed	81	39
Least Squares Mean (Standard Error) Unit of Measure: seconds
	1.27 (0.040)	1.48 (0.058)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Givinostat, Placebo
	Comments	Log transformation applied
	Type of Statistical Test	Superiority
	Comments	LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in 4SC at Month 18 with baseline values for: 4SC, time to rise from floor, time to run/walk 10 metres, distance walked in 6 minutes and re-derived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification factors.

Statistical Test of Hypothesis	P-Value	=0.0345
	Comments	LS Means, CIs, and p-values are obtained from ANCOVA model on change from baseline in 4SC at Month 18 with baseline values for: the above mentioned parameters as covariates, with steroid use and treatment group as independent classificat factors.
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	generalised least square mean ratio
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95% 0.745 to 0.989
	Estimation Comments	LS Means, CIs, and p-values are obtained from ANCOVA model on change from baseline in 4SC at Month 18 with baseline values for: the above mentioned parameters as covariates, with steroid use and treatment group as independent classificat factors.

2.Secondary Outcome


Title	Mean Change From Baseline in Time to Rise From Floor After 18 Months of Treatment
Description	An analysis of time (in seconds) to rise from the floor by change from...
Description	An analysis of time (in seconds) to rise from the floor by change from baseline at 18 months is presented for the Target Population in the ITT analysis set. The shorter the time, the better the outcome.
Time Frame	Baseline and 18 months

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Givinostat	Placebo
Arm/Group Description:	Givinostat oral suspension (10 mg/m...	Placebo oral suspension (10 mg/mL) ...
Arm/Group Description:	Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid	Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.
Overall Number of Participants Analyzed	81	39
Least Squares Mean (95% Confidence Interval) Unit of Measure: seconds
	9.33 (5.821 to 12.838)	12.61 (7.491 to 17.724)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Givinostat, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in time to rise from the Floor at Month 18 with baseline values for: 4SC, time to rise from floor, time to run/walk 10 m, distance walked in 6 minutes and re-derived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification factors.

Statistical Test of Hypothesis	P-Value	=0.3044
	Comments	See comment above
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	difference in least square means
	Estimated Value	-3.28
	Confidence Interval	(2-Sided) 95% -9.573 to 3.018
	Estimation Comments	See comment above

3.Secondary Outcome


Title	Mean Change From Baseline in the Six-minute Walking Test (6MWT) After 18 Months of Treatment
Description	This test measures the distance that a patient can quickly walk on a f...
Description	This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes. The 6-Minute Walk Test is a useful measure of functional capacity targeted at people with at least moderately severe impairment. A modified version of the 6MWT recommended by American Thoracic Society (2002) for use in adults was performed. The longer the walked distance the better the outcome.
Time Frame	Baseline and 18 months

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Givinostat	Placebo
Arm/Group Description:	Givinostat oral suspension (10 mg/m...	Placebo oral suspension (10 mg/mL) ...
Arm/Group Description:	Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid	Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.
Overall Number of Participants Analyzed	81	39
Least Squares Mean (95% Confidence Interval) Unit of Measure: meters
	-38.43 (-50.704 to -26.153)	-48.38 (-66.288 to -30.482)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Givinostat, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in distance walked at the end of the 6-minute walking test (6MWT) at Month 18 with baseline values for: 4SC, time to rise from floor, time to run/walk 10 metres, distance walked in 6 minutes and re-derived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification factors.

Statistical Test of Hypothesis	P-Value	=0.3723
	Comments	See comment above
	Method	ANCOVA
	Comments	LS means, CIs, p-values were obtained from analysis of covariance model on change from baseline in distance walked at the end of the 6MWT at Month18.

Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	9.96
	Confidence Interval	(2-Sided) 95% -12.071 to 31.983
	Estimation Comments	See comment above

4.Secondary Outcome


Title	Mean Change From Baseline in Total North Star Ambulatory Assessment (NSAA) Score After 18 Months of Treatment
Description	The total North Star Ambulatory Assessment (NSAA) is a 17-item rating ...
Description	The total North Star Ambulatory Assessment (NSAA) is a 17-item rating scale that is used to measure functional motor abilities in ambulant children with Duchenne Muscular Dystrophy (DMD). It is usually used to monitor the progression of the disease and treatment effects. The 17 items of the NSAA, ranging from standing to running 10 meters, were graded using the standard score card with each assessment rated as 0 - unable to achieve independently, 1 - modified method but achieves goal independent of physical assistance from another, or 2 - normal with no obvious modification of activity. This scale is ordinal with 0 as the minimum score (indicating full disfunctionality, i.e. the worst outcome) and with 34 as the maximum score indicating fully-independent function (the best outcome).
Time Frame	Baseline and 18 months

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Givinostat	Placebo
Arm/Group Description:	Givinostat oral suspension (10 mg/m...	Placebo oral suspension (10 mg/mL) ...
Arm/Group Description:	Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid	Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.
Overall Number of Participants Analyzed	81	39
Least Squares Mean (95% Confidence Interval) Unit of Measure: score on a scale
	-2.66 (-3.563 to -1.759)	-4.58 (-5.891 to -3.260)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Givinostat, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in total NSAA score at Month 18 with baseline values for: total NSAA score, 4SC, time to rise from floor, time to run/walk 10 metres, distance walked in 6 minutes and re-derived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification factors.

Statistical Test of Hypothesis	P-Value	=0.0209
	Comments	Same comment as above
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	1.91
	Confidence Interval	(2-Sided) 95% 0.295 to 3.533
	Estimation Comments	Same comment as above.

5.Secondary Outcome


Title	Cumulative Loss of Function on the NSAA
Description	Subject cumulative number of failures across all postbaseline visits w...
Description	Subject cumulative number of failures across all postbaseline visits was the endpoint of interest for analysis. For each subject at each postbaseline visit, failure to perform each of the 17 items of the NSAA was assessed, where "failure" was defined as a score transition from 2 or 1 at baseline to 0 at the respective visit. The total number of failed items for the visit was calculated (maximum of 17 failed items per visit per subject). The subject's cumulative number of failures across all visits was the sum of the total failures at each postbaseline visit.
Time Frame	over 18 months

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Givinostat	Placebo
Arm/Group Description:	Givinostat oral suspension (10 mg/m...	Placebo oral suspension (10 mg/mL) ...
Arm/Group Description:	Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid	Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.
Overall Number of Participants Analyzed	81	39
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: cumulative number of failures
	3.42 (2.692 to 4.334)	5.56 (4.002 to 7.715)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Givinostat, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Estimated cumulative failures, ratio of cumulative failures, CIs, and p-values are obtained from a negative binomial regression on the subject cumulative number of failures across all post-baseline visits. Total failed items at baseline, baseline values for: 4SC, time to rise from floor, time to run/walk 10 metres, distance walked in 6 minutes and re-derived age at first dose were included as independent covariates, with treatment group and steroid use included as indep classification factors.

Statistical Test of Hypothesis	P-Value	=0.0202
	Comments	same comment as above
	Method	negative binomial regression model
	Comments	Estimated cumulative failures, their ratio were obtained from a negative binomial regression on the cumulative N of failures across all visits.

Method of Estimation	Estimation Parameter	Ratio of cumulative failures
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95% 0.408 to 0.927
	Estimation Comments	A lower ratio indicates a greater reduction in cumulative loss of function across 18 months for givinostat compared with placebo. See also comment above.

6.Secondary Outcome


Title	Mean Change From Baseline of Muscle Strength Normalized Overtime
Description	The mean change of muscle strength normalized was evaluated by knee ex...
Description	The mean change of muscle strength normalized was evaluated by knee extension and elbow flexion normalized by subject weight, both measured by hand-held myometry (HHM).
Time Frame	Baseline and 18 months

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Givinostat	Placebo
Arm/Group Description:	Givinostat oral suspension (10 mg/m...	Placebo oral suspension (10 mg/mL) ...
Arm/Group Description:	Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid	Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.
Overall Number of Participants Analyzed	81	39
Least Squares Mean (95% Confidence Interval) Unit of Measure: Newtons/kg
Overall knee extension	-0.32 (-0.441 to -0.197)	-0.50 (-0.681 to -0.328)
Overall elbow flexion	-0.10 (-0.174 to -0.031)	-0.19 (-0.292 to -0.085)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Givinostat, Placebo
	Comments	Overall knee extension
	Type of Statistical Test	Superiority
	Comments	LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in normalised muscle strength at Month 18 with baseline normalised muscle strength and re-derived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification factors.

Statistical Test of Hypothesis	P-Value	=0.0902
	Comments	same comment as above
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95% -0.030 to 0.401
	Estimation Comments	same comment as above

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Givinostat, Placebo
	Comments	Overall elbow flexion
	Type of Statistical Test	Superiority
	Comments	LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in normalised muscle strength at Month 18 with baseline normalised muscle strength and re-derived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification factors.

Statistical Test of Hypothesis	P-Value	=0.1818
	Comments	same comment as above
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95% -0.041 to 0.213
	Estimation Comments	same comment as above

7.Secondary Outcome


Title	Mean Change From Baseline in Vastus Lateralis Muscle Fat Fraction (VL MFF) at 18 Months
Description	Vastus lateralis muscle fat fraction (VL MFF) was expressed as fat inf...
Description	Vastus lateralis muscle fat fraction (VL MFF) was expressed as fat infiltration in this muscle. Fat infiltration was assessed by Magnetic Resonance (MRS).
Time Frame	Baseline and 18 months

Outcome Measure Data

Analysis Population Description

MR cohort: the MR cohort included all subjects in the Target Population who were randomised to study treatment and completed at least one post-baseline MRI/MRS assessment.


Arm/Group Title	Givinostat	Placebo
Arm/Group Description:	Givinostat oral suspension (10 mg/m...	Placebo oral suspension (10 mg/mL) ...
Arm/Group Description:	Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid	Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.
Overall Number of Participants Analyzed	77	37
Least Squares Mean (95% Confidence Interval) Unit of Measure: percentage of fat
	7.63 (6.098 to 9.172)	10.56 (8.331 to 12.783)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Givinostat, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	LS Means, CIs, and p-values are obtained from an analysis of covariance (ANCOVA) model on change from baseline in VL MFF at Month 18 with baseline VL MFF and re-derived age at first dose fitted as covariates, with concomitant steroid use and treatment group as independent classification factors.

Statistical Test of Hypothesis	P-Value	=0.0354
	Comments	Same comment as above
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in least square means
	Estimated Value	-2.92
	Confidence Interval	(2-Sided) 95% -5.641 to -0.204
	Estimation Comments	Same comment as above

8.Secondary Outcome


Title	Number of Subjects Experiencing Treatment-emergent AEs (TEAEs), Serious AEs (SAEs), Mild TEAE Moderate TEAE, Severe TEAE
Description	Adverse Events are unfavorable changes in health, including abnormal l...
Description	Adverse Events are unfavorable changes in health, including abnormal laboratory findings, that occur in trial participants during the clinical trial or within a specified period following the trial. Serious Adverse Events include adverse events that result in death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent or significant disability/incapacity or result in a congenital anomaly/birth defect. Other important medical events, based upon appropriate medical judgment, may also be considered Serious Adverse Events if a trial participant's health is at risk and intervention is required to prevent an outcome mentioned.
Time Frame	Baseline through end of study, that is the end of 18° month

Outcome Measure Data

Analysis Population Description

SAF analysis set: the safety analysis set included all subjects who were randomized and received at least 1 dose of study drug.


Arm/Group Title	Givinostat	Placebo
Arm/Group Description:	Givinostat oral suspension (10 mg/m...	Placebo oral suspension (10 mg/mL) ...
Arm/Group Description:	Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid	Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.
Overall Number of Participants Analyzed	118	61
Measure Type: Count of Participants Unit of Measure: Participants
Subjects with TEAE	112 94.9%	57 93.4%
Subjects with serious AE	8 6.8%	2 3.3%
Subjects with mild AE	69 58.5%	39 63.9%
Subjects with moderate AE	38 32.2%	17 27.9%
Subjects with severe AE	5 4.2%	1 1.6%

9.Secondary Outcome


Title	Evaluation of Acceptability/Palatability of the Oral Suspension
Description	Acceptability and palatability of the oral suspension over time are pr...
Description	Acceptability and palatability of the oral suspension over time are presented. More in details, child perception of the medicine at the three timepoints hereunder specified; parent perception of the medicine based on the child's reaction at the same three timepoints; and parent problems administering the medication at the same timepoints are reported.
Time Frame	Week 4, EOS, early withdrawal

Outcome Measure Data

Analysis Population Description

SAF analysis set: the safety analysis set included all subjects who were randomised and received at least 1 dose of study drug.


Arm/Group Title	Givinostat	Placebo
Arm/Group Description:	Givinostat oral suspension (10 mg/m...	Placebo oral suspension (10 mg/mL) ...
Arm/Group Description:	Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid	Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.
Overall Number of Participants Analyzed	118	61
Measure Type: Count of Participants Unit of Measure: Participants
Child perception - week 4 - dislike very much	31 26.3%	11 18.0%
Child perception - week 4 - dislike a little	21 17.8%	17 27.9%
Child perception - week 4 - not sure	30 25.4%	16 26.2%
Child perception - week 4 - like a little	19 16.1%	12 19.7%
Child perception - week 4 - like very much	11 9.3%	3 4.9%
Child perception - EOS - dislike very much	21 17.8%	7 11.5%
Child perception - EOS - dislike a little	24 20.3%	13 21.3%
Child perception - EOS - not sure	34 28.8%	16 26.2%
Child perception - EOS - like a little	19 16.1%	10 16.4%
Child perception - EOS - like very much	7 5.9%	9 14.8%
Child perception - early withdrawal - dislike very much	1 0.8%	0 0.0%
Child perception - early withdrawal - dislike a little	1 0.8%	0 0.0%
Child perception - early withdrawal - not sure	2 1.7%	0 0.0%
Child perception - early withdrawal - like a little	1 0.8%	0 0.0%
Child perception - early withdrawal - like very much	0 0.0%	0 0.0%
Parent perception - week 4 - unpleasant	50 42.4%	31 50.8%
Parent perception - week 4 - not sure	28 23.7%	10 16.4%
Parent perception - week 4 - pleasant	35 29.7%	18 29.5%
Parent perception - EOS - unpleasant	42 35.6%	14 23.0%
Parent perception - EOS - not sure	40 33.9%	22 36.1%
Parent perception - EOS - pleasant	26 22.0%	19 31.1%
Parent perception - early withdrawal - unpleasant	1 0.8%	0 0.0%
Parent perception - early withdrawal - not sure	3 2.5%	0 0.0%
Parent perception - early withdrawal - pleasant	1 0.8%	0 0.0%
Parent admin problems - week 4 - yes	6 5.1%	1 1.6%
Parent admin problems - week 4 - no	107 90.7%	58 95.1%
Parent admin problems - EOS - yes	5 4.2%	0 0.0%
Parent admin problems - EOS - no	102 86.4%	55 90.2%
Parent admin - early withdrawal - yes	0 0.0%	0 0.0%
Parent admin - early withdrawal - no	5 4.2%	0 0.0%

Adverse Events

Time Frame	Throughout the study till the end of study (month 18, visit 15). More precisely at Visits 4 and 7 (month 1), at Visit 9 (month 2), at Visit 10 (month 3), at Visit 11 (month 6), at Visit 12 (month 9), at Visit 13 (month 12), at Visit 14 (month 15), at Visit 15 (EOS, month 18) and at the FUV (Follow-Up Visit to be performed after 4 weeks from the last dose of study drug (ie, 4 weeks ± 7 days)).
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Givinostat		Placebo
Arm/Group Description	Givinostat oral suspension (10 mg/m...		Placebo oral suspension (10 mg/mL) ...
Arm/Group Description	Givinostat oral suspension (10 mg/mL) twice daily givinostat: The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below: Givinostat or placebo starting dose > or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid > or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid > or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid > or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid > or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid > or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid > or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid > or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid > or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid		Placebo oral suspension (10 mg/mL) twice daily placebo: the oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.
All-Cause Mortality
	Givinostat		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/118 (0.00%)		0/61 (0.00%)
Serious Adverse Events Serious Adverse Events
	Givinostat		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/118 (6.78%)		2/61 (3.28%)
Gastrointestinal disorders
Abdominal pain ^† 1	1/118 (0.85%)	1	0/61 (0.00%)	0
Vomiting ^† 1	1/118 (0.85%)	1	0/61 (0.00%)	0
General disorders
Chest pain ^† 1	1/118 (0.85%)	1	0/61 (0.00%)	0
Infections and infestations
Gastroenteritis ^† 1	1/118 (0.85%)	1	2/61 (3.28%)	2
Gastroenteritis viral ^† 1	1/118 (0.85%)	1	0/61 (0.00%)	0
Influenza ^† 1	1/118 (0.85%)	1	0/61 (0.00%)	0
Injury, poisoning and procedural complications
Spinal fracture ^† 1	1/118 (0.85%)	1	0/61 (0.00%)	0
Nervous system disorders
Dizziness ^† 1	1/118 (0.85%)	1	0/61 (0.00%)	0
Skin and subcutaneous tissue disorders
Rash ^† 1	1/118 (0.85%)	1	0/61 (0.00%)	0
1 Term from vocabulary, MedDRA 24.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Givinostat		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	112/118 (94.92%)		57/61 (93.44%)
Blood and lymphatic system disorders
Thrombocytopenia ^† 1	19/118 (16.10%)	27	0/61 (0.00%)	0
Cardiac disorders
Cardiac disorders ^† 1	8/118 (6.78%)	12	1/61 (1.64%)	2
Ear and labyrinth disorders
Ear and labyrinth disorders ^† 1	6/118 (5.08%)	11	3/61 (4.92%)	4
Eye disorders
Eye disorders ^† 1	5/118 (4.24%)	8	4/61 (6.56%)	4
Gastrointestinal disorders
Diarrhoea ^† 1	43/118 (36.44%)	117	11/61 (18.03%)	16
Vomiting ^† 1	34/118 (28.81%)	64	8/61 (13.11%)	12
Abdominal pain ^† 1	25/118 (21.19%)	52	9/61 (14.75%)	16
Abdominal pain upper ^† 1	17/118 (14.41%)	21	7/61 (11.48%)	9
Nausea ^† 1	8/118 (6.78%)	9	4/61 (6.56%)	6
Constipation ^† 1	8/118 (6.78%)	9	1/61 (1.64%)	1
Dyspepsia ^† 1	2/118 (1.69%)	3	4/61 (6.56%)	4
General disorders
Pyrexia ^† 1	15/118 (12.71%)	18	5/61 (8.20%)	6
Fatigue ^† 1	9/118 (7.63%)	10	0/61 (0.00%)	0
Infections and infestations
Nasopharyngitis ^† 1	31/118 (26.27%)	50	19/61 (31.15%)	27
Upper respiratory tract infection ^† 1	7/118 (5.93%)	9	8/61 (13.11%)	9
Rhinitis ^† 1	6/118 (5.08%)	11	7/61 (11.48%)	8
Gastroenteritis ^† 1	9/118 (7.63%)	12	3/61 (4.92%)	3
Ear infection ^† 1	3/118 (2.54%)	5	4/61 (6.56%)	4
Influenza ^† 1	3/118 (2.54%)	3	4/61 (6.56%)	4
Injury, poisoning and procedural complications
Fall ^† 1	15/118 (12.71%)	24	13/61 (21.31%)	18
Contusion ^† 1	11/118 (9.32%)	32	3/61 (4.92%)	6
Ligament sprain ^† 1	8/118 (6.78%)	9	3/61 (4.92%)	4
Limb Injury ^† 1	6/118 (5.08%)	8	2/61 (3.28%)	2
Investigations
Platelet count decreased ^† 1	51/118 (43.22%)	82	9/61 (14.75%)	14
Blood triglycerides increased ^† 1	14/118 (11.86%)	19	3/61 (4.92%)	6
Metabolism and nutrition disorders
Hypertriglyceridaemia ^† 1	14/118 (11.86%)	22	1/61 (1.64%)	3
Decreased appetite ^† 1	8/118 (6.78%)	10	0/61 (0.00%)	0
Musculoskeletal and connective tissue disorders
Pain in extremity ^† 1	8/118 (6.78%)	14	7/61 (11.48%)	10
Back pain ^† 1	6/118 (5.08%)	9	8/61 (13.11%)	8
Myalgia ^† 1	11/118 (9.32%)	18	2/61 (3.28%)	2
Nervous system disorders
Headache ^† 1	28/118 (23.73%)	41	14/61 (22.95%)	30
Psychiatric disorders
Psychiatric disorders ^† 1	11/118 (9.32%)	14	4/61 (6.56%)	4
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	13/118 (11.02%)	13	9/61 (14.75%)	9
Epistaxis ^† 1	8/118 (6.78%)	21	5/61 (8.20%)	9
Oropharyngeal pain ^† 1	7/118 (5.93%)	8	1/61 (1.64%)	1
Skin and subcutaneous tissue disorders
Rash ^† 1	11/118 (9.32%)	18	1/61 (1.64%)	1
Vascular disorders
Vascular disorders ^† 1	6/118 (5.08%)	6	0/61 (0.00%)	0
1 Term from vocabulary, MedDRA 24.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Dr Paolo Bettica, MD and PhD
Organization:	Italfarmaco SpA
Phone:	+3902 66041503
EMail:	p.bettica@italfarmacogroup.com

Layout table for additonal information

Responsible Party:	Italfarmaco
ClinicalTrials.gov Identifier:	NCT02851797
Other Study ID Numbers:	EPYDIS (DSC/14/2357/48) 2016-000401-36 ( EudraCT Number )
First Submitted:	July 27, 2016
First Posted:	August 2, 2016
Results First Submitted:	December 2, 2022
Results First Posted:	February 2, 2023
Last Update Posted:	February 2, 2023

To Top