An 8-Week Dose-Finding Study to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents With Heterozygous Familial Hypercholesterolemia

Hypercholesterolaemia Clinical Trial

— ODYSSEY KIDS  

Official title:

An 8-Week Open-Label, Sequential, Repeated Dose-Finding Study to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents With Heterozygous Familial Hypercholesterolemia Followed by an Extension Phase

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02890992
• Other study ID #: DFI14223
• Secondary ID: 2015-003766-85U1
• Status: Completed
• Phase: Phase 2
• Start date: September 15, 2016
• Est. completion date: February 22, 2019

Study information

• Verified date: August 2019
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Primary Objective:

To evaluate the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) levels after 8 weeks of treatment in heterozygous familial hypercholesterolemia (heFH) participants aged of 8 to 17 years, with LDL-C >=130 milligrams per deciliter (mg/dL) (3.37 millimoles per litre [mmol/L]) on optimal stable daily dose of statin therapy +/- other lipid modifying therapies (LMTs) or a stable dose of non-statin LMTs in case of intolerance to statins for at least 4 weeks prior to the screening period.

Secondary Objective:

• To evaluate the safety and tolerability of alirocumab.

• To evaluate the pharmacokinetics profile of alirocumab.

• To evaluate the effects of alirocumab on other lipid parameters.

Description:

For Cohorts 1 to 3, a study duration of approximately 16-23 weeks (screening period: up to 6 (+1) weeks, open-label dose finding treatment period: 8 weeks, follow up period: 6-8 weeks).

For Cohort 4, a study duration of approximately 14-19 weeks (screening period up to 6 [+1] weeks, open-label dose finding treatment period: 12 weeks).

Optional extension period: up to a maximum of 2 years for the first participants enrolled in Cohorts 1 to 3, but a maximum of approximately 5 months for the first participants enrolled in Cohort 4.

For all participants who declined participation in the phase 3 study, their last alirocumab injection was on December 2018.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 42
• Est. completion date: February 22, 2019
• Est. primary completion date: September 13, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 17 Years

Eligibility

Inclusion criteria :

• Children and adolescent male and female participants aged of 8 to 17 years at the time of signed informed consent. For Russia only: Male and female participants aged >=12 and <=17 years at the time of signed informed consent.

• Participants with diagnosis of heterozygous familial hypercholesterolemia (heFH) through genotyping or clinical criteria.

• Participants treated with optimal dose of statin +/- other LMT(s) or non-statin LMT(s) if statin intolerant at stable dose for at least 4 weeks prior to screening lipid sampling.

• Participants with calculated LDL-C greater than or equal to 130 mg/dL (>=3.37 mmol/L) at the screening visit.

• Participants with body weight greater than or equal to 25 kg.

• Participants aged of 8 to 9 years to be at Tanner stage 1 and participants aged of 10 to 17 years to be at least at Tanner stage 2 in their development.

• A signed informed consent indicating parental permission with or without participant assent.

Exclusion criteria:

• Participant with secondary hyperlipidemia.

• Diagnosis of homozygous familial hypercholesterolemia.

• Participant who had received lipid apheresis treatment within 2 months prior to the screening period, or has plans to receive it during the study.

• Known history of type 1 or type 2 diabetes mellitus.

• Known history of thyroid disease.

• Known history of hypertension.

• Fasting triglycerides >350 mg/dL (3.95 mmol/L).

• Severe renal impairment (i.e., estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m^2).

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 x upper limit of normal (ULN).

• Creatinine phosphokinase (CPK) >3 x ULN.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Related Conditions & MeSH terms

• Hypercholesterolaemia
• Hypercholesterolemia
• Hyperlipoproteinemia Type II

Intervention

Drug:
• alirocumab SAR236553 (REGN727)
Pharmaceutical form: solution Route of administration: subcutaneous injection
• statins
Pharmaceutical form: tablet Route of administration: oral
• ezetimibe
Pharmaceutical form:tablet Route of administration: oral
• cholestyramine
Pharmaceutical form:tablet Route of administration: oral
• fenofibrate
Pharmaceutical form: tablet Route of administration: oral
• omega-3 fatty acids
Pharmaceutical form: tablet Route of administration: oral
• nicotinic acid
Pharmaceutical form: tablet Route of administration: oral

Locations

Country	Name	City	State
Canada	Investigational Site Number 1240001	Quebec
Czechia	Investigational Site Number 2030001	Brno
Czechia	Investigational Site Number 2030003	Praha 5 - Motol
Czechia	Investigational Site Number 2030002	Zlin
France	Investigational Site Number 2500001	Bron Cedex
Netherlands	Investigational Site Number 5280001	Amsterdam
Norway	Investigational Site Number 5780001	Oslo
Russian Federation	Investigational Site Number 6430001	Kemerovo
Russian Federation	Investigational Site Number 6430004	Saint-Petersburg
South Africa	Investigational Site Number 7100001	Parow
Spain	Investigational Site Number 7240004	A Coruna
Spain	Investigational Site Number 7240001	Madrid
Sweden	Investigational Site Number 7520001	Stockholm
United States	Investigational Site Number 8400005	Charlotte	North Carolina
United States	Investigational Site Number 8400001	Cincinnati	Ohio
United States	Investigational Site Number 8400002	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Sanofi	Regeneron Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada,  Czechia,  France,  Netherlands,  Norway,  Russian Federation,  South Africa,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at Week 8	Percent change in calculated LDL-C was defined as 100*(calculated LDL-C value at Week 8 - calculated LDL-C value at baseline)/calculated LDL-C value at baseline. All available baseline and post-baseline calculated LDL-C value during the OLDFI efficacy treatment period & within one of the analysis windows up to Week 8 were used in the model. OLDFI efficacy treatment period was defined as the period from first investigational medicinal product (IMP) injection to last OLDFI IMP injection + 21 days(for Cohorts 1 & 2) or +35 days (for Cohorts 3 & 4). Adjusted Least-squares (LS) mean & standard error (SE) at Week 8 were obtained from mixed-effect model with repeated measures (MMRM) analysis, with fixed categorical effects of alirocumab dose/dose regimen (30 mg Q2W [<50 kg], 40 mg Q2W [<50 kg], 50 mg Q2W [>=50 kg], 75 mg Q2W [>=50 kg], 75 mg Q4W [<50 kg],150 mg Q4W [>=50 kg], 150 mg Q4W [<50 kg] and 300 mg Q4W ([>=50 kg] dose), time point & dose/dose regimen-by-time point interaction.	Baseline, Week 8
Secondary	Absolute Change From Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at Week 8	Absolute change in LDL-C was calculated by subtracting baseline value from Week 8 value. Adjusted LS means and SE were obtained using MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction.	Baseline, Week 8
Secondary	Percentage of Participants Achieving Calculated Low Density Lipoprotein Cholesterol (LDL-C) <130 mg/dL (3.37 mmol/L) at Week 8	Combined estimate for percentage of participants was obtained by averaging out all the imputed percentage of participants reaching the level of interest. A two-step multiple imputation procedure was used to address missing values in the mITT population in the two steps respectively; with number of imputations = 1000. In the first step, the monotone missing pattern was induced in the multiply-imputed data. In the second step, the missing data at subsequent visits were imputed using the regression method for continuous variables.	At Week 8
Secondary	Percentage of Participants Achieving Calculated LDL-C <110 mg/dL (2.84 mmol/L) at Week 8	Combined estimate for percentage of participants was obtained by averaging out all the imputed percentage of participants reaching the level of interest. A two-step multiple imputation procedure was used to address missing values in the mITT population in the two steps respectively; with number of imputations = 1000. In the first step, the monotone missing pattern was induced in the multiply-imputed data. In the second step, the missing data at subsequent visits were imputed using the regression method for continuous variables.	At Week 8
Secondary	Percent Change From Baseline in Calculated LDL-C at Week 12: Cohort 4	Adjusted LS means and standard error at Week 12 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction.	Baseline, Week 12
Secondary	Percent Change From Baseline in Apolipoprotein (Apo) B at Week 8	Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline value and post-baseline values in at least one of the analysis windows used in the model.	Baseline, Week 8
Secondary	Percent Change From Baseline in Non-High Density Lipoprotein (HDL-C) at Week 8	Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baselines value and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.	Baseline, Week 8
Secondary	Percent Change From Baseline in Total Cholesterol (Total-C) at Week 8	Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.	Baseline, Week 8
Secondary	Percent Change From Baseline in Lipoprotein(a) at Week 8	Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets. The robust regression models included the fixed categorical effect of alirocumab dose/dose regimen. A two-step multiple imputation procedure was used to address missing values in the mITT population in the two steps respectively (with number of imputations = 1000). In the first step, the monotone missing pattern was induced in the multiply-imputed data. In the second step, the missing data at subsequent visits were imputed using the regression method for continuous variables.	Baseline, Week 8
Secondary	Percent Change From Baseline in Fasting Triglyceride at Week 8	Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets. The robust regression models included the fixed categorical effect of alirocumab dose/dose regimen. A two-step multiple imputation procedure was used to address missing values in the mITT population (in the two steps respectively; with number of imputations = 1000). In the first step, the monotone missing pattern was induced in the multiply-imputed data. In the second step, the missing data at subsequent visits were imputed using the regression method for continuous variables.	Baseline, Week 8
Secondary	Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 8	Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.	Baseline, Week 8
Secondary	Percent Change From Baseline in Apolipoprotein A-1 at Week 8	Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.	Baseline, Week 8
Secondary	Absolute Change From Baseline in Apolipoprotein B at Week 8	Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.	Baseline, Week 8
Secondary	Absolute Change From Baseline in Non-High-Density Lipoprotein (Non-HDL-C) at Week 8	Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.	Baseline, Week 8
Secondary	Absolute Change From Baseline in Total Cholesterol (Total-C) at Week 8	Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.	Baseline, Week 8
Secondary	Absolute Change From Baseline in Lipoprotein(a) at Week 8	Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets. The robust regression models included the fixed categorical effect of alirocumab dose/dose regimen. A two-step multiple imputation procedure was used to address missing values in the mITT population (in the two steps respectively; with number of imputations = 1000). In the first step, the monotone missing pattern was induced in the multiply-imputed data. In the second step, the missing data at subsequent visits were imputed using the regression method for continuous variables.	Baseline, Week 8
Secondary	Absolute Change From Baseline in HDL-C at Week 8	Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.	Baseline, Week 8
Secondary	Absolute Change From Baseline in Fasting Triglyceride at Week 8	Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets. The robust regression models included the fixed categorical effect of alirocumab dose/dose regimen. A two-step multiple imputation procedure was used to address missing values in the mITT population (in the two steps respectively; with number of imputations = 1000). In the first step, the monotone missing pattern was induced in the multiply-imputed data. In the second step, the missing data at subsequent visits were imputed using the regression method for continuous variables.	Baseline, Week 8
Secondary	Absolute Change From Baseline in Apolipoprotein A-1 at Week 8	Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.	Baseline, Week 8
Secondary	Absolute Change From Baseline in Ratio Apolipoprotein B/Apolipoprotein A-1 at Week 8	Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.	Baseline, Week 8