Actelion Pharmaceuticals Ltd. Gewerbestrasse 16 Allschwil 4123 Switzerland

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1 Trial information Subject disposition Subject analysis sets Baseline characteristics End points Adverse events More information TRIAL INFORMATION Trial identification Eudract number Sponsor protocol code Full title of trial AC 56A22 Single center, double blind, randomized, placebo controlled, twoperiod/two treatment crossover investigating the effect of miglustat on the nasal potential difference in patients with cystic fibrosis homozygous for the F58del mutation Additional identifiers ISRCTN number NCT number UTN number Sponsor details Sponsor 1 Name of organisation Street address Town/city Postal code Country Actelion Pharmaceuticals Ltd. Gewerbestrasse 16 Allschwil 4123 Switzerland SCIENTIFIC CONTACT POINT Name of organisation Functional contact point name Telephone number address Actelion Pharmaceuticals Ltd. Clinical Trials Disclosure Desk +() clinical trials disclosure@actelion.com PUBLIC CONTACT POINT Name of organisation Functional contact point name Telephone number address Actelion Pharmaceuticals Ltd. Clinical Trials Disclosure Desk +() clinical trials disclosure@actelion.com Paediatric regulatory details Is trial part of an agreed paediatric investigation plan (PIP)

2 EMA paediatric investigation plan(s) Does article 45 of regulation (EC) 191/26 apply yo this trial? Does article 46 of regulation (EC) 191/26 apply yo this trial? Results analysis stage Analysis stage Date of interim/final analysis Is this the analysis of the primary completion data? Primary completion date Global end of trial date reached? Global end of trial date Was the trial ended prematurely? Final yes yes General information about the trial Main objective of the trial Actual start date of recruitment Long term follow up planned Independent data monitoring committee (IMDC) involvement? Protection of trial subjects Background therapy Evidence for comparator(s) To demonstrate that miglustat restores the function of the cystic fibrosis transmembrane conductance regulator (CFTR), as reflected in nasal potential difference (NPD), in patients with cystic fibrosis homozygous for the F58del mutation This was conducted in full conformance with the principles of the Declaration of Helsinki, with the ICH Guidelines on Good Clinical Practice (GCP), and with the laws and regulations of the country in which the research was conducted. Written informed consent was obtained from each individual participating in the prior to any procedure and after adequate explanation of the aims, methods, objectives, and potential hazards of the. It was made clear to each subject that he or she was completely free to refuse to enter the, or to withdraw from it at any time for any reason. Miglustat or placebo was given on top of standard care. There were restrictions regarding concomitant medications except that other investigational drugs and/or therapies (e.g., gene therapy) were t allowed. Population of trial subjects TRIAL COUNTRY PLANNED NUMBER OF SUBJECTS ACTUAL NUMBER OF SUBJECTS ENROLLED Belgium 11 Total: worldwide 11 Total: EEA 11 AGE RANGE PLANNED NUMBER OF SUBJECTS ACTUAL NUMBER OF SUBJECTS ENROLLED In utero Preterm newborn infants (gestational age < 37 wks) Newborns ( 27 days) Infants and toddlers (28 days 23 months) Children (2 11 years) Adolescents (12 17 years) Adults (18 64 years) 11

3 From years 85 years and over SUBJECT DISPOSITION Details Recruitment details Screening details One investigational center in Belgium. A screening examination took place 3 21 days prior to the first administration of medication. Pre assignment period MILESTONES Started Completed INTERMEDIATE MILESTONES REASONS FOR NON COMPLETION Period 1 Period details Period title Is this the baseline period Allocation method Blinding type Roles blinded Blinding details Are arms mutually exclusive Subjects in period Baseline period yes Randomised controlled Double Blind Subject, Investigator, Monitor, Data analyst The investigator and staff, the patients, the monitors, and the sponsor staff remained blinded to the treatment until closure. The investigational drug and its matching placebo were indistinguishable and all patient kits were packaged in the same way. 11 Period arms TITLE TYPE DESCRIPTION PRODUCTS Miglustat Experimental Miglustat Name: Miglustat 2 mg t.i.d. Code: Other names: Dosage & administration: Miglustat 2 mg t.i.d. for 7 days and a single dose on Day 8, oral use, capsule Pharma forms: [Capsule] Route of Admin: [Oral use] Placebo Placebo Comparator Placebo Name: Matching placebo t.i.d. Code: Other names: Dosage & administration: Placebo t.i.d. for 7 days and a single dose on Day 8, oral use, capsule Pharma forms: [Capsule] Route of Admin: [Oral use]

4 Period milestone achievement MILESTONE/REASON MIGLUSTAT PLACEBO STARTED COMPLETED OTHER MILESTONES REASONS FOR NON COMPLETION REASONS FOR SUBJECT JOINING Period 2 Period details Period title Is this the baseline period Allocation method Blinding type Roles blinded Blinding details Are arms mutually exclusive Subjects in period Randomised controlled Double Blind Subject, Investigator, Monitor, Data analyst The investigator and staff, the patients, the monitors, and the sponsor staff remained blinded to the treatment until closure. The investigational drug and its matching placebo were indistinguishable and all patient kits were packaged in the same way. 11 Period arms TITLE TYPE DESCRIPTION PRODUCTS Miglustat Experimental Miglustat 2 mg t.i.d. Name: Miglustat 2 mg t.i.d. Code: Other names: Dosage & administration: Miglustat 2 mg t.i.d. for 7 days and a single dose on Day 8, oral use, capsule Pharma forms: [Capsule] Route of Admin: [Oral use] Placebo Placebo Comparator Placebo t.i.d. Name: Matching placebo t.i.d. Code: Other names: Dosage & administration: Placebo t.i.d. for 7 days and a single dose on Day 8, oral use, capsule Pharma forms: [Capsule] Route of Admin: [Oral use] Period milestone achievement MILESTONE/REASON MIGLUSTAT PLACEBO STARTED COMPLETED OTHER MILESTONES REASONS FOR NON COMPLETION REASONS FOR SUBJECT JOINING SUBJECT ANALYSIS SETS TITLE TYPE DESCRIPTION All randomized set Intention to treat NUMBER OF SUBJECTS

5 All randomized set 11 Safety set Safety analysis Safety set 11 Per protocol 11 BASELINE CHARACTERISTICS Baseline characteristics information The baseline period is How are baseline characteristics reported? Baseline period Per baseline period Reporting groups Reporting group 1 Title Subjects Baseline period Age characteristics Age categorical characteristic Characteristic title Units Categories Ready for collection values Age Categorical Years Age continuous characteristic Characteristic title Units Central tendency type Dispersion type Ready for collection values REPORTING GROUPS Age Continuous Year Arithmetic mean Standard deviation yes GROUP# TITLE TENDENCY STANDARD DEVIATION Group 1 SUBJECT ANALYSIS SETS SET# TITLE TENDENCY STANDARD DEVIATION Set 1 All randomized set Set 2 Safety set Set 3 Gender characteristics Characteristic title Gender Categorical

6 Units Categories Ready for collection values REPORTING GROUPS Subjects Female, Male yes GROUP# TITLE FEMALE MALE Group 1 Group 2 SUBJECT ANALYSIS SETS 5 6 Category totals 5 6 SET# TITLE FEMALE MALE Set 1 All randomized set 5 6 Set 2 Safety set Set 3 Study specific characteristics END POINTS End point 1 End point details End point title Timeframe End point type Countable/Measurable Measurable units Measure type Precision/Dispersion type Reporting groups Subject analysis sets Categories Change from baseline to end of treatment in TCS Total chloride secretion (TCS): defined as the sum of nasal potential difference (NPD) responses after perfusion with isoproterel and chloridefree buffer in the presence of amiloride. Schedule for nasal potential difference (NPD) assessments: Visit 2 and Visit 4 of Period 1, and Visit 5 and Visit 7/EOS of Period 2 Primary Measurable mv Arithmetic mean Standard deviation :Miglustat, :Placebo REPORTING GROUPS PERIOD# TITLE SUBJECTS MEASURE STANDARD DEVIATION Miglustat Placebo SUBJECT ANALYSIS SETS SET# TITLE SUBJECTS MEASURE STANDARD DEVIATION Comments: Not Set 1

7 applicable Statistical analysis overview Statistical analysis title Analysis description Analysis type Analysis specification Arm comparison groups Subject analysis comparison groups Primary analysis Analysis type comment Diff. in TCS change from baseline betw. treatments Paired difference (miglustat placebo) Other Pre specified Miglustat, Placebo LOWER LIMIT should be 3.56 Statistical test of hypothesis P value Value equality relation P value comment Analysis method.7426 = UNADJUSTED TREATMENT EFFECT paired t test Method of estimation Confidence interval Number of sides Lower limit Upper limit Point estimate Effect estimate Parameter Dispersion type Dispersion value 2 sided Mean difference (final values) Standard deviation End point 2 End point details End point title Timeframe End point type Countable/Measurable Measurable units Measure type Precision/Dispersion type Reporting groups Basal NPD change from baseline (mv) Schedule for nasal potential difference (NPD) assessments: Visit 2 and Visit 4 of Period 1, and Visit 5 and Visit 7/EOS of Period 2 Secondary Measurable mv Arithmetic mean Standard deviation :Miglustat, :Placebo

8 Subject analysis sets Categories REPORTING GROUPS PERIOD# TITLE SUBJECTS MEASURE STANDARD DEVIATION Miglustat Placebo SUBJECT ANALYSIS SETS SET# TITLE SUBJECTS MEASURE STANDARD DEVIATION Set 1 Comments: Not applicable Statistical analysis overview Statistical analysis title Analysis description Analysis type Analysis specification Arm comparison groups Subject analysis comparison groups Primary analysis Analysis type comment Other Pre specified Miglustat, Placebo Statistical test of hypothesis P value Value equality relation P value comment Analysis method.187 = paired t test Method of estimation Confidence interval Number of sides Lower limit Upper limit Point estimate Effect estimate Parameter Dispersion type Dispersion value Not applicable End point 3

9 End point details End point title Timeframe End point type Countable/Measurable Measurable units Measure type Precision/Dispersion type Reporting groups Subject analysis sets Categories Amiloride NPD change from baseline Schedule for nasal potential difference (NPD) assessments: Visit 2 and Visit 4 of Period 1, and Visit 5 and Visit 7/EOS of Period 2 Secondary Measurable mv Arithmetic mean Standard deviation :Miglustat, :Placebo REPORTING GROUPS PERIOD# TITLE SUBJECTS MEASURE STANDARD DEVIATION Miglustat Placebo SUBJECT ANALYSIS SETS SET# TITLE SUBJECTS MEASURE STANDARD DEVIATION Set 1 Comments: Not applicable Statistical analysis overview Statistical analysis title Analysis description Analysis type Analysis specification Arm comparison groups Subject analysis comparison groups Primary analysis Analysis type comment Other Pre specified Miglustat, Placebo Statistical test of hypothesis P value Value equality relation P value comment Analysis method.7353 = paired t test Method of estimation

10 Confidence interval Number of sides Lower limit Upper limit Point estimate Effect estimate Parameter Dispersion type Dispersion value End point 4 End point details End point title Timeframe End point type Countable/Measurable Measurable units Measure type Precision/Dispersion type Reporting groups Subject analysis sets Categories Chloride free buffer diffusion change Schedule for sweat chloride assessments: Visit 2 and Visit 4 of Period 1, and Visit 5 and Visit 7/EOS of Period 2 Secondary Measurable mv Arithmetic mean Standard deviation :Miglustat, :Placebo REPORTING GROUPS PERIOD# TITLE SUBJECTS MEASURE STANDARD DEVIATION Miglustat Placebo SUBJECT ANALYSIS SETS SET# TITLE SUBJECTS MEASURE STANDARD DEVIATION Set 1 Comments: Not applicable Statistical analysis overview Statistical analysis title Analysis description Analysis type Analysis specification Arm comparison groups Other Pre specified Miglustat, Placebo

11 Subject analysis comparison groups Primary analysis Analysis type comment Statistical test of hypothesis P value Value equality relation P value comment Analysis method.2643 = paired t test Method of estimation Confidence interval Number of sides Lower limit Upper limit Point estimate Effect estimate Parameter Dispersion type Dispersion value End point 5 End point details End point title Timeframe End point type Countable/Measurable Measurable units Measure type Precision/Dispersion type Reporting groups Subject analysis sets Categories ATP hyperpolarization change Schedule for nasal potential difference (NPD) assessments: Visit 2 and Visit 4 of Period 1, and Visit 5 and Visit 7/EOS of Period 2 Secondary Measurable mv Arithmetic mean Standard deviation :Miglustat, :Placebo REPORTING GROUPS PERIOD# TITLE SUBJECTS MEASURE STANDARD DEVIATION SUBJECT ANALYSIS SETS Miglustat Placebo

12 SET# TITLE SUBJECTS MEASURE STANDARD DEVIATION Set 1 Comments: Not applicable Statistical analysis overview Statistical analysis title Analysis description Analysis type Analysis specification Arm comparison groups Subject analysis comparison groups Primary analysis Analysis type comment Other Pre specified Miglustat, Placebo Statistical test of hypothesis P value Value equality relation P value comment Analysis method.2457 = paired t test Method of estimation Confidence interval Number of sides Lower limit Upper limit Point estimate Effect estimate Parameter Dispersion type Dispersion value End point 6 End point details End point title Timeframe End point type Countable/Measurable Measurable units Measure type Precision/Dispersion type NPD Clancy Index change Schedule for nasal potential difference (NPD) assessments: Visit 2 and Visit 4 of Period 1, and Visit 5 and Visit 7/EOS of Period 2 Secondary Measurable mv Arithmetic mean Standard deviation

13 Reporting groups Subject analysis sets Categories :Miglustat, :Placebo REPORTING GROUPS PERIOD# TITLE SUBJECTS MEASURE STANDARD DEVIATION Miglustat Placebo SUBJECT ANALYSIS SETS SET# TITLE SUBJECTS MEASURE STANDARD DEVIATION Set 1 Comments: Not applicable Statistical analysis overview Statistical analysis title Analysis description Analysis type Analysis specification Arm comparison groups Subject analysis comparison groups Primary analysis Analysis type comment Other Pre specified Miglustat, Placebo Statistical test of hypothesis P value Value equality relation P value comment Analysis method.6572 = paired t test Method of estimation Confidence interval Number of sides Lower limit Upper limit Point estimate Effect estimate Parameter Dispersion type Dispersion value

14 End point 7 End point details End point title Timeframe End point type Countable/Measurable Measurable units Measure type Precision/Dispersion type Reporting groups Subject analysis sets Categories NPD Wilschanski Index change Schedule for nasal potential difference (NPD) assessments: Visit 2 and Visit 4 of Period 1, and Visit 5 and Visit 7/EOS of Period 2 Secondary Measurable Percent Arithmetic mean Standard deviation :Miglustat, :Placebo REPORTING GROUPS PERIOD# TITLE SUBJECTS MEASURE STANDARD DEVIATION Miglustat Placebo SUBJECT ANALYSIS SETS SET# TITLE SUBJECTS MEASURE STANDARD DEVIATION Set 1 Comments: Not applicable Statistical analysis overview Statistical analysis title Analysis description Analysis type Analysis specification Arm comparison groups Subject analysis comparison groups Primary analysis Analysis type comment Other Pre specified Miglustat, Placebo Statistical test of hypothesis P value Value equality relation P value comment Analysis method.9116 = paired t test

15 Method of estimation Confidence interval Number of sides Lower limit Upper limit Point estimate Effect estimate Parameter Dispersion type Dispersion value End point 8 End point details End point title Timeframe End point type Countable/Measurable Measurable units Measure type Precision/Dispersion type Reporting groups Subject analysis sets Categories Sweat sodium concentration change Schedule for sweat sodium assessments: Visit 2 and Visit 4 of Period 1, and Visit 5 and Visit 7/EOS of Period 2 Secondary Measurable μmol/l Arithmetic mean Standard deviation :Miglustat, :Placebo REPORTING GROUPS PERIOD# TITLE SUBJECTS MEASURE STANDARD DEVIATION Miglustat Placebo SUBJECT ANALYSIS SETS SET# TITLE SUBJECTS MEASURE STANDARD DEVIATION Set 1 Comments: Not applicable Statistical analysis overview Statistical analysis title Analysis description

16 Analysis type Analysis specification Arm comparison groups Subject analysis comparison groups Primary analysis Analysis type comment Other Pre specified Miglustat, Placebo Statistical test of hypothesis P value Value equality relation P value comment Analysis method.554 = paired t test Method of estimation Confidence interval Number of sides Lower limit Upper limit Point estimate Effect estimate Parameter Dispersion type Dispersion value End point 9 End point details End point title Timeframe End point type Countable/Measurable Measurable units Measure type Precision/Dispersion type Reporting groups Subject analysis sets Categories Sweat chloride concentration change Schedule for sweat chloride assessments: Visit 2 and Visit 4 of Period 1, and Visit 5 and Visit 7/EOS of Period 2 Secondary Measurable μmol/l Arithmetic mean Standard deviation :Miglustat, :Placebo REPORTING GROUPS PERIOD# TITLE SUBJECTS MEASURE STANDARD DEVIATION Miglustat

17 Placebo SUBJECT ANALYSIS SETS SET# TITLE SUBJECTS MEASURE STANDARD DEVIATION Set 1 Comments: Not applicable Statistical analysis overview Statistical analysis title Analysis description Analysis type Analysis specification Arm comparison groups Subject analysis comparison groups Primary analysis Analysis type comment Other Pre specified Miglustat, Placebo Statistical test of hypothesis P value Value equality relation P value comment Analysis method.9697 = paired t test Method of estimation Confidence interval Number of sides Lower limit Upper limit Point estimate Effect estimate Parameter Dispersion type Dispersion value End point 1 End point details End point title Timeframe End point type Countable/Measurable Measurable units FEV1 change from baseline Schedule for FEV1 assessments: Visit 1 (Screening), Visit 2 and Visit 4 of Period 1, and Visit 5 and Visit 7/EOS of Period 2 Secondary Measurable Percent

18 Measure type Precision/Dispersion type Reporting groups Subject analysis sets Categories Arithmetic mean Standard deviation :Miglustat, :Placebo REPORTING GROUPS PERIOD# TITLE SUBJECTS MEASURE STANDARD DEVIATION Miglustat Placebo SUBJECT ANALYSIS SETS SET# TITLE SUBJECTS MEASURE STANDARD DEVIATION Set 1 Comments: Not applicable Statistical analysis overview Statistical analysis title Analysis description Analysis type Analysis specification Arm comparison groups Subject analysis comparison groups Primary analysis Analysis type comment Other Pre specified Miglustat, Placebo Statistical test of hypothesis P value Value equality relation P value comment Analysis method.6422 = paired t test Method of estimation Confidence interval Number of sides Lower limit Upper limit Point estimate Effect estimate Parameter Dispersion type

19 Dispersion value ADVERSE EVENTS No serious adverse events have been specified. Adverse events information Timeframe for adverse event reporting Adverse event reporting additional description Frequency threshold for reporting nserious adverse events AE reporting at Visit 1 (Screening) and from Visit 2 to Visit 7/EOS (i..e. up to 28 days); SAE reporting at Visit 1 (Screening) and from Visit 2 to Visit 8/Follow up (i..e. up to 57 days) Adverse events reporting groups Adverse event reporting group 1 Reporting group title Reporting group description Subjects exposed Subjects affected by serious adverse events Subjects affected by n serious adverse events Total number of deaths (all causes) Total number of deaths resulting from adverse events Miglustat Miglustat 2 mg t.i.d. for 7 days and a single dose on Day Adverse event reporting group 2 Reporting group title Reporting group description Subjects exposed Subjects affected by serious adverse events Subjects affected by n serious adverse events Total number of deaths (all causes) Total number of deaths resulting from adverse events Placebo Plaebo t.i.d. for 7 days and a single dose on Day Serious adverse events Non serious adverse events Non serious adverse event 1

20 Threshold for n serious adverse event Gastrointestinal disorders Diarrhoea 11. MIGLUSTAT PLACEBO Non serious adverse event 2 Threshold for n serious adverse event Gastrointestinal disorders Abdominal discomfort 11. MIGLUSTAT PLACEBO 11 Non serious adverse event 3 Nervous system disorders Headache

21 Threshold for n serious adverse event 11. MIGLUSTAT PLACEBO 11 Non serious adverse event 4 Threshold for n serious adverse event Gastrointestinal disorders Abdominal pain 11. MIGLUSTAT PLACEBO Non serious adverse event 5 Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain 11.

22 Threshold for n serious adverse event MIGLUSTAT PLACEBO 11 Non serious adverse event 6 Threshold for n serious adverse event Gastrointestinal disorders Aphthous stomatitis 11. MIGLUSTAT PLACEBO 11 Non serious adverse event 7 Threshold for n serious adverse event General disorders and administration site conditions Chills 11. MIGLUSTAT

23 PLACEBO 11 Non serious adverse event 8 Threshold for n serious adverse event Nervous system disorders Dizziness 11. MIGLUSTAT PLACEBO 11 Non serious adverse event 9 Threshold for n serious adverse event Gastrointestinal disorders Gastrointestinal disorder 11. MIGLUSTAT PLACEBO 11 Non serious adverse event 1 Vascular disorders

24 Threshold for n serious adverse event Hypertension 11. MIGLUSTAT PLACEBO 11 Non serious adverse event 11 Threshold for n serious adverse event Psychiatric disorders Insomnia 11. MIGLUSTAT PLACEBO 11 Non serious adverse event 12 Infections and infestations Pseudomonas infection

25 Threshold for n serious adverse event 11. MIGLUSTAT PLACEBO 11 Non serious adverse event 13 Threshold for n serious adverse event Gastrointestinal disorders Stomach discomfort 11. MIGLUSTAT PLACEBO 11 Non serious adverse event 14 Metabolism and nutrition disorders Decreased appetite 11.

26 Threshold for n serious adverse event MIGLUSTAT 11 PLACEBO Non serious adverse event 15 Threshold for n serious adverse event Respiratory, thoracic and mediastinal disorders Epistaxis 11. MIGLUSTAT 11 PLACEBO Non serious adverse event 16 Threshold for n serious adverse event Psychiatric disorders Initial insomnia 11. MIGLUSTAT 11 PLACEBO Non serious adverse event 17

27 Threshold for n serious adverse event Respiratory, thoracic and mediastinal disorders Rhirrhoea 11. MIGLUSTAT 11 PLACEBO MORE INFORMATION Substantial protocol amendments (globally) Were there any global substantial amendments to the protocol No Interruptions (globally) Were there any global interruptions to the trial? No Limitations and caveats Limitations and caveats applicable to this summary of the results The proportion of measurements with a residual TCS response ( 5 mv) was unexpectedly high (>6%), jeopardizing any meaningful interpretation of the primary endpoint. NPD measurements were highly variable, probably due to methodological aspects. Online references Sylogent, Inc.