Clinical Trial Results:
A multicenter, double-blind, randomized, placebo-controlled, parallel-group study to determine the efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease.
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Summary
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EudraCT number |
2017-003369-85 |
Trial protocol |
GB AT NL BE IE ES NO IT |
Global end of trial date |
02 Sep 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
25 Aug 2022
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First version publication date |
25 Aug 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ID-069A301
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03425539 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Idorsia Pharmaceuticals Ltd
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Sponsor organisation address |
Hegenheimermattweg 91, Allschwil, Switzerland, 4123
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Public contact |
Clinical Trial Disclosure Desk, Idorsia Pharmaceuticals Ltd, clinical-trials-disclosure@idorsia.com
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Scientific contact |
Clinical Trial Disclosure Desk, Idorsia Pharmaceuticals Ltd, clinical-trials-disclosure@idorsia.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Sep 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Sep 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
• To determine the effect of lucerastat on neuropathic pain in subjects with Fabry disease (FD).
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Protection of trial subjects |
The protocol and any material provided to the subject (such as a subject information sheet or description of the study used to obtain informed consent) were reviewed and approved by the appropriate Independent Ethics Committee (IEC) or Institutional Review Board (IRB) before the study was started.
Sponsor personnel and the investigators ensured that the study was conducted in full compliance with ICH-GCP guidelines, the principles of the “Declaration of Helsinki”, and with the laws and regulations of the countries in which the study was conducted.
Both the sponsor and the investigator had the right to terminate the study at any time, and in such a case, were responsible for protecting the subjects’ interests. The investigator was responsible for maintaining the subjects’ identities in strictest confidence.
Prior to any study procedure and after adequate explanation of the aims, methods, objectives, and potential hazards of the study, written informed consent was obtained from each participating subject. It was made clear to each subject that he or she was completely free to refuse to enter the study, or to withdraw from it at any time for any reason.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
08 May 2018
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
4 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Canada: 15
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Country: Number of subjects enrolled |
Australia: 9
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Country: Number of subjects enrolled |
United States: 32
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Country: Number of subjects enrolled |
Germany: 14
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Country: Number of subjects enrolled |
Switzerland: 1
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Country: Number of subjects enrolled |
Netherlands: 3
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Country: Number of subjects enrolled |
Norway: 2
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Country: Number of subjects enrolled |
Poland: 13
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Country: Number of subjects enrolled |
Spain: 13
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Country: Number of subjects enrolled |
United Kingdom: 11
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Country: Number of subjects enrolled |
Austria: 1
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Country: Number of subjects enrolled |
Belgium: 4
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Worldwide total number of subjects |
118
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EEA total number of subjects |
50
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
111
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From 65 to 84 years |
7
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 49 sites in 14 countries, including North America (USA, CAN), Europe (Austria, Belgium, Germany, Ireland, Italy, Netherlands, Norway, Poland, Spain, Switzerland, UK), and Australia. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Screening period: From signing informed consent to the day before subject randomization (6 to 7 weeks duration). | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Treatment period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst | ||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Lucerastat | ||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Lucerastat
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Investigational medicinal product code |
ACT-434964
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Lucerastat (ACT-434964) was provided as hard-gelatin capsules containing 250 mg of lucerastat. Capsules were administered orally b.i.d. to provide a lucerastat dose of 250, 500, 750, or 1000 mg b.i.d. based on the subject’s eGFR.
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Matching placebo capsules were administered orally b.i.d., with the number of capsules administered based on the subject’s eGFR.
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Baseline characteristics reporting groups
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Reporting group title |
Lucerastat
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Lucerastat
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Reporting group description |
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Reporting group title |
Placebo
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Reporting group description |
- | ||
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End point title |
Neuropathic pain monthly score (modified BPI-SF3): Change from baseline to Month 6 | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
From baseline to Month 6
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Statistical analysis title |
Neuropathic pain monthly score: ANCOVA | ||||||||||||
Statistical analysis description |
Neuropathic pain monthly score (modified BPI-SF3): main analysis of change from baseline to Month 6 (ANCOVA)
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Comparison groups |
Lucerastat v Placebo
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Number of subjects included in analysis |
117
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||
P-value |
= 0.3189 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS Mean difference vs. placebo | ||||||||||||
Point estimate |
0.42
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.4 | ||||||||||||
upper limit |
1.23 | ||||||||||||
| Notes [1] - An ANCOVA was applied to the change from baseline to Month 6 including the terms baseline value, the two stratification factors (sex and ERT treatment status), and the treatment group. |
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End point title |
Plasma Gb3 (ng/ml): Change from baseline to Month 6 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From baseline to Month 6
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Abdominal pain monthly score: Change from baseline to Month 6 | ||||||||||||
End point description |
From baseline to Month 6
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End point type |
Secondary
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End point timeframe |
From baseline to Month 6
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of days with diarrhea: Change from baseline to Month 6 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From baseline to Month 6
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events from the treatment period are reported.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.0
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Reporting groups
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Reporting group title |
Lucerastat
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Reporting group description |
Lucerastat | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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12 Apr 2018 |
1. The definition of neuropathic pain was split to improve readability and subject comprehension. The descriptor “numbness” was removed from the description as it was considered to be a distinct concept that does not necessarily describe neuropathic pain severity. The concept of intermittence was also added to the definition of neuropathic pain.
2. A new Patient Global Impression of Severity scale was added to assess the overall severity of neuropathic pain.
3. It was clarified that current guidelines for the diagnosis and treatment of FD were to be followed.
4. A more explicit definition of the global end of the study was included.
5. The process of eDiary data availability, transfer, encoding, and the measures taken to maintain privacy of the subject were clarified.
6. Exclusion criteria were adjusted to emphasize that any subject at high risk of developing clinical signs of organ involvement within the time period of the study, as per investigator judgment would be excluded from the study.
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25 Oct 2018 |
The results of a clinical drug-drug interaction (DDI) study (ID-069-105) with the organic cation transporter 2 (OCT2) inhibitor cimetidine led to the conclusion that lucerastat can be administered concomitantly with OCT2 inhibitors without need for dose adaptation. Therefore, respective protocol restrictions at study entry (exclusion criterion #15) and during the study (forbidden concomitant therapy) related to the use of OCT2 inhibitors have been removed. |
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01 Oct 2020 |
The main reason for the amendment was to change the methodology used to analyze the primary endpoint from a dichotomous responder analysis, based on a reduction of at least 30% from baseline to Month 6 in modified BPI-SF3 score, to an analysis of the change from baseline to Month 6 in modified BPI-SF3 score. Analyzing the primary endpoint as a continuous variable avoided a loss in information caused by the dichotomization of the endpoint variable. It required fewer subjects to maintain the statistical power to detect a difference between lucerastat and placebo. With the proposed continuous analysis, 99 subjects are required to achieve a power of 87.2%, which is comparable to the power in the range of 81.984.1% for the current responder analysis based on 108 subjects. The dichotomous responder analysis was documented to support and establish clinical relevance. This change was agreed with the FDA in order to help overcome challenges in recruitment of subjects with a rare disease in the context of the COVID 19 pandemic and complete the study. The change was restricted to the primary statistical analysis and did not alter the study population or the study's primary objective. |
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24 Aug 2021 |
The main purpose of the amendment was to change the statistical method used to analyze the secondary endpoint "Change from baseline to Month 6 in the number of days with at least 1 stool of a BSS consistency Type 6 or 7", from a parametric analysis (assuming normality) to a non-parametric analysis. This change in analysis was warranted because the blinded baseline data review suggested that the endpoint was not normally distributed. The necessity to make a change to this analysis method was discussed with the FDA; the change is restricted to the statistical analysis of the last secondary endpoint in the testing strategy and does not alter the study population and the primary and secondary objectives of the study. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
