Clinical Trial Results:
An Open-label Study to Evaluate Safety, Efficacy and Pharmacokinetics (PK) of Patisiran-LNP in Patients with Hereditary Transthyretin-mediated Amyloidosis (hATTR amyloidosis) with Disease Progression Post-Orthotopic Liver Transplant
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Summary
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EudraCT number |
2018-003519-24 |
Trial protocol |
GB FR PT DE ES IT |
Global end of trial date |
20 Oct 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Nov 2021
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First version publication date |
05 Nov 2021
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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 |
ALN-TTR02-008
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03862807 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Alnylam Pharmaceuticals, Inc.
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Sponsor organisation address |
675 West Kendall Street, Cambridge, United States, 02142
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Public contact |
Clinical Trial Information Line, Alnylam Pharmaceuticals, Inc, +1 18772569526, clinicaltrials@alnylam.com
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Scientific contact |
Clinical Trial Information Line, Alnylam Pharmaceuticals, Inc, +1 8772569526, clinicaltrials@alnylam.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 |
20 Oct 2020
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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 |
20 Oct 2020
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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 |
The purpose of this study is to evaluate the efficacy and safety of patisiran in subjects with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with disease progression after liver transplant.
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Protection of trial subjects |
A safety review committee was not utilized for this study; however, a transplant hepatologist was available for consultation on an as needed basis.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Mar 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Portugal: 3
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Country: Number of subjects enrolled |
Spain: 7
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Country: Number of subjects enrolled |
Sweden: 2
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
France: 5
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Country: Number of subjects enrolled |
Germany: 3
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Country: Number of subjects enrolled |
Italy: 2
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Worldwide total number of subjects |
23
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EEA total number of subjects |
22
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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) |
17
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From 65 to 84 years |
6
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with disease progression post-orthotopic liver transplant were enrolled at nine sites in France, Germany, Italy, Portugal, Spain, Sweden and the United Kingdom. | ||||||||
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Pre-assignment
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Screening details |
Subjects were screened to ensure that they met all the inclusion criteria and none of the exclusion criteria. Subjects demographic data and medical history/disease history were obtained. Medical history captured transplant history and evidence of disease progression. | ||||||||
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Pre-assignment period milestones
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Number of subjects started |
24 [1] | ||||||||
Number of subjects completed |
23 | ||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Did Not Receive Treatment: 1 | ||||||||
| Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: One subject stopped study participation after enrollment but prior to the first dose of patisiran due to failure to meet one of the eligibility criteria. |
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||
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Arms
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Arm title
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Patisiran | ||||||||
Arm description |
- | ||||||||
Arm type |
Experimental | ||||||||
Investigational medicinal product name |
Patisiran
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Investigational medicinal product code |
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Other name |
ONPATTRO, ALN-TTR02
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Pharmaceutical forms |
Solution for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received patisiran 0.3 milligrams/kilogram (mg/kg) via intravenous (IV) infusion once every 3 weeks (q3w) for 12 months. Dosing was based on actual body weight. For subjects weighing 100 kg or more, patisiran was administered at a total dose of 30 mg IV q3w.
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| Notes [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: One subject discontinued treatment with patisiran but continued to undergo study assessments and completed the study. |
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Baseline characteristics reporting groups
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Reporting group title |
Patisiran
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Patisiran
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Reporting group description |
- | ||
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End point title |
Average of Month 6 and Month 12 Percentage Reduction From Baseline in Serum Transthyretin (TTR) [1] | ||||||||
End point description |
Serum TTR was assessed using enzyme linked immunosorbent assay (ELISA).
Analysis population was subjects from the Safety Analysis Set, all subjects who received any amount of patisiran, with post-baseline TTR assessments collected within 24 days (inclusive) after receiving a complete dose of patisiran.
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End point type |
Primary
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End point timeframe |
Baseline, Months 6 and 12
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The reported data in the endpoint is the statistical analysis data. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in the Neuropathy Impairment Score (NIS) at Month 12 | ||||||||
End point description |
The NIS is a composite neurologic impairment score that assesses motor weakness (NIS-W), sensation (NIS-S) and reflexes (NIS-R) by physical exam. The minimum and maximum values are 0 and 244, respectively. A higher score indicates a worse outcome.
Analysis population was subjects from the Per Protocol (PP) Analysis Set, all subjects in the Safety Analysis Set who missed ≤2 doses of patisiran due to the COVID-19 pandemic during the study, with NIS data available at Month 12.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Score at Month 12 | ||||||||
End point description |
The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The minimum and maximum values are -4 and 136, respectively. A higher score indicates a worse outcome.
Analysis population is the PP Analysis Set: All subjects in the Safety Analysis Set who missed ≤2 doses of patisiran due to the COVID-19 pandemic during the study.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 12 | ||||||||
End point description |
The R-ODS is comprised of a 24-item linearly weighted scale that specifically captures activity and social participation limitations. The minimum and maximum values are 0 and 48, respectively. A higher score indicates a better outcome.
Analysis population was the PP Analysis Set: All subjects in the Safety Analysis Set who missed ≤2 doses of patisiran due to the COVID-19 pandemic during the study.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in the Composite Autonomic Symptom Score (COMPASS-31) at Month 12 | ||||||||
End point description |
The COMPASS-31 questionnaire is a measure of autonomic neuropathy symptoms. The questions evaluate 6 autonomic domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor). The minimum and maximum values are 0 and 100, respectively. A higher score indicates a worse outcome.
Analysis population was PP) Analysis Set, all subjects in the Safety Analysis Set who missed ≤2 doses of patisiran due to the COVID-19 pandemic during the study, with COMPASS-31 data available at Month 12.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in the Modified Body Mass Index (mBMI) at Month 12 | ||||||||
End point description |
Nutritional status of subjects was evaluated using the mBMI, calculated as BMI (kg/m^2) multiplied by albumin (g/L). An increase from baseline in mBMI suggests improvement, and a decrease from baseline suggests worsening.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 12
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects With Adverse Events | ||||||||
End point description |
An AE is any untoward medical occurrence in a subject or clinical investigational patient administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
Analysis population was the Safety Analysis Set: All subjects who received any amount of patisiran.
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End point type |
Secondary
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End point timeframe |
From baseline to end of study at Month 13
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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 |
From baseline to end of study at Month 13.
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Adverse event reporting additional description |
Safety Analysis Set: All participants who received any amount of patisiran.
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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 |
23.0
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Reporting groups
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Reporting group title |
Patisiran
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Reporting group description |
Subjects received patisiran 0.3 milligrams/kilogram (mg/kg) via intravenous (IV) infusion once every 3 weeks (q3w) for 12 months. Dosing was based on actual body weight. For subjects weighing 100 kg or more, patisiran was administered at a total dose of 30 mg IV q3w. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
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 | |||
