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| ID | Type | Description | Link |
|---|---|---|---|
| 2018-003519-24 | EudraCT Number |
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The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of patisiran in participants with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with disease progression after liver transplant.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patisiran | Experimental | Participants 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 participants weighing 100 kg or more, patisiran was administered at a total dose of 30 mg IV q3w. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Patisiran | Drug | Patisiran was administered via IV infusion. |
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| Measure | Description | Time Frame |
|---|---|---|
| Average of Month 6 and Month 12 Percentage Reduction From Baseline in Serum Transthyretin (TTR) | Serum TTR was assessed using enzyme linked immunosorbent assay (ELISA). The average of the percentage reduction in serum TTR observed at Month 6 and at Month 12 is first calculated for each patient and then the median (95% CI) of these averaged values is summarized for the Safety Analysis Set. | Baseline, Months 6 and 12 |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in the Neuropathy Impairment Score (NIS) at Month 12 | 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. | Baseline, Month 12 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Director | Alnylam Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinical Trial Site | Créteil | France | ||||
| Clinical Trial Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37639169 | Derived | Badri P, Habtemariam B, Melch M, Clausen VA, Arum S, Li X, Jay PY, Vest J, Robbie GJ. Pharmacokinetics and Pharmacodynamics of Patisiran in Patients with hATTR Amyloidosis and with Polyneuropathy After Liver Transplantation. Clin Pharmacokinet. 2023 Oct;62(10):1509-1522. doi: 10.1007/s40262-023-01292-w. Epub 2023 Aug 28. | |
| 35213769 |
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Access to Anonymized individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the US and/or the EU.
Data will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Requests for access to data can be submitted via the website www.vivli.org.
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Participants 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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| ID | Title | Description |
|---|---|---|
| FG000 | Patisiran | Participants 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 participants weighing 100 kg or more, patisiran was administered at a total dose of 30 mg IV q3w. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 7, 2018 | Nov 22, 2021 |
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| Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Score at Month 12 |
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. |
| Baseline, Month 12 |
| Change From Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 12 | 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. | Baseline, Month 12 |
| Change From Baseline in the Composite Autonomic Symptom Score (COMPASS-31) at Month 12 | 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. | Baseline, Month 12 |
| Change From Baseline in the Modified Body Mass Index (mBMI) at Month 12 | Nutritional status of participants 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. | Baseline, Month 12 |
| Percentage of Participants With Adverse Events | An AE is any untoward medical occurrence in a participant or clinical investigational patient administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. | From baseline to end of study at Month 13 |
| Le Kremlin-Bicêtre |
| France |
| Clinical Trial Site | Münster | Germany |
| Clinical Trial Site | Messina | Italy |
| Clinical Trial Site | Porto | Portugal |
| Clinical Trial Site | Barcelona | Spain |
| Clinical Trial Site | Huelva | Spain |
| Clinical Trial Site | Umeå | Sweden |
| Clinical Trial Site | London | United Kingdom |
| Schmidt HH, Wixner J, Plante-Bordeneuve V, Munoz-Beamud F, Llado L, Gillmore JD, Mazzeo A, Li X, Arum S, Jay PY, Adams D; Patisiran Post-LT Study Group. Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation. Am J Transplant. 2022 Jun;22(6):1646-1657. doi: 10.1111/ajt.17009. Epub 2022 Mar 26. |
| 35188911 | Derived | Seibert K, Wlodarski R, Sarswat N, Appelbaum D, Issa NP, Soliven B, Rezania K. Progressive Multiple Mononeuropathy in a Patient With Familial Transthyretin Amyloidosis After Liver Transplantation. J Clin Neuromuscul Dis. 2022 Mar 1;23(3):143-147. doi: 10.1097/CND.0000000000000368. |
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| Completed Treatment |
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| COMPLETED |
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| NOT COMPLETED |
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Safety Analysis Set: All participants who received any amount of patisiran.
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| ID | Title | Description |
|---|---|---|
| BG000 | Patisiran | Participants 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 participants weighing 100 kg or more, patisiran was administered at a total dose of 30 mg IV q3w. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Serum Transthyretin (TTR) | Median | Full Range | mg/L |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Average of Month 6 and Month 12 Percentage Reduction From Baseline in Serum Transthyretin (TTR) | Serum TTR was assessed using enzyme linked immunosorbent assay (ELISA). The average of the percentage reduction in serum TTR observed at Month 6 and at Month 12 is first calculated for each patient and then the median (95% CI) of these averaged values is summarized for the Safety Analysis Set. | Safety Analysis Set: All participants who received any amount of patisiran. | Posted | Median | 95% Confidence Interval | percent reduction | Baseline, Months 6 and 12 |
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| Secondary | Change From Baseline in the Neuropathy Impairment Score (NIS) at Month 12 | 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. | Participants from the Per Protocol (PP) Analysis Set, all participants 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. | Posted | Mean | Standard Error | score on a scale | Baseline, Month 12 |
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| Secondary | Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Score at Month 12 | 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. | Per Protocol (PP) Analysis Set: All participants in the Safety Analysis Set who missed ≤2 doses of patisiran due to the COVID-19 pandemic during the study. | Posted | Mean | Standard Error | score on a scale | Baseline, Month 12 |
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| Secondary | Change From Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 12 | 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. | Per Protocol (PP) Analysis Set: All participants in the Safety Analysis Set who missed ≤2 doses of patisiran due to the COVID-19 pandemic during the study. | Posted | Mean | Standard Error | score on a scale | Baseline, Month 12 |
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| Secondary | Change From Baseline in the Composite Autonomic Symptom Score (COMPASS-31) at Month 12 | 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. | Participants from the Per Protocol (PP) Analysis Set, all participants 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. | Posted | Least Squares Mean | Standard Error | score on a scale | Baseline, Month 12 |
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| Secondary | Change From Baseline in the Modified Body Mass Index (mBMI) at Month 12 | Nutritional status of participants 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. | Per Protocol (PP) Analysis Set: All participants in the Safety Analysis Set who missed ≤2 doses of patisiran due to the COVID-19 pandemic during the study. | Posted | Mean | Standard Error | (kg/m^2)*(g/L) | Baseline, Month 12 |
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| Secondary | Percentage of Participants With Adverse Events | An AE is any untoward medical occurrence in a participant or clinical investigational patient administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. | Safety Analysis Set: All participants who received any amount of patisiran. | Posted | Number | percentage of participants | From baseline to end of study at Month 13 |
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From baseline to end of study at Month 13.
Safety Analysis Set: All participants who received any amount of patisiran.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Patisiran | Participants 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 participants weighing 100 kg or more, patisiran was administered at a total dose of 30 mg IV q3w. | 0 | 23 | 5 | 23 | 23 | 23 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atrial thrombosis | Cardiac disorders | MedDRA (23.0) | Systematic Assessment |
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| Cardiac failure | Cardiac disorders | MedDRA (23.0) | Systematic Assessment |
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| Cholangitis | Hepatobiliary disorders | MedDRA (23.0) | Systematic Assessment |
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| Infusion related reaction | Immune system disorders | MedDRA (23.0) | Systematic Assessment |
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| Pneumonia | Infections and infestations | MedDRA (23.0) | Systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA (23.0) | Systematic Assessment |
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| Hip fracture | Injury, poisoning and procedural complications | MedDRA (23.0) | Systematic Assessment |
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| Syncope | Nervous system disorders | MedDRA (23.0) | Systematic Assessment |
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| Haematuria | Renal and urinary disorders | MedDRA (23.0) | Systematic Assessment |
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| Urinary retention | Renal and urinary disorders | MedDRA (23.0) | Systematic Assessment |
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| Atelectasis | Respiratory, thoracic and mediastinal disorders | MedDRA (23.0) | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vertigo | Ear and labyrinth disorders | MedDRA (23.0) | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA (23.0) | Systematic Assessment |
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| Bile acid malabsorption | Gastrointestinal disorders | MedDRA (23.0) | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA (23.0) | Systematic Assessment |
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| Asthenia | General disorders | MedDRA (23.0) | Systematic Assessment |
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| Chest pain | General disorders | MedDRA (23.0) | Systematic Assessment |
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| Fatigue | General disorders | MedDRA (23.0) | Systematic Assessment |
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| Oedema peripheral | General disorders | MedDRA (23.0) | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA (23.0) | Systematic Assessment |
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| Infusion related reaction | Immune system disorders | MedDRA (23.0) | Systematic Assessment |
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| Bronchitis | Infections and infestations | MedDRA (23.0) | Systematic Assessment |
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| Cystitis | Infections and infestations | MedDRA (23.0) | Systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA (23.0) | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | MedDRA (23.0) | Systematic Assessment |
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| Skin laceration | Injury, poisoning and procedural complications | MedDRA (23.0) | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (23.0) | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (23.0) | Systematic Assessment |
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| Oliguria | Renal and urinary disorders | MedDRA (23.0) | Systematic Assessment |
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| Poor venous access | Vascular disorders | MedDRA (23.0) | Systematic Assessment |
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It is intended that after completion of the study, the data are to be submitted for publication in a scientific journal and/or for reporting at a scientific meeting. A separate publication by Institution or PI may not be submitted for publication until after this primary manuscript is published or following 12 months after completion of the study. A copy of any proposed publication based on this study, must be provided and confirmed received at the Sponsor at least 30 days before its submission.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Chief Medical Officer | Alnylam Pharmaceuticals Inc. | 866-330-0326 | clinicaltrials@alnylam.com |
| Prot_002.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 8, 2020 | Nov 22, 2021 | SAP_003.pdf |
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| ID | Term |
|---|---|
| D028226 | Amyloidosis, Familial |
| C567782 | Amyloidosis, Hereditary, Transthyretin-Related |
| ID | Term |
|---|---|
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D000686 | Amyloidosis |
| D057165 | Proteostasis Deficiencies |
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| ID | Term |
|---|---|
| C000606954 | patisiran |
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