Patisiran in Patients With Hereditary Transthyretin-mediated Amyloidosis (hATTR Amyloidosis) Disease Progression Post-Liver Transplant

• Sponsor: Alnylam Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03862807
• Collaborator: (none)
• Enrollment: 24
• Locations: 9
• Arm: 1
• Actual Duration (Months): 18.8
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Amyloidosis, Familial; Transthyretin Amyloidosis	Drug: Patisiran	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Mar 27, 2019
• Actual Primary Completion Date: Oct 6, 2020
• Actual Study Completion Date: Oct 20, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Patisiran; Patisiran was administered via IV infusion.; Other Names: ALN-TTR02 ONPATTRO

Outcome Measures

Primary Outcome Measures

1. Average of Month 6 and Month 12 Percentage Reduction From Baseline in Serum Transthyretin (TTR) [Baseline, Months 6 and 12]

   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.

Secondary Outcome Measures

1. Change From Baseline in the Neuropathy Impairment Score (NIS) at Month 12 [Baseline, 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.

2. Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Score at Month 12 [Baseline, 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.

3. Change From Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 12 [Baseline, 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.

4. Change From Baseline in the Composite Autonomic Symptom Score (COMPASS-31) at Month 12 [Baseline, 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.

5. Change From Baseline in the Modified Body Mass Index (mBMI) at Month 12 [Baseline, 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.

6. Percentage of Participants With Adverse Events [From baseline to end of study at Month 13]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Received liver transplant for treatment of hATTR amyloidosis ≥12 months before study start

• Has increase in polyneuropathy disability (PND) score after liver transplant

• Has received stable immunosuppressive regimen with ≤10 mg/day of prednisone for at least 3 months before study start

• Has Karnofsky Performance Status (KPS) of ≥70%

• Has vitamin A level greater than or equal to lower limit of normal

Exclusion Criteria:

• Has previously received inotersen or patisiran

• Has clinically significant liver function test abnormalities

• Has known portal hypertension with ascites

• Has estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m^2

• Has known leptomeningeal amyloidosis

• Has infection with hepatitis B, hepatitis C or human immunodeficiency virus (HIV)

• Has New York Heart Association heart failure classification of >2

• Is wheelchair bound or bedridden

• Has received organ transplants other than liver transplant

• Will be using another tetramer stabilizer during the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Trial Site	Créteil		France
2	Clinical Trial Site	Le Kremlin-Bicêtre		France
3	Clinical Trial Site	Münster		Germany
4	Clinical Trial Site	Messina		Italy
5	Clinical Trial Site	Porto		Portugal
6	Clinical Trial Site	Barcelona		Spain
7	Clinical Trial Site	Huelva		Spain
8	Clinical Trial Site	Umeå		Sweden
9	Clinical Trial Site	London		United Kingdom

Sponsors and Collaborators

• Alnylam Pharmaceuticals

Investigators

• Study Director: Medical Director, Alnylam Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Oct 7, 2018
• Statistical Analysis Plan - Oct 8, 2020

More Information

Publications

None provided.

• Responsible Party: Alnylam Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03862807
• Other Study ID Numbers: ALN-TTR02-008; 2018-003519-24
• First Posted: Mar 5, 2019
• Last Update Posted: Dec 21, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Amyloidosis, Familial; Amyloidosis; Disease Progression

Study Results

Participant Flow

Recruitment Details	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.

Arm/Group Title	Patisiran
Arm/Group Description	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.
Period Title: Overall Study
STARTED	24
Treated	23
Completed Treatment	22
COMPLETED	23
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Patisiran
Arm/Group Description	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.
Overall Participants	23
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.1 (9.9)
Sex: Female, Male (Count of Participants)
Female	10 43.5%
Male	13 56.5%
Race/Ethnicity, Customized (Count of Participants)
White	22 95.7%
Asian	1 4.3%
Race/Ethnicity, Customized (Count of Participants)
Not Hispanic or Latino	23 100%
Serum Transthyretin (TTR) (mg/L) [Median (Full Range) ]
Median (Full Range) [mg/L]	192.140

Outcome Measures

1. Primary Outcome

Title	Average of Month 6 and Month 12 Percentage Reduction From Baseline in Serum Transthyretin (TTR)
Description	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.
Time Frame	Baseline, Months 6 and 12

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: All participants who received any amount of patisiran.

Arm/Group Title	Patisiran
Arm/Group Description	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.
Measure Participants	22
Median (95% Confidence Interval) [percent reduction]	91.0

2. Secondary Outcome

Title	Change From Baseline in the Neuropathy Impairment Score (NIS) at Month 12
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.
Time Frame	Baseline, Month 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Patisiran
Arm/Group Description	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.
Measure Participants	20
Mean (Standard Error) [score on a scale]	-3.7 (2.7)

3. Secondary Outcome

Title	Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Score at Month 12
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.
Time Frame	Baseline, Month 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Patisiran
Arm/Group Description	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.
Measure Participants	21
Mean (Standard Error) [score on a scale]	-6.5 (4.9)

4. Secondary Outcome

Title	Change From Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 12
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.
Time Frame	Baseline, Month 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Patisiran
Arm/Group Description	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.
Measure Participants	21
Mean (Standard Error) [score on a scale]	-0.1 (1.1)

5. Secondary Outcome

Title	Change From Baseline in the Composite Autonomic Symptom Score (COMPASS-31) at Month 12
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.
Time Frame	Baseline, Month 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Patisiran
Arm/Group Description	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.
Measure Participants	20
Least Squares Mean (Standard Error) [score on a scale]	-5.0 (2.6)

6. Secondary Outcome

Title	Change From Baseline in the Modified Body Mass Index (mBMI) at Month 12
Description	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.
Time Frame	Baseline, Month 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Patisiran
Arm/Group Description	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.
Measure Participants	21
Mean (Standard Error) [(kg/m^2)*(g/L)]	4.4 (21.8)

7. Secondary Outcome

Title	Percentage of Participants With Adverse Events
Description	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.
Time Frame	From baseline to end of study at Month 13

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: All participants who received any amount of patisiran.

Arm/Group Title	Patisiran
Arm/Group Description	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.
Measure Participants	23
Number [percentage of participants]	100 434.8%

Adverse Events

Time Frame	From baseline to end of study at Month 13.
Adverse Event Reporting Description	Safety Analysis Set: All participants who received any amount of patisiran.
Arm/Group Title	Patisiran
Arm/Group Description	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.
All Cause Mortality
	Patisiran
	Affected / at Risk (%)	# Events
Total	0/23 (0%)
Serious Adverse Events
	Patisiran
	Affected / at Risk (%)	# Events
Total	5/23 (21.7%)
Cardiac disorders
Atrial thrombosis	1/23 (4.3%)
Cardiac failure	3/23 (13%)
Hepatobiliary disorders
Cholangitis	1/23 (4.3%)
Immune system disorders
Infusion related reaction	1/23 (4.3%)
Infections and infestations
Pneumonia	1/23 (4.3%)
Urinary tract infection	1/23 (4.3%)
Injury, poisoning and procedural complications
Hip fracture	1/23 (4.3%)
Nervous system disorders
Syncope	1/23 (4.3%)
Renal and urinary disorders
Haematuria	1/23 (4.3%)
Urinary retention	1/23 (4.3%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/23 (4.3%)
Other (Not Including Serious) Adverse Events
	Patisiran
	Affected / at Risk (%)	# Events
Total	23/23 (100%)
Ear and labyrinth disorders
Vertigo	2/23 (8.7%)
Gastrointestinal disorders
Abdominal pain	2/23 (8.7%)
Bile acid malabsorption	2/23 (8.7%)
Diarrhoea	8/23 (34.8%)
General disorders
Asthenia	2/23 (8.7%)
Chest pain	2/23 (8.7%)
Fatigue	3/23 (13%)
Oedema peripheral	5/23 (21.7%)
Pyrexia	3/23 (13%)
Immune system disorders
Infusion related reaction	6/23 (26.1%)
Infections and infestations
Bronchitis	2/23 (8.7%)
Cystitis	2/23 (8.7%)
Urinary tract infection	2/23 (8.7%)
Injury, poisoning and procedural complications
Fall	3/23 (13%)
Skin laceration	2/23 (8.7%)
Musculoskeletal and connective tissue disorders
Back pain	5/23 (21.7%)
Nervous system disorders
Headache	3/23 (13%)
Renal and urinary disorders
Oliguria	2/23 (8.7%)
Vascular disorders
Poor venous access	2/23 (8.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.