The Study of an Investigational Drug, Patisiran (ALN-TTR02), for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis in Participants Who Have Already Been Treated With ALN-TTR02 (Patisiran)

• Patisiran (Drug), also known as ALN-TTR02: Patisiran was administered IV.

Primary outcomes

• Percentage of Participants With Adverse Events (AEs) Leading to Study Discontinuation [First dose up to 28 days after last dose of study drug (approximately 5.6 years)]: AE is any untoward medical occurrence in a participant or clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.

Secondary outcomes

• Change From Baseline in the Total Neuropathy Impairment Score (NIS) at Year 5 [Baseline, Year 5]: The NIS assessment is a 244-point composite measure of neurologic impairment which includes a physical exam of lower limbs, upper limbs, and cranial nerves to assess the components: motor strength/weakness (NIS-W), reflexes (NIS-R), and sensation (NIS-S). NIS total score is obtained by combining all the component scores, ranging from 0 to 244. Higher scores represent a greater severity of disease. A positive change from baseline indicates the worsening of neuropathy.
• Change From Baseline in the Total Modified NIS (mNIS +7) Composite Score At Year 3 [Baseline, Year 3]: The mNIS+7 is a composite measure of neurologic impairment which includes the following components: physical exam of lower limbs, upper limbs, and cranial nerves to assess motor strength/weakness (192 points), reflexes (20 points), electrophysiologic measurement of small and large nerve fiber function (10 points), sensory testing (80 points), and postural blood pressure (2 points). The total mNIS+7 composite score is obtained by combining all the component scores, ranging from 0 (no impairment) to 304 (maximum impairment). A negative change from baseline indicates an improvement in neuropathy.
• Change From Baseline in the NIS+7 Total Score at Week 52 [Baseline, Week 52]: The NIS+7 provides additional, objective measures of nerve fibre function and autonomic nerve function in participants with diabetic neuropathy. The NIS+7 includes the full NIS, sum of 5 nerve conduction studies (NCS) (Sural sensory nerve action potential \[SNAP\], tibial motor nerve distal latency, peroneal compound motor action potential \[CMAP\], motor nerve conduction velocity, motor nerve distal latency), vibration detection threshold, and pulse rate response to deep breathing. The total NIS+7 score is obtained by combining all the component scores, ranging from 0 (no impairment) to 270 points (maximum impairment). A positive change from baseline indicates worsening.
• Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) Questionnaire Total Score at Year 5 [Baseline, Year 5]: The Norfolk QoL-DN questionnaire is a standardized 47-item patient-reported outcomes measure, sensitive to the perception of the effects of diabetic neuropathy by the participant. The scores range from -4 (best possible QOL) to 136 (worst possible QOL). A negative change from baseline represents improved QOL.
• Change From Baseline in the EuroQOL-5 Dimensions-5 Levels (EQ-5D-5L) Index Score at Year 5 [Baseline, Year 5]: The EQ-5D-5L is a patient-reported measure of QoL based on 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The overall score is rated on a scale from 0 (worst) to 1 (no impairment). Higher scores indicate a higher QoL. A negative change from baseline indicates worsening of QoL.
• Change From Baseline in the EuroQoL Visual Analogue Scale (EQ-VAS) Score at Year 5 [Baseline, Year 5]: EQ-VAS measures the participant's self-rated health on a vertical scale evaluated on a scale of 0 ("worst health you can imagine") to 100 ("best health you can imagine"). Higher scores indicate a higher QOL. A negative change from baseline indicates worsening of QoL.
• Change From Baseline in the Composite Autonomic Symptom Score (COMPASS 31) Total Score at Week 52 [Baseline, Week 52]: COMPASS 31 questionnaire measures autonomic symptoms in participants with neuropathy. The questionnaire consists of 31 clinically selected questions evaluating 6 autonomic domains (orthostatic intolerance, secretomotor, gastrointestinal, bladder, and pupillomotor). COMPASS 31 is measured on a scale from 0 to 100, with 100 representing maximum impairment.
• Change From Baseline in the Modified Body Mass Index (mBMI) at Year 5 [Baseline, Year 5]: Nutritional status of participants was evaluated using the mBMI, calculated as BMI (kilograms per square meter \[kg/m\^2\]) multiplied by the concentration of serum albumin (grams per liter \[g/L\]). A positive change from baseline indicates improvement in nutritional status.
• Change From Baseline in the Rasch-built Overall Disability Scale (R-ODS) at Year 5 [Baseline, Year 5]: The R-ODS is a 24-item patient-reported questionnaire that specifically captures activity and social participation limitations. It measures the level of disability on a scale of 0 (worst) to 48 (best, no limitations), higher score indicates a better outcome. A negative change from baseline indicates worsening of disability.
• Change From Baseline in the NIS+7 Component: NIS-Weakness (NIS-W) Score at Year 5 [Baseline, Year 5]: The NIS+7 provides additional, objective measures of nerve fiber function and autonomic nerve function in participants with diabetic neuropathy. The NIS+7 includes the full NIS (NIS-W, NIS-R, NIS-S), sum of 5 nerve conduction studies (NCS) (Sural SNAP, tibial motor nerve distal latency, peroneal CMAP, motor nerve conduction velocity, motor nerve distal latency), vibration detection threshold, and pulse rate response to deep breathing. NIS-W is a measure of motor strength, comprised of cranial nerve and both upper and lower limb motor assessments. The score ranges from 0 to 192. A higher score indicates greater severity of disease.
• Change From Baseline in the 10-meter Walk Test (10-MWT) Speed at Year 5 [Baseline, Year 5]: 10-MWT is a measure of ambulatory ability and walk speed. It measures the speed (in meters per second \[m/s\]) of a participant to walk 10 meters. A negative change from baseline represents decreased ambulatory ability.
• Change From Baseline in the Hand Grip Strength at Week 52 [Baseline, Week 52]: Hand grip strength was measured by dynamometer. Grip strength in the dominant arm is a measure of motor function, with a higher grip strength indicating better motor function. The mean change from baseline in the hand grip strength was reported.
• Number of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Stage [Baseline, Year 5]: PND measures changes in the ambulatory ability including the need of walking aids on the following stages: 0 (no symptoms), I (sensory disturbances but preserved walking capability), II (impaired walking capability but ability to walk without a stick or crutches), IIIA (walking with help of 1 stick/crutch), IIIB (with help of 2 sticks/crutches), and IV (confined to wheelchair or bedridden). Lower scores indicate greater ambulatory function. The number of participants with change in the stage from baseline was reported as: Improved or worsened.
• Number of Participants With Change From Baseline in the Familial Amyloidotic Polyneuropathy (FAP) Stage [Baseline, Year 5]: FAP measures changes in the ambulatory ability including the need of walking aids on the following stages: 0 (no symptoms), I (unimpaired ambulation; mostly mild sensory, motor, and autonomic neuropathy in the lower limbs), II (assistance with ambulation required; moderate impairment of the lower limbs, upper limbs, and trunk), and III (wheelchair-bound or bedridden; severe sensory, motor, and autonomic involvement of all limbs). Lower scores indicate greater ambulatory function. The number of participants with change in the stage from baseline was reported as: Improved or worsened.
• Number of Participants With Change From Baseline in the New York Heart Association (NYHA) Classification [Baseline, Year 5]: NYHA classification grades the severity of heart failure symptoms into the following stages: I (no symptoms; ordinary physical activity such as walking and climbing stairs does not cause fatigue or dyspnea), II (symptoms with ordinary physical activity; walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, in cold weather, in wind or when under emotional stress causes undue fatigue or dyspnea), III (symptoms with less than ordinary physical activity; walking 1 to 2 blocks on the level and climbing more than 1 flight of stairs in normal conditions causes undue fatigue or dyspnea), IV (symptoms at rest; inability to carry on any physical activity without fatigue or dyspnea). The number of participants with change in the stage from baseline was reported as: Improved or worsened.
• Change From Baseline in the Intraepidermal Nerve Fiber Density (IENFD) at Year 5 [Baseline, Year 5]: IENFD (fibers/millimeter \[mm\]) is a measure for the pathologic evaluation of sensory and autonomic innervation. It is obtained by tandem 3 mm skin punch biopsies: one set of biopsies taken from the distal thigh and one set from the distal lower leg. An increase in nerve fiber density suggests improvement, while a decrease in nerve fiber density suggests worsening.
• Change From Baseline in the Sweat Gland Nerve Fiber Density (SGNFD) at Year 5 [Baseline, Year 5]: SGNFD (meter/cubic millimeter \[m/mm\^3\]) is a measure for the pathologic evaluation of sensory and autonomic innervation. It is obtained by tandem 3 mm skin punch biopsies: one set of biopsies taken from the distal thigh and one set from the distal lower leg. An increase in nerve fiber density suggests improvement, while a decrease in nerve fiber density suggests worsening.
• Change From Baseline in the Dermal Amyloid Burden at Year 5 [Baseline, Year 5]: Dermal Amyloid Burden is a measure for the pathologic evaluation of sensory and autonomic innervation and reported as % congo red stain. It is obtained by tandem 3 mm skin punch biopsies: one set of biopsies taken from the distal thigh and one set from the distal lower leg.
• Change From Baseline in the Cardiac Biomarker: Serum Troponin I at Year 5 [Baseline, Year 5]: Manifestations of cardiac amyloid involvement were assessed through measurement of serum levels of the cardiac biomarker: troponin (micrograms per liter \[µg/L\]). The troponin I values <0.1 μg/L were imputed to 0.1 thus the actual changes cannot be calculated for values <0.1 μg/L.
• Change From Baseline in the Cardiac Biomarker: N-terminal Prohormone of B-type Natriuretic Peptide (NT-proBNP) at Year 5 [Baseline, Year 5]: Manifestations of cardiac amyloid involvement were assessed through measurement of serum levels of the cardiac biomarker: NT-proBNP (nanograms per liter \[ng/L\]).
• Change From Baseline in the Echocardiogram Parameter: Average Peak Longitudinal Strain at Year 5 [Baseline, Year 5]: The echocardiogram parameters analyzed included measures of systolic function: Average peak longitudinal strain (percentage \[%\]).
• Change From Baseline in the Echocardiogram Parameter: Left Ventricular (LV) Mass at Year 5 [Baseline, Year 5]: The echocardiogram parameters analyzed included measures of cardiac structure: LV mass (grams \[g\]).
• Change From Baseline in the Echocardiogram Parameter: LV End-diastolic Volume at Year 5 [Baseline, Year 5]: The echocardiogram parameters analyzed included measures of diastolic function: LV end-diastolic volume (milliliters \[mL\]).
• Change From Baseline in the Echocardiogram Parameter: LV Relative Wall Thickness at Year 5 [Baseline, Year 5]: The echocardiogram parameters analyzed included measures of cardiac structure: LV relative wall thickness (ratio).
• Change From Baseline in the Echocardiogram Parameter: Mean LV Wall Thickness at Year 5 [Baseline, Year 5]: The echocardiogram parameters analyzed included measures of cardiac structure: Mean LV wall thickness (centimeters \[cm\]).
• Change From Baseline in the Echocardiogram Parameter: Cardiac Output at Year 5 [Baseline, Year 5]: The echocardiogram parameters analyzed included measures of systolic function: Cardiac output (liters per minute \[L/min\]).
• Percent Change From Baseline in Serum TTR Levels at Year 5 [Baseline, Year 5]: Serum TTR was assessed using enzyme linked immunosorbent assay (ELISA).

Sex: All, ages: 18 Years to 85 Years

Inclusion Criteria:

* Have completed a patisiran study (i.e., completed the last efficacy visit in the parent study) and, in the opinion of the investigator, tolerated study drug
* Be willing and able to comply with the protocol-required visit schedule and visit requirements and provide written informed consent

Exclusion Criteria:

* Any new or uncontrolled condition that could make the participant unsuitable for participation

Participant flow

Outcome results

• Percentage of Participants With Adverse Events (AEs) Leading to Study Discontinuation (Primary), Number, percentage of participants: Prior Placebo Group of Study 004 49.0; Prior Patisiran Group of Study 004 16.8; Prior Patisiran Group of Study 003 0.0
• Change From Baseline in the Total Neuropathy Impairment Score (NIS) at Year 5 (Secondary), Mean, score on a scale: Prior Placebo Group of Study 004 81.47 +/- 41.674; Prior Patisiran Group of Study 004 62.26 +/- 37.875; Prior Patisiran Group of Study 003 35.48 +/- 28.686
• Change From Baseline in the Total Modified NIS (mNIS +7) Composite Score At Year 3 (Secondary), Mean, score on a scale: Prior Placebo Group of Study 004 101.07 +/- 43.774; Prior Patisiran Group of Study 004 74.72 +/- 42.584; Prior Patisiran Group of Study 003 45.66 +/- 31.640
• Change From Baseline in the NIS+7 Total Score at Week 52 (Secondary), Mean, score on a scale: Prior Placebo Group of Study 004 98.42 +/- 42.281; Prior Patisiran Group of Study 004 78.74 +/- 39.417; Prior Patisiran Group of Study 003 49.66 +/- 31.319
• Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) Questionnaire Total Score at Year 5 (Secondary), Mean, score on a scale: Prior Placebo Group of Study 004 72.7 +/- 28.10; Prior Patisiran Group of Study 004 54.5 +/- 30.87; Prior Patisiran Group of Study 003 34.0 +/- NA
• Change From Baseline in the EuroQOL-5 Dimensions-5 Levels (EQ-5D-5L) Index Score at Year 5 (Secondary), Mean, score on a scale: Prior Placebo Group of Study 004 0.4614 +/- 0.03347; Prior Patisiran Group of Study 004 0.6444 +/- 0.01856; Prior Patisiran Group of Study 003 0.7663 +/- 0.03336
• Change From Baseline in the EuroQoL Visual Analogue Scale (EQ-VAS) Score at Year 5 (Secondary), Mean, score on a scale: Prior Placebo Group of Study 004 46.0 +/- 2.86; Prior Patisiran Group of Study 004 57.8 +/- 1.82; Prior Patisiran Group of Study 003 69.1 +/- 4.20
• Change From Baseline in the Composite Autonomic Symptom Score (COMPASS 31) Total Score at Week 52 (Secondary), Mean, score on a scale: Prior Placebo Group of Study 004 33.92 +/- 18.185; Prior Patisiran Group of Study 004 25.37 +/- 17.010; Prior Patisiran Group of Study 003 15.93 +/- 15.116
• Change From Baseline in the Modified Body Mass Index (mBMI) at Year 5 (Secondary), Mean, kg.g/m^2.L: Prior Placebo Group of Study 004 881.8 +/- 219.10; Prior Patisiran Group of Study 004 970.7 +/- 218.40; Prior Patisiran Group of Study 003 1002.3 +/- 173.80
• Change From Baseline in the Rasch-built Overall Disability Scale (R-ODS) at Year 5 (Secondary), Mean, score on a scale: Prior Placebo Group of Study 004 20.3 +/- 12.74; Prior Patisiran Group of Study 004 29.7 +/- 12.56; Prior Patisiran Group of Study 003 36.7 +/- 10.29
• Change From Baseline in the NIS+7 Component: NIS-Weakness (NIS-W) Score at Year 5 (Secondary), Mean, score on a scale: Prior Placebo Group of Study 004 47.01 +/- 31.323; Prior Patisiran Group of Study 004 33.26 +/- 27.434; Prior Patisiran Group of Study 003 15.02 +/- 17.988
• Change From Baseline in the 10-meter Walk Test (10-MWT) Speed at Year 5 (Secondary), Mean, m/s: Prior Placebo Group of Study 004 0.538 +/- 0.0553; Prior Patisiran Group of Study 004 0.851 +/- 0.0422; Prior Patisiran Group of Study 003 1.262 +/- 0.0826
• Change From Baseline in the Hand Grip Strength at Week 52 (Secondary), Mean, kg: Prior Placebo Group of Study 004 10.23 +/- 1.293; Prior Patisiran Group of Study 004 18.03 +/- 1.081; Prior Patisiran Group of Study 003 27.86 +/- 2.626
• Number of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Stage (Secondary), Count of participants, Participants: Prior Placebo Group of Study 004 1; Prior Patisiran Group of Study 004 9; Prior Patisiran Group of Study 003 3
• Number of Participants With Change From Baseline in the Familial Amyloidotic Polyneuropathy (FAP) Stage (Secondary), Count of participants, Participants: Prior Placebo Group of Study 004 0; Prior Patisiran Group of Study 004 3; Prior Patisiran Group of Study 003 1
• Number of Participants With Change From Baseline in the New York Heart Association (NYHA) Classification (Secondary), Count of participants, Participants: Prior Placebo Group of Study 004 2; Prior Patisiran Group of Study 004 13; Prior Patisiran Group of Study 003 1
• Change From Baseline in the Intraepidermal Nerve Fiber Density (IENFD) at Year 5 (Secondary), Mean, fibers/mm: Prior Placebo Group of Study 004 4.71 +/- 5.249; Prior Patisiran Group of Study 004 5.41 +/- 5.291; Prior Patisiran Group of Study 003 8.99 +/- 10.027
• Change From Baseline in the Sweat Gland Nerve Fiber Density (SGNFD) at Year 5 (Secondary), Mean, m/mm^3: Prior Placebo Group of Study 004 10.82 +/- 6.638; Prior Patisiran Group of Study 004 9.67 +/- 4.942; Prior Patisiran Group of Study 003 9.14 +/- 4.802
• Change From Baseline in the Dermal Amyloid Burden at Year 5 (Secondary), Mean, percent congo red stain: Prior Placebo Group of Study 004 8.163 +/- 10.6544; Prior Patisiran Group of Study 004 8.205 +/- 10.8725; Prior Patisiran Group of Study 003 5.908 +/- 7.6646
• Change From Baseline in the Cardiac Biomarker: Serum Troponin I at Year 5 (Secondary), Mean, µg/L: Prior Placebo Group of Study 004 0.109 +/- 0.0360; Prior Patisiran Group of Study 004 0.112 +/- 0.0963; Prior Patisiran Group of Study 003 0.088 +/- 0.0263
• 8 more outcome measures not shown.

Adverse events

Time frame: First dose up to 28 days after last dose of study drug (approximately 5.6 years)

Serious adverse events by term

160 more terms not shown.

Other adverse events by term

51 more terms not shown.

• Results publication: Adams D, Wixner J, Polydefkis M, Berk JL, Conceicao IM, Dispenzieri A, Peltier A, Ueda M, Bender S, Capocelli K, Jay PY, Yureneva E, Obici L; patisiran Global OLE study group. Five-Year Results With Patisiran for Hereditary Transthyretin Amyloidosis With Polyneuropathy: A Randomized Clinical Trial With Open-Label Extension. JAMA Neurol. 2025 Mar 1;82(3):228-236. doi: 10.1001/jamaneurol.2024.4631. PMID 39804640
• Results publication: Lin KP, Yang CC, Lee YC, Lee MJ, Vest J, Sweetser MT, White MT, Badri P, Hsieh ST, Chao CC. Patisiran, an RNAi therapeutic for hereditary transthyretin-mediated amyloidosis: Sub-analysis in Taiwanese patients from the APOLLO study. J Formos Med Assoc. 2024 Sep;123(9):975-984. doi: 10.1016/j.jfma.2024.03.008. Epub 2024 Mar 27. PMID 38548524
• Results publication: Adams D, Polydefkis M, Gonzalez-Duarte A, Wixner J, Kristen AV, Schmidt HH, Berk JL, Losada Lopez IA, Dispenzieri A, Quan D, Conceicao IM, Slama MS, Gillmore JD, Kyriakides T, Ajroud-Driss S, Waddington-Cruz M, Mezei MM, Plante-Bordeneuve V, Attarian S, Mauricio E, Brannagan TH 3rd, Ueda M, Aldinc E, Wang JJ, White MT, Vest J, Berber E, Sweetser MT, Coelho T; patisiran Global OLE study group. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Lancet Neurol. 2021 Jan;20(1):49-59. doi: 10.1016/S1474-4422(20)30368-9. Epub 2020 Nov 16. PMID 33212063

• Study Protocol (PDF, 2017-05-02)
• Statistical Analysis Plan (PDF, 2017-07-12)

• Medical Director, Study director, Alnylam Pharmaceuticals

NIH grants: 2014