eTable. Treatment approaches and selected study results in ATTR amyloidosis.

Substance/study		Design	Population/observation period	Endpoints	Effects and spread [95% confidence interval]	Adverse events	Licensing status
Tafamidis	Coelho et al. 2012 (NCT00409175) (35)	Phase II/III, multicenter, double-blind, placebo-controlled, 1:1 randomization (tafamidis 20 mg/d vs. placebo)	128 pat. (18–75 y) with early-stage neurological manifestation of ATTR amyloidosis and positivity for Val30Met mutation – n = 162 pat. screened – n = 128 pat. randomized (n = 65 tafamidis, n = 63 placebo) – 13 pat./arm received LTX – n = 19 drop-outs before 12 months – Intention-to-treat population (ITT) n = 125 – Population analyzable regarding efficacy (EE) n = 87 – Observation period 18 months	Primary: 1. Percentage of responders measured using NIS-LL at 18 months; response: improvement or stabilization (change by <2 points compared with baseline) 2. Changes in Norfolk QOL-DN Total Quality of Life (TQOL) score at 18 months compared with baseline Secondary: 1. Changes in NIS-LL at 6, 12, 18 months compared with baseline 2. Percentage of responders measured using NIS-LL at 6 and 12 months 3. Changes in Norfolk QOL-DN Total Quality of Life (TQOL) score at 6 and 12 months compared with baseline 4. Changes in Norfolk QOL-DN Domain score at 6, 12 and 18 months compared with baseline 5. Change in Summated 7 score to determine the function of large nerve fibers at 6, 12 and 18 months compared with baseline 6. Change in NTSFnds (small fibers) at 6, 12 and 18 months compared with baseline 7. Change in mBMI at 6, 12, 18 months compared with baseline 8. Percentage of pat. with stabilized TTR (at 8 weeks, 6, 12, 18 months)	Evaluation of tafamidis vs. placebo – Intention-to-treat analysis: NIS-LL response rate 45.3% vs 29.5%, p = 0.068, NNT 6.3; TQOL 2.0 vs 7.2; p = 0.116 – Per-protocol analysis: NIS-LL response rate 60.0% vs 38.1%, p = 0.041; TQOL 0.1 vs 8.9; p = 0.045 – Secondary endpoints predominantly positive – TTR stabilization in 98% vs. 0%; p <0.0001	AEs with tafamidis similar to placebo – Interruption of study medication 6.2% vs. 4.8% – SAE 9.2% vs. 7.9% – Urinary tract infections in 2 pat. (SAE) in tafamidis arm, no other AE in more than 1 pat. – Death due to LTX-associated complications in 2 pat. (tafamidis) vs. 3 pat. (placebo)	Licensed in Germany for pat. with grade I polyneuropathy in ATTRv amyloidosis
	Coelho et al. 2013 (NCT00791492) (34)	Phase II/III, open-label extension study	Neurological manifestation of ATTR amyloidosis with evidence of Val30Met mutation – n = 86 pat. (tafamidis–tafamidis n = 44; placebo–tafamidis n = 41) – 1 pat. received no treatment – Observation period 12 months	Primary: 1. Percentage of responders measured using NIS-LL at 6 months 2. Percentage of responders measured using NIS-LL at 12 months 3. Changes in Norfolk QOL-DN Total Quality of Life (TQOL) score at 6 months compared with baseline 4. Changes in Norfolk QOL-DN Total Quality of Life (TQOL) score at 12 months compared with baseline Secondary: 1. Changes in NIS-LL at 6 and 12 months compared with baseline 2. Changes in Norfolk QOL-DN Domain score at 6 and 12 months compared with baseline 3. Change in Summated 7 score to determine the function of large nerve fibers at 6 and 12 months compared with baseline 4. Change in NTSFnds (small fibers) at 6 and 12 months compared with baseline 5. Change in mBMI at 6 and 12 months compared with baseline 6. Change in troponin I concentration at 6 weeks, 3, 6, 12 months compared with baseline 7. Change in NT-proBNP concentration at 6 weeks, 3, 6, 12 months compared with baseline 8. Intraepidermal nerve fiber density (baseline) 9. Percentage of pat. with stabilized TTR (6 and 12 months)	Evaluation of tafamidis initially vs. placebo initially – Group with initial verum: stable rate of change from NIS-LL 0.08 ►0.11 months (p = 0.60) and TQOL −0.03 ► 0.25 (p = 0.16) – Group with initial placebo: rate of change from NIS-LL 0.34 ► 0.16/month (p = 0.01), TQOL score 0.61 ► −0.16 (p <0.001) – Pat. with 30 months’ tafamidis treatment had better preservation of neurological function (NIS-LL) (55.9%) – TTR stabilization in 94.1% of pat. with 30 months’ tafamidis treatment (vs. 93.3% in placebo–tafamidis group)	Similar incidence of AEs and SAEs as for placebo, no treatment discontinuations due to AEs	Licensed in Germany for pat. with grade I polyneuropathy in ATTRv amyloidosis; so far only in Japan and USA for ATTR-related cardiomyopathy; licensing in Germany expected in 2020
Tafamidis	ATTR-ACT, Maurer et al. 2018 (NCT01994889) (36)	Phase III, multicenter, double-blind, placebo-controlled, 2 : 1 : 2 randomization (tafamidis 80 mg/d vs. tafamidis 20 mg/d vs. placebo)	441 pat. (18–90 y) with cardiac manifestation of ATTRwt or ATTRv amyloidosis (n = 106) – Tafamidis 20/80 mg: n = 264 (n = 63 ATTRv, n = 201 ATTRwt) – Placebo: n = 177 (n = 43 ATTRv, n = 134 ATTRwt) – Observation period 30 months	Primary: Combination of overall mortality and incidence of cardiovascular-related hospitalization (baseline vs. 30 months) Secondary (baseline vs. 30 months) : 1. Overall mortality 2. Incidence of cardiovascular-related hospitalization 3. Change in walking distance in 6-min walking test 4. Change in KCCQ overall score 5. Cardiovascular-related mortality 6. Percentage of pat. with stabilized TTR at 1 month	Evaluation of tafamidis pooled vs. placebo: – Overall mortality (all-cause): 78 of 264 (29.5%) vs. 76 of 177 (42.9%); hazard ratio 0.70 [0.51; 0.96] – Frequency of cardiovascular hospitalization 0.48 vs. 0.70/year, relative risk ratio 0.68; [0.56; 0.81] – At 30 months, less deterioration in 6-min walking test: 75.7 m [standard error ± 9.2; p <0.001]; first differences at 6 months – At 30 months, less deterioration in KCCQ overall score: 13.7 [standard error ± 2.1; p <0.001]; first differences at 6 months	Safety profile comparable between tafamidis and placebo, previously described increased frequency of diarrhea and urogenital infections not confirmed	Licensed in Germany for pat. with grade I polyneuropathy in ATTRv amyloidosis; so far only in Japan and USA for ATTR-related cardiomyopathy; licensing in Germany expected in 2020
Tolcapone	Gamez et al. 2019 (NCT02191826) (e12)	Phase IIa (proof-of-concept study)	n = 17 – ATTRwt: n = 6; ATTRv (Val30Met): n = 11 – Phase A: single dose 200 mg tolcapone; phase B: 3 × 100 mg tolcapone at 4-h intervals	Primary: TTR stabilization Secondary: 1. Pharmacodynamics (24–32 h) 2. Safety (24 h)	– TTR stabilization in all participants –2 h after administration: TTR stabilization of at least 20% in 82% of pat. from phase A, 93% of pat. from phase B – Phase A: 52% increase in TTR stabilization 2 h after administration with decrease to 23% after 8 h – Phase B: Increase to 39% 2 h after first administration; preserved at 10 h, decrease at 24 h	No SAEs	Not licensed
		No phase-III trials published
AG-10	Judge et al. 2019 (NCT03458130) (e13)	Phase II, randomized, double-blind, placebo-controlled(AG-10 vs. placebo)	Cardiomyopathy in ATTRv/wt amyloidosis – n = 49 – Observation period 28 days	Primary: Safety and tolerance (AEs) Secondary: Pharmacokinetics and pharmacodynamics	Good tolerance, almost complete stabilization		Not licensed
	ATTRIBUTE-CM (NCT03860935)	Phase III, randomized, double-blind, placebo-controlled(AG-10 vs. placebo)	Cardiomyopathy in ATTRv/wt amyloidosis – 510 participants planned	Primary: Walking distance in 6-min walking test at 12 months Overall mortality and frequency of cardiovascular-related hospitalization at 30 months Secondary: 1. Change in KCCQ overall sum scores at 12 months compared with baseline 2. C hange in 6-min walking test at 30 months compared with baseline 3. Change in KCCQ overall sum scores at 30 months compared with baseline 4. Incidence of treatment-associated events (SAE, AEs) within 12 months 5. Incidence of treatment-associated events (SAE, AEs) within 30 months 6. Overall mortality at 30 months 7. Incidence of cardiovascular-related hospitalization within 30 months 8. Cardiovascular-related mortality at 30 months 9. Diverse pharmacodynamic parameters	Study currently recruiting	To be reported	Not licensed
Diflunisal	Berk et al. 2013 (NCT00294671) (e7)	Phase III, double-blind, placebo-controlled, 1:1 randomization (diflunisal 2 × 250 mg vs. placebo)	Pat. with neuronal manifestation of biopsy-confirmed ATTRv amyloidosis (18–75 y) – 130 pat. (n = 64 diflunisal, n = 66 placebo) – Observation period 2 y	Primary: Difference in progression of polyneuropathy between treatments, documented by means of NIS+7 (baseline, at 1 and 2 y) Secondary: 1. Changes in Kumamoto Neurologic Scale compared with baseline (1 and 2 y) 2. mBMI (baseline, at 1 and 2 y) 3. SF-36 Physical Component Score (baseline, at 1 and 2 y) 4. SF-36 Mental Component Score (baseline, at 1 and 2 y)	Placebo vs. diflunisal – NIS + 7 score increase by 25.0 [18. 4; 31.6] vs. 8.7 [3.3; 14.1] points, difference 16.3 [8.1; 24.5] points (p <0.001). – Mean SF-36 Physical Scores decreased by 4.9 [−7.6; −2.2] points with placebo and rose by 1.5 [−0.8; 3.7] points with diflunisal (p <0.001) – Mean SF-36-Mental-Score fell by 1.1 [−4.3; 2.0] points with placebo, rose by 3.7 [1.0; 6.4] points with diflunisal (p = 0.02). – 29.7% of pat. with diflunisal and 9.4% with placebo showed neurological stabilization at 2 y (<2-point increase in nis + 7 score; p = 0.007)	Incidence of gastrointestinal, renal, cardiac and hematological AEs similar to placebo; incidence of musculoskeletal and general AE higher with diflunisal, no higher rate of SAEs, 4 pat. discontinued treatment due to diflunisal-associated AE (gastrointestinal bleeding, cardiac decompensation, glaucoma, nausea) vs. 2 pat. in placebo group (headache, renal failure)	Not licensed
Patisiran	APOLLO, Adams et al. (2018) NCT01969348) (27)	Phase III, multicenter, double-blind, placebo-controlled,2 : 1 randomization (patisiran 0.3 mg/kg vs. placebo every 3 weeks)	Pat. (18–85 y) with neuronal manifestation of ATTRv amyloidosis n = 225, cardiac involvement in n = 126 (56%) – Patisiran n = 148 – Placebo n = 77 – Observation period 18 months	Primary: mNIS + 7 Secondary (changes baseline vs. 18 months): 1. Norfolk QoL-DN Questionnaire 2. Neurological Impairment Score–Weakness (NIS-W) 3. R-ODS score 4. 10-min walking test 5. mBMI 6. „Autonomic Symptoms Questionnaire (Composite Autonomic Symptom Score [COMPASS 31])	Evaluation of patisiran vs. placebo (baseline vs. 18 months): – mNIS + 7 change −6.0 ± 1.7 vs. 28.0 ± 2.6 (difference −34.0 points; p < 0.001) – Change in Norfolk-QoL-DN: −6.7 ±  1.8 vs. 14.4 ± 2.7 (difference −21.1 points; p <0.001) – Change in walking speed in 10-min walking test: 0.08 ± 0.02 m/sec vs. – 0.24 ± 0.04 m/sec (difference 0.31 m/sec; p <0.001) – Change in mBMI: −3.7 ± 9.6 vs. −119.4 ± 14.5 (difference 115.7; p <0.001)	Overall incidence and type of AEs similar for patisiran and placebo, but 20% mild to moderate infusion reactions in patisiran arm vs. 10% in placebo arm	Licensed in Germany for pat. with grade I–II polyneuropathy in ATTRv amyloidosis
Revusiran	ENDEAVOUR (NCT02319005)	Phase II, multicenter, double-blind, placebo-controlled (revusiran vs. placebo)	Pat. (18–90 y) with ATTRv cardiomyopathy, n = 206 – Revusiran n = 140 – Placebo n = 66 – Observation period 18 months	Primary: 1. Distance in 6-min walking test 2. TTR serum level Secondary (changes baseline vs. 18 months): 1. Combination of cardiovascular mortality and cardiovascular-related hospitalization 2. NYHA class 3. KCCQ score 4. Cardiovascular mortality 5. Cardiovascular-related hospitalization 6. Overall mortality		Higher mortality in revusiran arm	Not licensed
Vutrisiran	HELIOS-A (NCT03759379)	Phase III, multicenter, randomized, open-label,3:1 randomization (vutrisiran 25 mg s. c. every 3 months vs. patisiran 0.3 mg/kg every 3 weeks)	ATTRv pat. with neurological involvement – n = 160 planned – Observation period 18 months	Primary: 1. Changes in mNIS + 7 at 9 months compared with baseline 2. Changes in Norfolk QoL-DN overall score at 9 months compared with baseline Secondary: 1. Changes in 10-min walking test at 9 and 18 months compared with baseline 2. Changes in mBMI at 9 and 18 months compared with baseline 3. Changes in R-ODS at 9 and 18 months compared with baseline 4. Percentage reduction of serum TTR level at 9 and 18 months compared with baseline 5. Overall mortality and/or overall hospitalization rate up to month 18 6. Overall mortality and/or overall hospitalization rate of the participants with cardiac involvement up to 18	Study currently recruiting	To be reported	Not licensed
Inotersen	NEURO-TTR Benson et al. 2018 (NCT01737398) (29)	Phase III, multicenter, double-blind, placebo-controlled,2:1 randomization (inotersen 300 mg s.c. vs. placebo)	Pat. (18–82 y) with neuronal manifestation of ATTRv amyloidosis n = 173, cardiac involvement in n = 108 (63%) – Inotersen n = 112 – Placebo n = 60 – 81% without premature discontinuation – 64 weeks; observation period 66 weeks	Primary: 1. Change in mNIS+7 composite score (baseline vs. week 66) 2. Change in Norfolk QoL DN Questionnaire (baseline vs. week 66) Secondary: 1. Changes in Norfolk QoL-DN Symptoms Domain score (baseline vs. week 66) 2. Changes in Norfolk QoL-DN Physical Functioning/Large- Fiber Neuropathy Domain score (baseline vs. week 66) 3. Change in mBMI (baseline vs. week 65) 4. Change in BMI (baseline vs. week 65) 5. Changes in NIS (baseline vs. week 66) 6. Changes in modified+ 7 score (baseline vs. week 66) 7. Changes in NIS + 7 (baseline vs. week 66) 8. Change in GLS (baseline vs. week 65) 9. Change in GLS in cardiomyopathy subgroup (baseline vs. 65 weeks) 10. Changes in TTR level (baseline vs. week 65) 11. Changes in RPB level (baseline vs. week 65) 12. Peak measured inotersen concentration 13. Other pharmacokinetic/pharmacodynamic parameters	– Change in mNIS+7: −19.7 points [−26.4; −13.0]; (p <0.001) – Change in Norfolk QOL-DN score −11.7 points [−18.3; −5.1]; (p <0.001) – Independent of disease stage, mutation type, and possible cardiomyopathy	Glomerulonephritis, thrombocytopenia (3%, 1 pat. died of cerebral hemorrhage due to grade-IV thrombocytopenia) 5 pat. died overall (4 due to underlying disease)	Licensed in Germany for pat. with grade I–II polyneuropathy in ATTRv amyloidosis; phase-III trial for pat. with ATTR cardiomyopathy started
EGCG	Kristen et al. 2012 (e8)	Single-center study	Pat. with ATTR-related cardiomyopathy – n = 19 (ATTRv n = 10, 53%; ATTRwt n = 9, 47%) – EGCG for at least 12 months	Primary: Left-ventricular wall thickness	– Study drop-outs: n = 2 deaths, n = 2 discontinuation of EGCG intake, n = 1 due to heart transplantation – 2 pat. died (heart failure after 1 st month of treatment; multiorgan failure on drainage of a retroperitoneal hematoma after a complicated disease course with several months of intensive care) – Total cholesterol 193 ± 9 (baseline) ►173 ± 9 mg/dL (12 months) (p <0.01); ldl 106 ± 8 ► 90 ± 8 mg/dl (at 12 months) (p <0.01); hdl 59 ± 4 (baseline) ► 55 ± 5 mg/dl (12 months) (p <0.01) – Decrease in septal thickness of 6.5% (p = 0.008): decrease in 12/14 pat. (86%) – Posterior wall unchanged (p = 0.03) – No increase in left ventricular mass (p = 0.084) – Significant improvement in the systolic velocity of the lateral mitral annulus (MASV) (p = 0.022) – Decrease in LV mass of 12.5% (p = 0.004) – LVEF unchanged (56.7 ± 4.7 vs. 57.2 ± 3.7%; ns.)	No SAEs	Not licensed
	aus dem Siepen et al. 2015 (e9)	Single-center study	Pat. with ATTR-related cardiomyopathy (64–80 y) – n = 25 (only ATTRwt) – 600 mg EGCG for at least 12 months	Primary: Left-ventricular mass and ejection fraction (measured on cMRI)	– Decrease in LV mass of 6% on cMRI (196 g [100; 247] vs. 180 g [85; 237]; p = 0.03) – Decrease in total cholesterol of 8.4% (191 [118; 267] vs. 173 [106; 287] mg/dL; p = 0.006) – LVEF stable on cMRI (53% [33%; 69%] vs. 54% [28%; 71%]; p = 0.75) – Echocardiographically documented stable left ventricular wall thickness (17 [13; 21] vs. 18 [14; 25] mm; p = 0.1) – Echocardiographically documented stable MAPSE (10 [5; 23] vs. 8 [4; 13] mm; p = 0.3)	None reported	Not licensed
EGCG	Cappelli et al. 2018 (e10)	Single-center study, retrospective	Pat. with ATTR-related cardiomyopathy – EGCG 675 mg/d for at least 9 months – n = 30 (EGCG: ATTRwt n = 21, ATTRv n = 9) vs. n = 35 (control group: ATTRwt n = 30, ATTRv n = 5)	Primary: Overall mortality	– No survival advantage with EGCG (60 ± 15% [EGCG] vs. 61 ± 12% [placebo], p = 0.276)	Study discontinuation due to diarrhea in 2 pat., no other AEs	Not licensed
Doxycycline	(NCT03481972)	Phase III, randomization, open- label study (doxycycline/TUDCA vs. standard care)	Cardiomyopathy in ATTRwt and ATTRv – 102 participants planned – Observation period 30 months	Primary: Efficacy of doxycycline/TUDCA Overall mortality at 18 months Secondary: Overall mortality at 18 and 30 months	Study currently recruiting	To be reported	Not licensed
	Obici et al. 2012 (e11) (NCT01171859)	Phase II, single center, open-label study (doxycycline 2 × 100 mg/TUDCA 250 mg 3 ×/d)	Pat. with symptomatic neuronal or cardiac manifestation of ATTR amyloidosis (>18 y) – 20 pat. included – Observation period 12 months	Primary: Treatment response (defined as mBMI reduction <10% and nis-ll change  <2 [in pnp] or nt-probnp increase <30% or 300 pg/ml [in isolated cardiomyopathy]) Secondary: 1. Safety and tolerance (hematological, hepatic, renal) 2. SF-36 3. Response regarding autonomic dysfunction, sensorimotor peripheral neuropathy and visceral organ involvement 4. Echocardiographic parameters 5. Doxycycline pharmacokinetics 6. Nerve conduction velocity, study discontinuation due to clinical and laboratory AEs	– 7 pat. tolerated 12 months, 10 pat. 6 months of treatment; 2 treatment discontinuations within first 2 months; 1 pat. lost during follow-ups – Therapeutic doxycycline doses documented at 6 months (7 ± 2.4 ug/mL), mean increase to 1.3 ug/mL 2 h after intake – Primary endpoint: PNP n = 6, 12 months’ treatment: NIS-LL >2 in 1 pat., NIS-LL stable in 4 pat., improvement in 1 pat. with stable mBMI – Cardiomyopathy subset (n = 7), 12 months’ treatment: NT-proBNP increased in 3 pat., stable in 4 pat.; echocardiographically stable in 5 pat., improved in 2 pat.; no change in NYHA class – Increasing improvement in QoL at 6 and 12 months (PCS and MCS, not statistically significant) – Kumamoto score at 6 and 12 months worse in 1 pat., better in 1 pat., and stable in 4 pat.	No SAEs; stomach ache, persistent nausea, loss of appetite	Not licensed

AEs, Adverse events; cMRI, cardiac magnetic resonance imaging; EGCG, epigallocatechin-3-gallate; GLS, global longitudinal strain; KCCQ, Kansas City Cardiomyopathy Questionnaire; LTX, liver transplantation; LVEF, left ventricular ejection fraction; MAPSE, mitral annular plane systolic excursion; mBMI, modified body mass index; MCS, mental component scale; mNIS + 7, modified seven-item neuropathy impairment score; NIS-LL, neuropathy impairment score in the lower limbs; NNT, number needed to treat; Norfolk QoL-DN, Norfolk quality of life-diabetic neuropathy; Norfolk QOL-DN TQOL score, Norfolk QOL-DN Total Quality of Life score; NT-pro BNP, N-terminal pro brain natriuretic peptide; NTSFnds, Summated 3 score for small nerve fiber function; pat., patient(s); PCS, physical component scale; PNP, peripheral polyneuropathy; R-ODS, Rasch-built overall disability scale, SAEs, severe adverse events; SF-36, 36-item short form quality of life questionnaire; Summated 7 score, Summated 7 score for large nerve fiber function; y, years;