Coelho T, Maia L, Martins da Silva A, et al.

Tafamidis for transthyretin familial

amyloid polyneuropathy: a randomized, controlled trial.

Supplementary Material

Classification of Evidence

Does 18 months of treatment with tafamidis 20 mg QD reduce clinical progression in

patients with transthyretin familial amyloid polyneuropathy (TTR-FAP), as measured by

2 primary outcomes, the neuropathy impairment score–lower limbs (NIS-LL) and the

Norfolk quality of life–diabetic neuropathy (QOL-DN) score? This study provides Class II

evidence that 20 mg tafamidis QD was associated with a nonsignificant decrease in

clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the

Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in

peripheral neurologic impairment with tafamidis, which was well tolerated over 18

months.

Methods

This supplemental material provides a description of the outcome measures used for

the coprimary endpoints—NIS-LL and the Norfolk QOL-DN score, and outcome

measures used for the secondary endpoints in the study.

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Neuropathy Impairment Score of the Lower Limb (NIS-LL)

The NIS is a composite clinical scoring system that has been widely used to objectively

assess the severity of peripheral neuropathy. The NIS-LL is a subset of the NIS that

assesses function of the lower limbs, the extremities most affected early in TTR-FAP

disease progression. The NIS-LL quantifies the findings of the neurologic examination

by attributing a score (ranging from 0 [normal] to 88 [total impairment]) to the clinical

abnormalities noted in the physical assessment of sensation, muscle power, and tendon

reflexes. Each component of the NIS-LL measures a different attribute of peripheral

nervous system function, all of which are believed to have merit in the assessment of

the complex system that controls human movement. The components of the NIS-LL

include the following:

 Sensation (touch pressure, pinprick, vibration, joint position). The components of

the sensory examination, except for joint position, are assessed on the dorsal

surface at the base of the right and left great toenails. Joint position is assessed

by moving the terminal phalanx of the right and left great toes. Sensory

assessment is scored as 0 (normal), 1 (decreased), or 2 (absent). As

assessments are performed on the right and left feet, the maximum total score

possible for the sensory component is 16.

 Reflexes (quadriceps femoris, triceps surae [Achilles]). Reflex assessment is

scored as 0 (normal), 1 (decreased), or 2 (absent). Adjustment is made for the

age of the patient (eg, absent reflexes in a patient older than 60 years of age is

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 assessed as 0, or normal). As assessments are performed on the right and left

feet, the maximum total score possible for the reflex component is 8.

 Muscle weakness (hip flexion, hip extension, knee flexion, knee extension, ankle

dorsiflexors, ankle planter flexors, toe extensors, toe flexors). Muscle weakness

is scored as 0 (normal), 1 (25% weak), 2 (50% weak), 3 (75% weak), 3.25 (move

against gravity), 3.5 (movement, gravity eliminated), 3.75 (muscle flicker, no

movement), or 4 (paralysis). As assessments are performed on the right and left

lower extremities, the maximum total score possible for the muscle component is

64.

Norfolk QOL-DN

The Norfolk QOL-DN is a self-administered questionnaire that quantifies the impact of

neuropathy on patients’ QOL. The 35 scored questions are numbered items that

comprise the entire (total) scale, or TQOL, to yield a score of –2 to 138. Each item is

attributed to 1 of the following 5 domains:

 Physical functioning/large-fiber neuropathy. Functions related to large-nerve

fibers, including motor function, and those sensory functions related to large

sensory fibers, especially tactile discrimination.

 Activities of daily living (ADLs). Items associated with the impact of neuropathy

on routine activities of daily life, related to large-fiber function.

 Symptoms. An inventory of the common symptoms of neuropathy at each of 4

body sites (feet, legs, hands, and arms).

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  Small-fiber neuropathy. Sensory function related to pain and loss of thermal

sensation.

 Autonomic nerve function. Neuropathy-related items, including orthostasis,

gastrointestinal, and genitourinary functions.

The scores across the 5 domains are summed to provide the TQOL score. The Norfolk

QOL-DN was shown to discriminate the presence of neuropathy and distinguish among

5 neuropathic disease stages in a population of German patients with diabetic

polyneuropathy.e1 The Norfolk QOL-DN underwent linguistic validation for each country

and language.

Summated 7-nerve tests–normal deviates (Σ7 NTs nds)

The Σ7 NTs nds combines results from 5 nerve conduction studies (sural nerve sensory

nerve action potential, peroneal nerve compound muscle action potential, peroneal

nerve motor conduction velocity, peroneal nerve distal motor latency, and tibial distal

motor latency) with vibration detection threshold (VDT) of the hallux, and heart rate

response to deep breathing (HRDB) at 6 breaths/minute. The components of the Σ7

NTs nds are primarily measures of large-fiber function. The score ranges from –26

(extreme normal function) to 26 (extreme abnormal function). HRDB is a sensitive

measure of parasympathetic cardiac control, and normative values by age have been

determined.

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Summated 3-nerve tests–small-fiber normal deviates (Σ3 NTSF nds)

The Σ3 NTSF nds includes 3 assessments of small-fiber function: cooling detection

threshold (CDT), heat/pain detection threshold (HPDT), and HRDB. All were assessed

using the Computer Aided Sensory Evaluator V4, a computerized test of sensory

threshold determination. The thermal sensations of cooling and heat pain assess small

myelinated and unmyelinated sensory nerve function. The score ranges from –11.2

(extreme normal function) to 11.2 (extreme abnormal function).

Modified body mass index (mBMI)

mBMI is obtained by multiplying the BMI (weight [kg]/height2 [m2]) by serum albumin

concentration (g/L). As an endpoint, mBMI may be more reflective of nutritional status

than BMI because it corrects for the effect of edema due to low serum albumin level on

BMI.e2

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Table e-1. Patient demographics and baseline data

Tafamidis Placebo

Characteristic (n = 64) (n = 61)

Men, n (%) 32 (50) 26 (43)

Age, yr

Mean ± SD 39.8 ± 12.7 38.4 ± 12.9

Race/ethnicity, n (%)

Caucasian 56 (88) 54 (89)

Latino 6 (9) 6 (10)

Other 2 (3) 1 (2)

mBMI (BMI × serum

albumin)

Mean ± SD 1004.6 ± 165.20 1011.5 ± 212.92

Median 974.7 983.8

25th, 75th percentile 867.2, 1155.1 896.4, 1094.7

Disease duration, mo

Mean ± SD 47.0 ± 48.40 34.7 ± 32.88

Median 28.0 21.0

25th, 75th percentile 13.8, 41.7 13.5, 72.2

NIS-LL (range, 0–88)

Mean ± SD 8.4 ± 11.40 11.4 ± 13.54

Median 4.0 6.0

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 25th, 75th percentile 0.0, 13.0 2.0, 9.3

Norfolk QOL-DN (TQOL)

(range, –2 to 138)

Mean ± SD 27.3 ± 24.17 30.8 ± 26.7

Median 19.0 22.0

25th, 75th percentile 11.0, 40.0 10.0, 43.5

Σ7 NTs nds (large-fiber

range, –26 to 26)

Mean ± SD 7.8 ± 9.1 8.7 ± 8.5

Median 7.4 9.7

25th, 75th percentile 1.0, 15.0 1.0, 15.0

Σ3 NTSF nds (small-fiber

range, –11.2 to 11.2)

Mean ± SD 5.5 ± 4.5 5.6 ± 4.1

Median 4.8 5.0

25th, 75th percentile 1.8, 11.2 2.0, 9.1

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 Table e-2. Most common AEs.*

Tafamidis Placebo

(n = 65) (n = 63)

Event Subjects, n (%)

Subjects with ≥1 AE 60 (92.3) 61 (96.8)

Diarrhea 17 (26.2) 11 (17.5)

Urinary tract infection 15 (23.1) 8 (12.7)

Pain in extremity 11 (16.9) 6 (9.5)

Influenza 10 (15.4) 9 (14.3)

Headache 10 (15.4) 12 (19.0)

Nasopharyngitis 9 (13.8) 8 (12.7)

Upper abdominal pain 8 (12.3) 2 (3.2)

Nausea 8 (12.3) 8 (12.7)

Vomiting 7 (10.8) 8 (12.7)

Lacrimation decreased 6 (9.2) 7 (11.1)

Myalgia 5 (7.7) 2 (3.2)

Punctate keratitis 5 (7.7) 3 (4.8)

Back pain 5 (7.7) 4 (6.3)

Vaginal infection 4 (6.2) 1 (1.6)

Peripheral edema 4 (6.2) 8 (12.7)

Constipation 4 (6.2) 7 (11.1)

Pharyngitis 4 (6.2) 5 (7.9)

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 Upper respiratory tract infection 4 (6.2) 3 (4.8)

Thermal burn 4 (6.2) 5 (7.9)

Anxiety 4 (6.2) 3 (4.8)

Depression 4 (6.2) 3 (4.8)

Erectile dysfunction 4 (6.2) 4 (6.3)

Paresthesia 3 (4.6) 10 (15.9)

Abdominal pain 3 (4.6) 5 (7.9)

Weight decreased 3 (4.6) 5 (7.9)

Vertigo 3 (4.6) 4 (6.3)

Neuralgia 2 (3.1) 12 (19.0)

Pharyngolaryngeal pain 2 (3.1) 7 (11.1)

Muscle spasms 2 (3.1) 7 (11.1)

AV block, first degree 2 (3.1) 6 (9.5)

Dizziness 2 (3.1) 4 (6.3)

Hypoesthesia 1 (1.5) 4 (6.3)

Fatigue 0 (0.0) 6 (9.5)

Anemia 0 (0.0) 5 (7.9)

*Reported by >5% of subjects in either treatment group.

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Figure e-1. Patient disposition and analysis populations. AE = adverse event; I/E =

inclusion/exclusion criteria; ITT = intent-to-treat; VDT = vibration detection threshold.

e-References

1. Vinik EJ, Paulson JF, Ford-Molvik SL, Vinik AI. German-translated Norfolk quality

of life (QOL-DN) identifies the same factors as the English version of the tool and

discriminates different levels of neuropathy severity. J Diabetes Sci Technol

2008;2:1075-1086.

2. Suhr O, Danielsson A, Holmgren G, Steen L. Malnutrition and gastrointestinal

dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy. J

Intern Med 1994;235:479-485.

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