The impact of clinical heterogeneity on conducting network meta-analyses in transthyretin amyloidosis with polyneuropathy

Figures & data

Table 1. Study designs and interventions investigated in ATTR-PN trials.

Study	Phase	Study design	Sample Size^a	Intervention			Comparator
				Treatment	Dose	Regimen	Treatment	Regimen
Fx-005	II/III	RCT, DB, active comparator, PC	128	Tafamidis (Vyndaqel)	20 mg	PO, qd	Placebo	PO, qd
APOLLO	III	RCT, DB, active comparator, PC	225	Patisiran (Onpattro) with steroids	0.3 mg/kg body weight	IV, q3w	Placebo with steroids	IV, q3w
NEURO-TTR	II/III	RCT, DB, active comparator, PC	173	Inotersen (Tegsedi)	300 mg	SC, q1w (3 doses in week 1)	Placebo	SC, q1w (3 doses in week 1)

^aRandomized patients.

Abbreviations. DB, Double blind; IV, Intravenous; PC, Placebo-controlled; PO, Oral; q1w, Once weekly; q3w, Once every 3 weeks; qd, Once daily; RCT, Randomized controlled trial; SC, Subcutaneous.

Table 2. Summary of key eligibility criteria in ATTR-PN trials.

Study	Population	Age range (years)	Mutation in TTR	Previous treatment for ATTR-PN	Karnofsky performance status^c (0–100)	Previous liver transplantation
Fx-005	ATTR-PN (Stages undefined)	18–75	Val30Met	No history of chronic NSAID use (defined as >3–4 uses per month)^a	≥50	Excluded
APOLLO	ATTR-PN (Stages undefined)	18–85	Mixed	Washout (3 months) for antisense oligonucleotide therapy^b Washout (2 weeks) for diflunisal, tafamidis, doxycycline or tauroso-deoxycholic acid	≥60	Excluded
NEURO-TTR	ATTR-PN (Stages 1 and 2)	18–82	Mixed	Washout (2 weeks) for tafamidis or diflunisal	≥50	Excluded

^aThis criterion applies to patients prescribed the NSAID and TTR stabilizer diflunisal prior to enrollment.

^bIncludes inotersen (the active drug in the NEURO-TTR trial).

^cClassifies functional impairment, where a score of 100 represents no evidence of disease and a score of 0 represents death³¹.

Abbreviations. ATTR-PN, Transthyretin amyloidosis with polyneuropathy; NSAID, Non-steroidal anti-inflammatory drug; TTR, Transthyretin; Val30Met, Valine to methionine point mutation at position 30.

Figure 1. Evidence networks in ATTR-PN trials. (A) Network of RCTs for the Norfolk TQOL and safety outcomes (any adverse events, serious adverse events, and withdrawals due to adverse events). (B) Network of RCTs for the mBMI outcome. Abbreviations. INO, Inotersen; mBMI, Modified body mass index; PAT, Patisiran; PBO, Placebo; RCT, Randomized controlled trial; TAF, Tafamidis; TQOL, Total Quality of Life Score.

Figure 2. Distribution of baseline disease-related characteristics across ATTR-PN trials. Abbreviations. ATTR-PN, Transthyretin amyloidosis with polyneuropathy; TTR, Transthyretin; Val30Met, Valine to methionine point mutation at position 30.

Figure 3. Distribution of baseline demographic characteristics across ATTR-PN trials. Abbreviations. ATTR-PN, Transthyretin amyloidosis with polyneuropathy; Eur., Europe; N. Am., North America; S. Am., South America; W. Eur., Western Europe.

Figure 4. Placebo response for commonly defined outcomes across ATTR-PN trials (ITT populations). ^†Small numerical difference in range reported for the Norfolk TQOL scale between studies. Abbreviations. AE, Adverse event; ATTR-PN, Transthyretin amyloidosis with polyneuropathy; ITT, Intention to treat; LS, Least squares; mBMI, Modified body mass index; NR, Not reported; SAE, Serious adverse event; TQOL, Total Quality of Life; WDAE, Withdrawal due to adverse events.

Péus D, Newcomb N, Hofer S. Appraisal of the Karnofsky Performance Status and proposal of a simple algorithmic system for its evaluation. BMC Med Inform Decis Mak. 2013;13(1):72.

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