Correction: Dagenais et al. Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review. J. Clin. Med. 2021, 10, 23

Renée V. E. Dagenais; Victoria C. Su; Bradley S. Quon

doi:10.3390/jcm11020318

,

and

¹

Adult Cystic Fibrosis Program, St. Paul’s Hospital, Vancouver, BC V6Z 1Y6, Canada

²

Department of Pharmacy, St. Paul’s Hospital, Vancouver, BC V6Z 1Y6, Canada

³

Department of Medicine, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada

⁴

Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC V6Z 1Y6, Canada

J. Clin. Med.2022, 11(2), 318;https://doi.org/10.3390/jcm11020318

This article belongs to the Special Issue Cystic Fibrosis (CF): The Future of CF Care in an Era of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators

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In the original article [1], there was a mistake in Table 1 as published. Reference citation [34] was wrong. The corrected Table 1 appears below. The authors state that the scientific conclusions are unaffected. The original article has been updated.

Table 1. Summary of characteristics and results of cohort or survey studies with full manuscript.

In the original article [1], there was a mistake in Table 2 as published. Subtitle “Lumacaftor/Ivacaftor” was wrong. The corrected Table 2 appears below. The authors state that the scientific conclusions are unaffected. The original article has been updated.

Table 2. Summary of characteristics and results of cohort or survey studies in abstract form.

In the original article [1], there was a mistake in Table A2 as published. Reference citation [48,49,53,54] were wrong. “Talkwalker” was misspelled. The corrected Table A2 appears below. The authors state that the scientific conclusions are unaffected. The original article has been updated.

Table A2. Summary of methodological ratings of included case series ^a,b.

Reference

Dagenais, R.V.E.; Su, V.C.; Quon, B.S. Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review. J. Clin. Med. 2021, 10, 23. [Google Scholar] [CrossRef]

Table 1. Summary of characteristics and results of cohort or survey studies with full manuscript.

Ref	Study Design & Location	Population ^a	n	Recruitment Period & Follow-Up Duration	Overall Adverse Events (AE) ^b,c			Dose Modification, Interruption, or Discontinuation Due to AE ^b,c
Ivacaftor
[29]	Prospective Cohort ^d United States	Baseline Age Pediatric and Adult - Mean: 33 yr - Range: 10–61 yr CFTR Genotype ≥1 copy G551D Baseline ppFEV₁ Mean: 30%	44	Recruitment Period Prior to commercial availability Follow-Up Duration NS	AE in n = 38 (86%):	n	%	Discontinuation:	n	%
					- Pulmonary exacerbation - Hemoptysis - Increased sputum - Increased cough - URTI - Dyspnea - Abnormal respiration - Respiratory tract congestion - Headache - Rash	20 7 7 6 6 3 3 3 5 4	45 16 16 14 14 7 7 7 11 9	- Severe abdominal pain - Dizziness/tinnitus	1 1	2 2
					SAE in n = 14 (32%):
					- Pulmonary exacerbation - Hemoptysis - Pneumothorax - Acute respiratory failure - URTI - Abdominal pain - Gastroenteritis - Abnormal LFTs - Syncope - Secondary adrenocortical insufficiency	NS NS NS NS NS NS NS NS NS NS	- - - - - - - - - -
[55]	Prospective Cohort United States Canada Italy	Baseline Age Pediatric and Adult - Mean: 17 yr - Range: 5–61 yr CFTR Genotype ≥1 gating mutation Baseline ppFEV₁ Mean: 86%	23	Recruitment Period Mar 2014 to Aug 2015 Follow-Up Duration 3 mo	49 AE in n = 21 (91%):	n	%	None reported
					- Respiratory, unspecified - Gastrointestinal, unspecified - Infection, unspecified - Headache - Weakness - Dizziness - Fatigue	NS NS NS NS NS NS NS	- - - - - - -
					5 SAE in n = 3 (13%):	n	%
					- Respiratory infection - Acute changes in metabolic and liver status	4 1	17 4
[56]	Retrospective Cohort United Kingdom (1 center)	Baseline Age Pediatric - Mean: 9 yr - Range: 6–14 yr CFTR Genotype 1 copy G551D Baseline ppFEV₁ Mean: 68% ^e	4	Recruitment Period Jan 2013 to Jun 2015 Follow-Up Duration Mean: 24 mo	- Transaminitis (<3 x ULN)	n 1	% 25	None reported
[57]	Retrospective Cohort Scotland (11 centers)	Baseline Age Pediatric - Median: 9 yr CFTR Genotype ≥1 copy G551D Baseline ppFEV₁ Mean: 85%	26	Recruitment Period NS (Jan 2013 to Mar 2013 for 85%) Follow-Up Duration Mean: 17 mo		n	%	None reported
[57]	Retrospective Cohort Scotland (11 centers)		26		- Headache - Swollen ear - Cataracts	1 1 2	4 4 17 ^f
[58]	Retrospective Cohort France (25 centers)	Baseline Age Pediatric and Adult - Median: 18 yr - Range: 6–52 yr CFTR Genotype ≥1 copy G551D Baseline ppFEV₁ Mean: 72%	57	Recruitment Period Pre-1 Jun 2013 up to 30 Sep 2014 Follow-Up Duration Up to 2 yr	34 AE in n = 21 (37%):	n	%	Interruption in n = 7 (12%):	n	%
					- Transaminitis - Rhinopharyngitis - Asthma - Fever - Chest pain - Abdominal pain - Nausea or vomiting - Intestinal dysmotility - Headache - Fatigue - Rash or eczema - Depression - Myalgia - Arthritis - Breast hypertrophy - Orchitis - Atrial fibrillation	3 NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS	5 - - - - - - - - - - - - - - - -	- Hepatitis - Rhinopharyngitis - Abdominal pain - Vomiting - Headache - Rash - Severe depression	NS NS NS NS NS NS NS	- - - - - - -
								Discontinuation:
								- Transaminitis - Liver cirrhosis diagnosis	1 1	2 2
[30]	Retrospective Cohort ^d Germany (multicenter)	Baseline Age Adult - Mean: 34 yr CFTR Genotype ≥1 copy G551D Baseline ppFEV₁ Mean: 25%	14	Recruitment Period Sep 2012 to Apr 2013 Follow-Up Duration Mean: 235 days	- Increased bronchial and nasal secretions - Headache - Worsening RLS - Abdominal pain - Hyperbilirubinemia (mild) - Transaminitis (<3 to 4x ULN)	n 3 1 1 1 1 1	% 21 7 7 7 7 7	Discontinuation: - Increased bronchial and nasal secretions * * Trial of reduced dose before discontinuation	n 1	% 7
Lumacaftor/Ivacaftor
[41]	Prospective Cohort France (1 center)	Baseline Age Pediatric - Mean: 16 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 87%	32	Recruitment Period Mar 2016 to Dec 2016 Follow-Up Duration 4 h post-first dose	- Acute drop in ppFEV₁ - Wheeze	n 32 3	% 100 9	None reported
[41]	Prospective Cohort France (1 center)		32
[42]	Prospective Cohort France (47 centers)	Baseline Age Pediatric and Adult - Mean: 22 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 65%	845	Recruitment Period 1 Jan 2016 to 31 Dec 2016 Follow-Up Duration 12 mo	AE in n = 494 (59%):	n	%	Interruption:	n	%
[42]	Prospective Cohort France (47 centers)		845		- Respiratory - Digestive - Menstrual abnormality - Fatigue - Headache - CK > 5xULN - Transaminitis (> 3xULN)	316 181 53 37 19 20 5	37 21 6 4 2 2 0.6	- Respiratory - ‘Non-respiratory’ Discontinuation: Respiratory - Chest tightness/dyspnea - Bronchospasm - Increased cough/sputum - Hemoptysis - Pneumothorax Non-respiratory - Diarrhea, abdominal pain - CK >10xULN + myalgia - Fatigue - Headache - Depression - Metrorrhagia - Transaminitis (>6xULN) - Cutaneous rash - Tachycardia	16 8 n 38 24 9 2 1 18 5 5 4 4 3 2 1 1	2 1 % 5 3 1 0.2 0.1 2 0.6 0.6 0.5 0.5 0.4 0.2 0.1 0.1
[59]	Prospective Cohort United States (1 center)	Baseline Age Pediatric and Adult - Mean: 23 yr - Range: 12–48 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 70%	26	Recruitment Period NS Follow-Up Duration 6 mo	See Discontinuation			Discontinuation: - Transaminitis - Unspecified AE	n 1 4	% 4 15
[31]	Prospective Cohort ^d Switzerland (1 center)	Baseline Age Adult - Mean NR CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Median: 30%	20	Recruitment Period Jan 2016 to Jan 2017 Follow-Up Duration 1 mo		n	%	Reduced dose:	n	%
[31]	Prospective Cohort ^d Switzerland (1 center)		20		- Dyspnea - 3 h - 24 h - 1 mo - Chest tightness - 3 h - 24 h - 1 mo - Increased sputum - 3 h - 24 h - 1 mo - Pulmonary exacerbation - 1 mo	0 1 1 1 10 1 1 8 3 2	- 5 5 5 50 5 5 40 15 10	- Respiratory intolerance Discontinuation: - Chest tightness (at 24 h)	3 1	15 5
[32]	Prospective Cohort Australia (1 center)	Baseline Age Adult - Mean: 27 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Median: 36%	12	Recruitment Period Jan 2016 to Oct 2016 Follow-Up Duration 1 mo		n	%	Discontinuation:	n	%
[32]	Prospective Cohort Australia (1 center)		12		- Acute drop in ppFEV₁ - Respiratory AE overall - 4 h - 24 h - 1 mo - Dyspnea - 4 h - 24 h - 1 mo - Chest tightness - 4 h - 24 h - 1 mo - Increased sputum - 4 h - 24 h - 1 mo - Pulmonary exacerbation	12 5 10 8 2 6 7 4 8 5 0 2 1 6	100 42 83 67 17 50 58 33 67 42 - 17 8 50	- Chest tightness/dyspnea * * n = 2 discontinued after 1mo follow-up (5 wk and 9 wk)	3	25
[33]	Prospective Cohort France (11 centers)	Baseline Age Adult - Mean: 31 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 32%	53	Recruitment Period Jan 2016 to Jun 2016 Follow-Up Duration 3 mo	AE in n = 34 (63%):	n	%	Discontinuation:	n	%
[33]	Prospective Cohort France (11 centers)		53		- Abnormal respiration - Dyspnea - Increased cough - Abdominal pain, nausea, diarrhea, or vomiting - Fatigue - Rash - Pruritus - Breast tension	13 11 3 9 2 1 1 1	25 21 6 17 4 2 2 2	- Respiratory intolerance - Vomiting - Fatigue	13 1 1	25 2 2
[25]	Prospective Cohort ^d,g Australia (1 center)	Baseline Age Adult - Mean: 27 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 36%	10	Recruitment Period NS Follow-Up Duration 52 wk	AE in n = 6 (60%):	n	%	None reported
[25]	Prospective Cohort ^d,g Australia (1 center)		10	Recruitment Period NS Follow-Up Duration 52 wk	- Chest tightness/dyspnea - Headache	6 2	60 20
[43]	Retrospective Cohort Ireland (1 center)	Baseline Age Pediatric - Mean: 14 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 77%	15	Recruitment Period Sep 2016 to Aug 2017 Follow-Up Duration NS		n	%	None reported
[43]	Retrospective Cohort Ireland (1 center)		15		- Acute drop in ppFEV₁ - Chest tightness - Increased sputum	14 2 2	93 13 13
[44]	Retrospective Cohort United States (1 center)	Baseline Age Pediatric and Adult - Mean: 25 yr - Range: 12–59 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 67%	116	Recruitment Period NS Follow-Up Duration Up to 11 mo	AE in n = 46 (40%):	n	%	Reduced dose:	n	%
[44]	Retrospective Cohort United States (1 center)		116		- Chest tightness - Dyspnea - Increased cough - Diarrhea - Nausea - Decreased appetite - Rash	23 12 10 5 3 2 2	20 10 9 4 3 2 2	- AE not specified Discontinuation: - Reasons not specified ^h	10 20	9 17
[60]	Retrospective Cohort Greece (1 center)	Baseline Age Pediatric and Adult - Mean: 16 yr ⁱ - Range: 12–23 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean 92% ⁱ	62	Recruitment Period Mar 2016 to Aug 2017 Follow-Up Duration 12 mo	- Chest tightness	n 2	% 3	Discontinuation: - Transaminitis - Cataract	n 1 1	% 2 2
[34]	Retrospective Cohort ^d Spain (multicenter)	Baseline Age Pediatric and Adult - Mean: 27 yr - Range: 10–45 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 32%	20	Recruitment Period 2016 Follow-Up Duration 6 mo	AE in n = 15 (75%):	n	%	Discontinuation:	n	%
[34]	Retrospective Cohort ^d Spain (multicenter)		20	Recruitment Period 2016 Follow-Up Duration 6 mo	- Chest tightness - Dyspnea - Headache - Weight loss - ‘Sickness’ (not defined) - Asthenia - Abdominal pain - Transaminitis	9 8 5 5 3 3 2 2	45 40 25 25 15 15 10 10	- Decreased ppFEV₁ - AE not specified	1 6	5 30
[45]	Retrospective Cohort Canada (1 center)	Baseline Age Adult - Median: 32 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Median: 40%	22	Recruitment Period Apr 2016 to Jun 2018 Follow-Up Duration Median: 10 mo	AE in n = 19 (86%):	n	%	Discontinuation:	n	%
[45]	Retrospective Cohort Canada (1 center)		22		- Chest tightness - Wheeze - Dyspnea - Increased sputum - Increased cough - Flu-like symptoms - Elevated blood pressure - Headache - Nausea - Elevated AST - Anxiety - Bradycardia - Pleuritic chest pain	14 4 3 3 2 1 5 4 2 1 1 1 1	64 18 14 14 9 5 23 18 9 5 5 5 5	- Respiratory symptoms - Asymptomatic hypertension - Symptomatic hypertension - Headache - Hypertensive emergency - Anxiety	3 2 1 1 1	14 9 5 5 5
[61]	Retrospective Cohort United States (1 center)	Baseline Age Adult - Mean NR CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	82	Recruitment Period Jul 2015 to Jun 2016 Follow-Up Duration 12 mo	See Discontinuation			Discontinuation: Total overall: - Chest tightness * - Diarrhea - Abdominal pain - Nausea - Dysphagia - Elevated LFTs - Pericarditis - Allergic reaction ** - Suspected Stevens–Johnson syndrome * n = 3 also had significant drop in ppFEV₁ ** n = 1 also discontinued due to chest tightness	n 17 11 2 1 1 1 1 1 1 1	% 21 13 2 1 1 1 1 1 1 1
[26]	Retrospective Cohort ^d,g Australia (7 centers)	Baseline Age Adult - Mean: 31 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 37%	72	Recruitment Period Nov 2015 to Mar 2017 Follow-Up Duration 12 mo		n	%	Discontinuation:	n	%
[26]	Retrospective Cohort ^d,g Australia (7 centers)		72		- Chest tightness/dyspnea - Increased sputum - Decrease in ppFEV₁ - Headache - Fatigue - Nausea - Rash	40 4 2 2 5 1 2	56 6 3 3 7 1 3	- Chest tightness/dyspnea	22	31
[27]	Case Series (Survey) ^j International (31 centers)	Baseline Age Adult - Mean: 30 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 59%	26	Recruitment Period Questionnaire sent in 2018–2019 Follow-Up Duration NS		n	%	Discontinuation:	n	%
[27]	Case Series (Survey) ^j International (31 centers)		26		- Pulmonary exacerbation - Post-partum acute myelocytic leukemia	1 1	4 4	- Chest tightness	2	8

^a When adult and pediatric patients both included, age range reported when possible; ^b Rates not reported for all AE, as indicated by ‘NS’; ^c To avoid redundancy, if AE only reported in context of dose modification, interruption, and/or discontinuation of therapy, it was not listed in overall AE; ^d Study population part of a compassionate, ‘expanded access’, ‘managed access’, or ‘named patient’ program; ^e Mean calculated from n = 3 (75%) of study subjects, as baseline not reported for n = 1 (25%); ^f Frequency of 17% based on n = 12 screened; 8% frequency for overall cohort of n = 26; ^g Study was case-control, but only LUM/IVA-treated participants included in systematic review; therefore, assessed as cohort study; ^h Reason for discontinuation was not consistently assessed, and may include reasons unrelated to AE; ⁱ Mean baseline age and ppFEV₁ based on n = 52 in final analysis of outcomes assessing effectiveness; n = 10 excluded from this analysis; ^j This case series is included in Table 1 due to results being presented in aggregate. AST, aspartate aminotransferase; CFTR, cystic fibrosis transmembrane conductance regulator; CK, creatine kinase; h, hour(s); LFT, liver function test; mo, month(s); NR, not reported; NS, not specified; ppFEV₁, percent predicted Forced Expiratory Volume in 1 sec; RLS, restless leg syndrome; SAE, serious adverse events; ULN, upper limit of normal; URTI, upper respiratory tract infection; wk, week(s); yr, year(s).

Table 2. Summary of characteristics and results of cohort or survey studies in abstract form.

Ref	Study Design	Population	n	Overall Adverse Events (AE) ^a,b			Dose Modification, Interruption, or Discontinuation Due to AE ^a,b
Ivacaftor
[62]	Prospective Cohort	Baseline Age Pediatric - Mean: 5 yr CFTR Genotype ≥1 gating mutation Baseline ppFEV₁ Mean NR	4	AE in n = 2 (50%):	n	%	None reported
[62]	Prospective Cohort		4	- URTI - Nasal congestion - Headache	NS NS NS	- - -
[63]	Retrospective Cohort	Baseline Age Pediatric - Mean: 6 yr CFTR Genotype ≥1 gating mutation Baseline ppFEV₁ Median: 87%	10	- Transient rash - Increased obesity	n 2 1	% 20 10	None reported
[64]	Prospective Cohort	Baseline Age Pediatric and Adult - Mean NR CFTR Genotype ≥1 copy S549R Baseline ppFEV₁ Mean: 54%	15	- Liver enzyme derangement	n	%	None reported
[64]	Prospective Cohort		15	- Liver enzyme derangement	2	13
[65]	Cross-sectional Survey	Baseline Age Adult - Mean: 26 yr CFTR Genotype ≥1G551D Baseline ppFEV₁ Mean: 62%	11 ^d	AE in n = 8 (73%) ^d: - Transient rash - Dizziness - Unspecified AE	n NS NS NS	% - - -	None reported
Lumacaftor/Ivacaftor
[66]	Prospective Cohort	Baseline Age Pediatric - Mean: 13 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 91%	14		n	%	*Reduced dose :**	n	%
[66]	Prospective Cohort		14	- Acute drop in ppFEV₁ (asymptomatic) - Chest tightness, tachypnea (requiring oxygen)	1 1	7 7	- Chest tightness, tachypnea * Eventual titration to full dose	1	7
[67]	Prospective Cohort	Baseline Age Pediatric - Mean: 14 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 87%	13		n	%	None reported
				- Drop in ppFEV₁ requiring salbutamol	7	54
						54
[68]	Prospective Cohort	Baseline Age Pediatric and Adult - Mean: 23 yr ^e CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean 61% ^e	369		n	%	Discontinuation:	n	%
[68]	Prospective Cohort		369	- Bronchospasm - Dyspnea - Abnormal respiration - Unspecified respiratory AE - Unspecified AE	15 12 7 4 120	4 3 2 1 33	- Unspecified AE	16	4
[69]	Prospective Cohort	Baseline Age Pediatric and Adult - Mean: 25 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	311	379 AE in n = 213 (68%): - Dyspnea - Cough - GI discomfort (e.g., diarrhea, nausea, abdominal pain) - Headache - Fatigue - Unspecified	n ^f NS NS NS NS NS NS	% 31 6 31 6 5 NR	Interruption (stop/restart): - Unspecified AE and other reasons ^g Discontinuation: - Unspecified AE and other reasons ^g	n 12 42	% 4 14
[35]	Prospective Cohort ^c	Baseline Age Adult - Median: 31 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Median: 28%	14		n	%	Discontinuation:	n	%
[35]	Prospective Cohort ^c		14	- Chest tightness, breathless - Rash	7 1	50 7	- Respiratory AE and/or rash	4	29
[70]	Prospective Cohort	Baseline Age Adult - Mean NR CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	29		n	%	Reduced dose:	n	%
[70]	Prospective Cohort		29	- Chest tightness * * n = 4 cases severe, requiring hospitalization for IV steroids and antibiotics	13	45	- Chest tightness Discontinuation: - Chest tightness	2 5	7 17
[36]	Prospective Cohort ^c	Baseline Age Mean NR ^h CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	32	AE in 88%:	n ^f	%	Interruption (stop/restart):	n	%
[36]	Prospective Cohort ^c		32	- Respiratory AE - Drop in ppFEV₁	NS NS	87 -	- Unspecified AEA Discontinuation: - Unspecified AE	1 8	3 25
[71]	Retrospective Cohort	Baseline Age Pediatric and Adult - Mean NR CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	34	AE in n = 29 (85%): - Pulmonary exacerbation - Chest tightness - Dyspnea - Diarrhea - Abdominal pain	n 16 9 3 3 3	% 47 26 9 9 9	Discontinuation: - Unspecified AE	n 10	% 29
				Serious AE in n = 8 (24%):
				- Respiratory failure ⁱ - Unspecified AE	1 7	3 21
[72]	Retrospective Cohort	Baseline Age Pediatric and Adult - Mean: 26 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 68%	103	See Discontinuation			Interruption/discontinuation ^j:	n	%
[72]	Retrospective Cohort		103				- Chest tightness and/or pain - Elevated LFTs	17 NS	17 -
[73]	Retrospective Cohort	Baseline Age Adult - Mean: 31 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 50%	71	AE in n = 41 (58%):	n	%	Discontinuation:	n	%
[73]	Retrospective Cohort		71	- Chest tightness - Dyspnea - Increased cough - GI (pain, constipation, or diarrhea) - Rash - Pruritus - Irregular menses or metrorrhagia - Breast tension - Headache - Myalgia	22 8 4 6 4 1 3 2 1 1	31 11 6 9 6 1 4 3 1 1	- Dyspnea - Chest tightness - Increased cough - Fatigue	7 6 3 1	10 9 4 1
[74]	Retrospective Cohort	Baseline Age Mean NR ^h CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	54	See Discontinuation			Discontinuation:	n	%
[74]	Retrospective Cohort		54				- Chest tightness, dyspnea, and/or drop in ppFEV₁	8	15
[75]	Retrospective Cohort	Baseline Age Adult - Mean: 31 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	28	- Increased work of breathing or chest tightness - Drop in ppFEV₁	n 12 5	% 43 18	Discontinuation - Respiratory intolerance vs. pulmonary exacerbation - Persistent respiratory intolerance/chest tightness - Rash and swelling of face - Increased anxiety	n 1 3 1 1	% 4 11 4 4
[76]	Retrospective Cohort	Baseline Age Adult - Mean NR CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	46		n	%	Discontinuation:	n	%
[76]	Retrospective Cohort		46	- Drop in ppFEV₁ - Transaminitis	21 2	46 4	- Dyspnea, cough, CFPEx, and/or chest tightness - Transaminitis - Headache - Muscle ache - Fatigue - Rash	4 1 NS NS NS NS	9 2 - - - -
[77]	Retrospective Cohort	Baseline Age Adult - Mean NR CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	28	See Discontinuation			Discontinuation:	n	%
[77]	Retrospective Cohort		28				- SOB and/or drop in ppFEV₁	15	54
[78]	Retrospective Cohort	Baseline Age Mean: 32 yr ^h CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 62%	20	Overall AE:	n	%	Interruption (stop/restart):	n	%
[78]	Retrospective Cohort		20	- Chest tightness - Elevated LFTs - Upset stomach - Increased stool output - Rash - Elevated thyroid function test - RA exacerbation	NS NS NS NS NS NS NS	- - - - - - -	- Unspecified AE - full-dose restart - half-dose restart Discontinuation: - Unspecified AE	2 4 2	10 20 10
[79]	Retrospective Cohort	Baseline Age Mean NR ^h CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	60	- Heartburn/reflux - Abdominal pain - Loose/oily stools	n 20 19 17	% 33 32 28	None reported
[80]	Retrospective Cohort	Baseline Age Mean: 29 yr ^h,k CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 80% ^k	34	See Discontinuation			Discontinuation:	n	%
[80]	Retrospective Cohort		34				Overall total: - Respiratory AE (70%) ^f - Unspecified reasons ^g	11 NS NS	32 - -
[81]	Cohort ^l	Baseline Age Pediatric - Mean NR CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	39		n	%	None reported
[81]	Cohort ^l		39	- AST >3x ULN	2	5
[82]	Cohort ^l	Baseline Age Pediatric and Adult - Range: 13–48 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	47	See Discontinuation			Discontinuation:	n	%
[82]	Cohort ^l		47				- Thoracic oppression and unspecified AE	4	9
[83]	Cohort ^l	Baseline Age Adult - Mean: 28 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 61%	46	See Discontinuation			Discontinuation:	n	%
[83]	Cohort ^l		46				- Dyspnea, increased sputum, and unspecified AE	6	13
[37]	Cohort ^c,l	Baseline Age Adult - Mean: 31 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 28%	30	- Drop in ppFEV₁ - Dyspnea, chest tightness, or chest pain - Increased sputum *Based on 31 trials of LUM/IVA in 30 patients	n 30 * 25 * NS	% 97 81 -	Discontinuation: - Respiratory AE, unspecified - Hypertension	n 3 1	% 10 3
[84]	Cohort ^l	Baseline Age Adult - Mean: 31yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 40%	8	See Interruption			Interruption in n = 1 (13%):	n	%
[84]	Cohort ^l		8				- Drop in ppFEV₁ - Eczema	1 1	13 13
[38]	Cohort ^c,l	Baseline Age Mean NR ^h CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	19	See Discontinuation			Discontinuation:	n	%
[38]	Cohort ^c,l		19				- Chest tightness and dyspnea	4	21
[85]	Cross-sectional questionnaire	Baseline Age Mean NR ^h CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	11	AE in n = 5 (46%): - Increased cough - Chest pain - Trouble breathing - Chest tightness - Stomach pain	n	%	Discontinuation:	n	%
[85]	Cross-sectional questionnaire		11		4 2 2 1 1	36 18 18 9 9	- Increased cough	1	9
Tezacaftor/Ivacaftor
[86]	Prospective Cohort	Baseline Age Pediatric - Mean: 16 yr CFTR Genotype ∆F508 homozygous or heterozygous Baseline ppFEV₁ Mean: 82%	72	See Discontinuation			Discontinuation: Overall total: - New-onset hemoptysis - Persistent nausea/vomiting - Elevated LFTs - Mental health changes - Alterations in blood glucose - Acholic stools	n 8 NS NS NS NS NS NS	% 11 - - - - - -
[87]	Prospective Cohort	Baseline Age Mean NR ^h CFTR Genotype NR Baseline ppFEV₁ Mean NR	50		n	%	Discontinuation:	n	%
[87]	Prospective Cohort		50	- AE not specified	5	10	- Liver function abnormalities	1	2
[88]	Prospective Cohort	Baseline Age Adult - Mean: 34 yr CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean: 51%	5 ^m	AE in n = 5 (11%) ^m:	n	% ^m	Discontinuation:	n	% ^m
[88]	Prospective Cohort		5 ^m	- Sleep pattern disturbance - Out of body experience - Visual hallucination - Depersonalization - “Brain fog” - Severe migraine	2 1 1 1 1 1	5 2 2 2 2 2	- Out of body experience, visual hallucination - Depersonalization, “brain fog” - Severe migraine	1 1 1	2 2 2
[89]	Retrospective Cohort	Baseline Age Adult - Mean NR CFTR Genotype ∆F508/∆F508 Baseline ppFEV₁ Mean NR	18	See Discontinuation			Discontinuation:	n	%
[89]	Retrospective Cohort		18				- Hair loss and fatigue	1	6
[39]	Cohort ^c,l	Baseline Age Adult - Mean NR CFTR Genotype NR Baseline ppFEV₁ Mean: 34%	22	AE in n = 3 (14%): - Rash - Blurred vision - Viral symptoms	n	%	Discontinued:	n	%
[39]	Cohort ^c,l		22		2 1 1	9 5 5	- Blurred vision	1	5
Elexacaftor/Tezacaftor/Ivacaftor
[40]	Retrospective Cohort	Baseline Age Adult - Mean: 36 yr CFTR Genotype ≥1 copy ∆F508 Baseline ppFEV₁ Mean: 31%	11		n	%	None reported
[40]	Retrospective Cohort		11	- Transaminitis	4	36

^a Rates not reported for all AE, as indicated by ‘NS’; ^b To avoid redundancy, if AE only reported in context of dose modification, interruption, and/or discontinuation of therapy, it was not listed in overall AE; ^c Study population part of a compassionate, ‘early access’, ‘expanded access’, ‘managed access’, or ‘named patient’ program; ^d Total study cohort of n = 11, but only n = 9 patients completed symptom questionnaire; AE frequency calculated based on total n = 11, ^e Mean baseline age and ppFEV₁ based on n = 135 in final analysis of outcomes assessing effectiveness; n = 234 excluded from this analysis; ^f As reported, unable to accurately determine the absolute number of patients who experienced AE; ^g Frequency of specific reasons for interruption or discontinuation not clear and include reasons unrelated to AE; ^h Included age groups (i.e., pediatric and/or adult) not specified; ⁱ Respiratory failure occurred in 1 individual on two occasions, both within 24 h of initiating and reinitiating LUM/IVA; ^j Of the n = 25 who stopped, 9 restarted and 6 of experienced the same AE; unclear which AE the 3 who restarted experienced and whether the 6 who experienced the same AE then discontinued permanently; ^k Mean baseline age and ppFEV₁ based on n = 23 in final analysis of outcomes assessing effectiveness; n = 11 excluded from this analysis; ^l Unable to discern if prospective versus retrospective based on reported information; ^m Total study cohort of n = 44, but focused on neurocognitive AE in n = 5; AE frequencies calculated based on total n = 44. AST, aspartate aminotransferase; CFTR, cystic fibrosis transmembrane conductance regulator; CFPEx, cystic fibrosis pulmonary exacerbation; GI, gastrointestinal; LFT, liver function test; LUM/IVA, lumacaftor/ivacaftor; NR, not reported; NS, not specified; ppFEV₁, percent predicted forced expiratory volume in 1 sec; RA, rheumatoid arthritis; SOB, shortness of breath; ULN, upper limit of normal; URTI, upper respiratory tract infection; yr, year(s).

Table A2. Summary of methodological ratings of included case series ^a,b.

Criteria	McKinzie et al., 2017 [47]	Nash et al., 2020 [27]	Rotolo et al., 2020 [52]	Safirstein et al., 2020 [53]	Talwalkar et al., 2017 [48]
1. Study objective clearly stated	Y	Y	N	Y	Y
2. Study population clearly defined, using case definition	N	N	N	N	N
3. Cases consecutive	NR	NR	NR	NR	NR
4. Subjects comparable	CD	CD	CD	N	N
5. Intervention clearly described	Y	Y	Y	Y	Y
6. Outcome measures clearly defined, valid, reliable, implemented consistently	N	N	N	Y	N
7. Adequate length of follow-up	Y	Y	Y	Y	CD
8. Statistical methods well-described	N/A	N/A	N/A	N/A	N
9. Results well-described	Y	N	Y	Y	Y
Final rating	Poor	Poor	Fair	Good	Poor

^a Studies were rated against the 9 criteria of the Quality Assessment for Case Series Studies from the National Institutes of Health, National Heart, Lung, and Blood Institute [24] from the standpoint of AE assessment; ^b Only case series with a full manuscript were assessed for quality. AE, adverse event; CD, cannot determine; N, no; N/A, not applicable; NR, not reported; Y, yes.

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Correction: Dagenais et al. Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review. J. Clin. Med. 2021, 10, 23

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