Table 1 Study characteristics of included interventions

Pharmacological agents

Azathioprine

Raghu et al. 1991 [21]

Mean Age: 56 years

Primary outcomes: not stated as primary or secondary: measurable change in lung function (FVC, DLCO, P[A-a]O2) at 12 months; survival

Unclear risk

Country: USA

M/F%: 55/45

Design: RCT

Time since diagnosis: 2 years

Number of centres: 2

FVC: 67%

Funding: Grant from Virginia Mason ResearchCentre, Seattle, USA

Length of follow-up: 12 months

Interventions:

1. Prednisone and placebo, n = 13

2. Prednisone and azathioprine, n = 14

Duration of treatment: 12 months

BIBF-1120

Richeldi et al. 2011 [22]

Mean Age: 65 years

Primary outcomes: annual rate of decline in FVC

Low risk

Country: 25 countries including Italy, Mexico,

M/F%: 75/25

Germany, USA, Korea, UK, France.

Time since diagnosis: 1.2

Secondary outcomes: % predicted FVC; DLCO; SpO2; TLC; 6MWT, SGRQ, decrease in FVC of more than 10% or more than 200 ml; SpO2 decrease of more than 4%; acute exacerbations; survival; death from a respiratory cause; adverse events

Design: RCT (dose finding phase II study)

years

Number of centres: 92

FVC: 80%

Funding: supported by Boehringer Ingelheim

Interventions:

1. BIBF 1120 50 mg/day, n = 86

2. BIBF 1120 50 mg twice per day (100 mg/day), n = 86

Length of follow-up: 54 weeks

3. BIBF 1120 100 mg twice per day (200 mg/day), n = 86

4. BIBF 1120 150 mg twice per day (300 mg/day), n = 85

5. Placebo, n = 85

Duration of treatment: 52 weeks

N-Acetylcysteine (alone or in combination)

Demedts et al. 2005 [18]

Mean Age: 63 years

Primary outcomes: absolute changes in VC and DLCO at 12 months

Low risk

Country: Belgium, France, Germany, Italy, Spain, the Netherlands

M/F%: 72/28

Design: RCT

Time since diagnosis: 1.6 years

Secondary outcomes: % predicted VC, % predicted DLCO, alveolar volume change and % predicted, CRP score, dyspnoea score, maximum exercise indexes, HRCT outcomes, SGRQ, adverse events, withdrawals, and mortality

Number of centres: 36

FVC: 66%

Funding: sponsored by the Zambon group

Interventions:

1. N-acetylcysteine, prednisolone, azathioprine, n = 92 (80 analysed)

2. Placebo, prednisolone, azathioprine, n = 90 (75 analysed)

Length of follow-up: 12 months

Duration of treatment: not stated, assume 12 months.

Raghu et al., (IPFCRN) 2012 [19]

Mean Age: 68 years

Primary outcomes: change in FVC at 60 weeks

Low risk

Country: USA

M/F%: 75/25

Design: RCT (PANTHER study)

Time since diagnosis: 1 year

Secondary outcomes: rate of death, time until death, frequency of acute exacerbation, frequency of maintained FVC response, time to disease progression, clinical and physiological measures including: DLCO, 6MWT, CPI, UCSD SBQ, SGRQ, SF-36, EQ-5D. Adverse events.

Number of centres: 25

FVC: 71%

Funding: grants from the NHLBI; the Cowlin Family fund. NAC and placebo donated by Zambon

Interventions:

1. N-acetylcysteine and placebo (data not presented in article as ‘ongoing’ data collection), n = 81

2. N-acetylcysteine/prednisolone/azathioprine, n = 77

Length of follow-up: 60 weeks in the planned analysis. The study was stopped early. The mean follow-up was 32 weeks.

3. Placebo, n = 78

Duration of treatment: up to 60 weeks

Homma et al. 2012 [20]

Mean Age: 68 years

Primary outcomes: absolute change in FVC at 48 weeks

Unclear risk

Country: Japan

M/F%: 76/24

Design: RCT

Time since diagnosis: 3 years

Number of centres: 27

FVC: 89%

Secondary outcomes: changes in lowest aterial O2 saturation, 6MWT distance, PFT parameters (VC, % predicted VC, TLC, % predicted TLC, DLCO, predicted DLCO), serum markers of pneumocyte injury; disease progression as determined by HRCT; subjective changes in symptoms such as dyspnoea, adverse events.

Funding: grant from Ministry of Health, Labour and Welfare

Interventions:

1. N-acetylcysteine inhaled, n = 51 (38 analysed)

2. Control, n = 49 (38 analysed) Duration of treatment: 48 weeks

Length of follow-up: 48 weeks

Pirfenidone

Noble et al., 2011 [15]

Mean Age: 67 years

Primary outcomes: change in per cent predicted FVC

Low risk

Capacity study 006

M/F%: 72/28

Country: Australia, Belgium, Canada, France, Germany, Ireland, Italy, Mexico, Poland, Spain, Switzerland, UK, USA

Time since diagnosis: ≤1

year: 59%

Secondary outcomes: categorical FVC (5-point scale), progression-free survival, worsening IPF, dyspnoea, 6MWT distance, worst peripheral oxygen saturation (SpO2) during the 6MWT, per cent predicted DLco, fibrosis, mortality.

FVC: 74%

Design: RCT

Number of centres: 110 centres

Funding: InterMune

Interventions:

1. Pirfenidone 2403 mg/day, n = 171

Length of follow-up: 72 weeks from the date the last patient was enrolled.

2. Placebo, n = 173

Duration of treatment: 72 weeks

Noble et al., 2011 [15]

Mean Age: 66 years

Primary outcomes: change in per cent predicted FVC

Low risk

Capacity study 004

M/F%: 71/29

Country: Australia, Belgium, Canada, France, Germany, Ireland, Italy, Mexico, Poland, Spain, Switzerland, UK, USA

Time since diagnosis: ≤1

year: 48%

Secondary outcomes: categorical FVC (5-point scale), progression-free survival, worsening IPF, dyspnoea, 6MWT distance, worst peripheral oxygen saturation (SpO2) during the 6MWT, per cent predicted DLco, mortality.

FVC: 75%

Design: RCT

Number of centres: 110 centres

Funding: InterMune

Interventions:

1. Pirfenidone 2403 mg/day, n = 174

Length of follow-up: 72 weeks from the date thelast patient was enrolled

2. Pirfenidone 1197 mg/day, n = 87

3. Placebo, n = 174

Duration of treatment: 72 weeks

Taniguchi et al., 2010 [16]

Mean Age: 65 years

Primary outcomes: change in vital capacity to week 52

Unclear risk

Country: Japan

M/F%: 78/22

Design: RCT

Time since diagnosis: <1

Number of centres: 73

year: 37%

Secondary outcomes: Progression-free survival time, change in lowest SpO2 during the 6MET. Pa,O2, PA-a,O2, TLC and DLCO, acute exacerbation, markers of interstitial pneumonias, symptoms.

Funding: public sector grants. Drug and placebo from Shionogi & Co, Ltd.

FVC: 78%

1. Pirfenidone 1800 mg/day, n = 108

2. Pirfenidone 1200 mg/day, n = 55

3. Placebo, n = 104

Length of follow-up: 52 weeks

Duration of treatment: 52 weeks

Azuma et al., 2005 [17]

Mean Age: 64 years

Primary outcomes: change in the lowest SpO2 during the 6MET

Unclear risk

Country: Japan

M/F%: 90/10

Design: RCT

Time since diagnosis: <1

Number of centres: 25

year: 22%

Secondary outcomes: resting PFTs while breathing air (VC, TLC, DLCO PaO2), disease progression by HRCT patterns, acute exacerbation, serum markers of pneumocyte damage, QoL

Funding: Shionogi & co, Ltd

FVC: 80%

Interventions:

1. Pirfenidone 1800 mg/day, n = 73

2. Placebo, n = 36

Duration of treatment: 9 months

Length of follow-up: minimum of 9 months

Thalidomide

Horton et al., 2012 [24]

Mean Age: 68 years

Primary outcomes: cough-specific quality of life (CQLQ)

Low risk

Country: USA

M/F%: 78/22

Design: randomised cross-over trial

Time since diagnosis: 1.7

Number of centres: one

years

Secondary outcomes: cough, respiratory quality of life.

Funding: Celgene Corporation

FVC: 70%

Interventions:

1. Thalidomide, n = 23

Method of assessing outcome: Cough-specific quality of life measured by CQLQ. Cough measured by 10 cm VAS. Respiratory quality of life measured by SGRQ.

2. Placebo, n = 23

Duration of treatment: 12 weeks each treatment with a 2 week washout period between treatments.

Length of follow-up: 12 weeks.

Sildenafil (severe IPF)

Zisman and colleagues IPFCRN, 2010 [23]

Mean Age: 69 years

Primary outcomes: presence or absence of an improvement of at least 20% in the 6MWT distance at 12 weeks.

Unclear risk

Country: USA

M/F%: 84/16

Design: RCT

Time since diagnosis: 1.9

Number of centres: 14

years

Funding: NHLBI; the Cowlin Fund (Chicago Community trust); Pfizer; Masimo.

FVC: 57%

Secondary outcomes: changes in the 6MWT distance, degree of dyspnoea, quality of life, FVC, DLCO, arterial partial pressure of oxygen and arterial oxygen saturation, and the alveolar-arterial oxygen gradient while breathing ambient air, adverse events, hospitalisations, death.

1. Sildenafil, n = 89

2. Placebo, n = 91

Duration of treatment: 12 weeks.

Length of follow-up: 12 weeks

Non-pharmacological interventions

Disease management programme/Pulmonary Rehabilitation

Lindell et al. 2010 [26]

Mean Age: 66 years

Primary outcomes: Not specified as primary or secondary outcomes. Dyspnoea (UCSDSBQ); Anxiety (BAI); Depression (BDI-II); Stress (PSS); QoL (SF-36)

Unclear risk

Country: USA

M/F%: 76/24

Design: RCT

Time since diagnosis: NR

Number of centres: one

FVC: >55: 70%

Funding: Fairbanks-Horix Foundation

Interventions:

Length of follow-up: Unclear

1. Program to Reduce IPF Symptoms and Improve Management (PRISIM), n = 10 pairs

2. Usual care, n = 11 pairs

Duration of treatment: 6 weeks

Jastrzebski et al. 2008 [27]

Mean Age: 56 years

Primary outcomes: not specified as primary or secondary. Dyspnoea (oxygen cost diagram, baseline dyspnoea index). QoL (SF-36), 6MWT (distance, dyspnoea in Borg’s scale), maximal inspiratory pressure, lung function tests (IC, TLC, VC, FEV1, DLCOSB, DLCO/VA).

High risk

Country: Poland

M/F%: 64/36

Design: CCT

Time since diagnosis: >2

Number of centres: one

years

Funding: not translated

FVC: 68%

Interventions:

1. Inspiratory muscle training, n = 16

2. Control, n = 14

Length of follow-up: 12 weeks

Duration of treatment: 12 weeks (two six week cycles)

Nishiyama et al. 2008 [25]

Mean Age: 66 years

Primary outcomes: not specified as primary or secondary. Pulmonary function tests (FVC, FEV1, TLC, PaO2,PaCO2,) DLCO, 6MWT; BDI; SGRQ

Unclear risk

Country: Japan

M/F%: 76/24

Design: RCT

Time since diagnosis: NR

Number of centres: one

FVC: 67%

Funding: Japanese ministry of health, labor and welfare

Length of follow-up: 10 weeks after the start of the programme.

Interventions:

1. Pulmonary rehabilitation programme (PRP), n = 15 (13 analysed)

2. Control, n = 15

Duration of treatment: 10 week programme.