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Clinical Trial Results:
A pilot trial of intravenous iron for the treatment of iron deficiency in adult patients with cystic fibrosis

Summary
EudraCT number	2018-002366-39
Trial protocol	GB
Global end of trial date	30 Sep 2021

Results information
Results version number	v1(current)
This version publication date	23 Apr 2023
First version publication date	23 Apr 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

12800

ISRCTN number

US NCT number

NCT03632525

WHO universal trial number (UTN)

Sponsor organisation name

University of Oxford / Clinical Trials and Research Governance

Sponsor organisation address

Joint Research Office, Boundary Brook House, Churchill Drive, Headington, Oxford, United Kingdom, OX3 7LE

Public contact

CTRG, University of Oxford / Clinical Trials and Research Governance, 00 000000, ctrg@admin.ox.ac.uk

Scientific contact

CTRG, University of Oxford / Clinical Trials and Research Governance, 00 000000, ctrg@admin.ox.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Interim

Date of interim/final analysis

02 May 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Mar 2020

Global end of trial reached?

Yes

Global end of trial date

30 Sep 2021

Was the trial ended prematurely?

Main objective of the trial

To assess the early safety profile of IV iron in adults with CF by comparing the incidence of new infective events during the 4 weeks before and after IV iron

Protection of trial subjects

The trial interventions were all standard clinical interventions to which the participants could be exposed in routine clinical practice, and all were delivered with the same safeguards/safety measures that would have been used in routine clinical practice. Trial-specific data and samples were handled /managed according to standard GCP and clinical trial regulations.

Background therapy

Participants continued on their standard background therapy for cystic fibrosis, including antibiotics and mucolytic therapy. The details of this therapy varied between participants, and was not influenced by participation in the clinical trial.

Evidence for comparator

This was an interventional cohort study in which all participants received the main study intervention (intravenous iron, as ferric carboxymaltose). The primary comparison was between the incidence of new infective events in the four weeks before and the four weeks after the study intervention.

Actual start date of recruitment

11 Mar 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 20

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were all recruited in a single centre (Oxford) in the UK, during the period 11/03/2019 to 12/12/2019.

Screening details

Participants with iron deficiency were identified by the clinical team, and screened for eligibility based on the inclusion/exclusion criteria.

Number of subjects started

Number of subjects completed

Period 1 title

Pre iron

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

No blinding or allocation method - all participants received the study intervention (intravenous ferric carboxymaltose) in an open label design.

All participants (pre iron)

Arm description

Participants were studied as a single group in this intervention cohort study, in which the primary comparison is bring made between the pre- and post-iron periods for the cohort.

Arm type

Experimental

Investigational medicinal product name

Ferric carboxymaltose (Ferinject)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

The dose of ferric carboxymaltose (Ferinject) used was 20 mg/kg, up to a maximum dose of 1000 mg for patients with a haemoglobin concentration less than 14 g/dL or a maximum of 500 mg for patients with a haemoglobin concentration more than or equal to 14 g/dL. The appropriate dose was given in 250 ml of normal (0.9%) saline over 15 minutes.

Number of subjects in period 1	All participants (pre iron)
Started	20
Visit 1 (baseline, 4 weeks pre iron)	20
Visit 2 (day of iron administration)	20
Completed	20

Period 2 title

Post iron

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

No blinding or allocation method - all participants received the study intervention (intravenous ferric carboxymaltose) in an open label design

All participants (post iron)

Arm description

Participants were studied as a single group in this intervention cohort study, in which the primary comparison is bring made between the pre- and post-iron periods for the cohort.

Arm type

Experimental

Investigational medicinal product name

Ferric carboxymaltose (Ferinject)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 2	All participants (post iron)
Started	20
Visit 3 (4 weeks post iron)	20
Visit 4 (12 weeks post iron)	20
Completed	20

Baseline characteristics

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Reporting group title

Pre iron

Reporting group description

Reporting group values	Pre iron	Total
Number of subjects	20	20
Age categorical
Units: Subjects
Adults (18-64 years)	20	20
Age continuous
Age of participants at recruitment
Units: years
arithmetic mean (standard deviation)	30.1 ( 10.2 )	-
Gender categorical
Units: Subjects
Female	10	10
Male	10	10
Chronic Pseudomonas colonisation
Number of patients known to have chronic Pseudomonas colonisation.
Units: Subjects
Pseudomonas colonisation	10	10
No Pseudomonas colonisation	10	10
Body mass index
Units: kg/m2
arithmetic mean (standard deviation)	22.7 ( 4.4 )	-
Forced expiratory volume in 1 second (FEV1)
Units: % predicted value
arithmetic mean (standard deviation)	63 ( 22.2 )	-
Ferritin
Units: microgram(s)/litre
arithmetic mean (standard deviation)	11.9 ( 10.1 )	-
Haemoglobin
Blood haemoglobin concentration
Units: gram(s)/litre
arithmetic mean (standard deviation)	124 ( 21 )	-

Subject analysis set title

All participants

Subject analysis set type

Full analysis

Subject analysis set description

All participants

Subject analysis sets values	All participants
Number of subjects	20
Age categorical
Units: Subjects
Adults (18-64 years)	20
Age continuous
Age of participants at recruitment
Units: years
arithmetic mean (standard deviation)	30.1 ( 10.2 )
Gender categorical
Units: Subjects
Female	10
Male	10
Chronic Pseudomonas colonisation
Number of patients known to have chronic Pseudomonas colonisation.
Units: Subjects
Pseudomonas colonisation	10
No Pseudomonas colonisation	10
Body mass index
Units: kg/m2
arithmetic mean (standard deviation)	22.7 ( 4.4 )
Forced expiratory volume in 1 second (FEV1)
Units: % predicted value
arithmetic mean (standard deviation)	63 ( 22.2 )
Ferritin
Units: microgram(s)/litre
arithmetic mean (standard deviation)	11.9 ( 10.1 )
Haemoglobin
Blood haemoglobin concentration
Units: gram(s)/litre
arithmetic mean (standard deviation)	124 ( 21 )

End points

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Reporting group title

All participants (pre iron)

Reporting group description

Participants were studied as a single group in this intervention cohort study, in which the primary comparison is bring made between the pre- and post-iron periods for the cohort.

Reporting group title

All participants (post iron)

Reporting group description

Participants were studied as a single group in this intervention cohort study, in which the primary comparison is bring made between the pre- and post-iron periods for the cohort.

Subject analysis set title

All participants

Subject analysis set type

Full analysis

Subject analysis set description

All participants

Primary: New infective events (4 weeks)

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End point title

New infective events (4 weeks)

End point description

The primary outcome is a comparison of the incidence of new infective events in the 4-week period before iron infusion (i.e. between the baseline visit and visit 2) and the 4-week period after iron infusion (i.e. between visits 2 and 3). A deterioration of infective status was defined as ANY one of the following: • New microbiological isolate in sputum (i.e. an organism not cultured during the prior 12 months) • Clinical infection requiring intravenous antibiotics (as judged by the clinical team) • Admission to hospital for infection-related reason (as judged by clinical team) • More than 10% fall in FEV1, not otherwise explained (as judged by clinical team)

End point type

Primary

End point timeframe

Comparison of infective events in four weeks prior to IV ferric carboxymaltose and four weeks following

End point values	All participants (pre iron)	All participants (post iron)	All participants
Number of subjects analysed	20 ^[1]	20 ^[2]	20
Units: % experiencing infective event
number (not applicable)	20	20	20

Attachments

Baseline characteristics and primary outcome

Notes
[1] - Cohort study: the 20 patients in the pre-iron group are the same as those in the post-iron group.
[2] - Cohort study: the 20 patients in the pre-iron group are the same as those in the post-iron group.

Incidence of infective events (primary outcome)

Statistical analysis description

Comparison on incidence of infective events in four weeks prior to iron, compared with four weeks after iron administration, using McNemar's test.

Comparison groups

All participants (pre iron) v All participants (post iron)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

> 0.9 ^[4]

Method

Mcnemar

Confidence interval

Notes
[3] - This is an interventional cohort study in which the primary comparison is between the four week period before iron administration and the four week period after iron administration. All 20 participants (i.e. the whole study cohort) are included in the analysis. The automatically populated data above wrongly suggests that 40 participants are included because the pre- and post-iron groups (which are in fact the same participants) have been added together.
[4] - No evidence for any difference in the incidence of infective events in the four week period before iron compared with the four week period after iron administration.

Adverse events

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Timeframe for reporting adverse events

From start of baseline visit to end of final study visit

Adverse event reporting additional description

All adverse events included, whether before or after iron. Note that the protocol includes a list of symptoms/clinical events that occur commonly in patients with cystic fibrosis. These symptoms/events were recorded as adverse events only if new or worse than usual for the patients (or if felt to be directly attributable to iron administration).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

All participants

Reporting group description

This is an interventional cohort study, so there is a single reporting group. All 20 participants received a single dose of ferric carboxymaltose. Adverse events occuring both before and after the iron administration are included.

Serious adverse events	All participants
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 20 (35.00%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0
Gastrointestinal disorders
Distal intestinal obstruction syndrome
Additional description: Distal intestinal obstruction syndrome (DIOS) requiring admission.
subjects affected / exposed	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Respiratory, thoracic and mediastinal disorders
Haemoptysis
Additional description: Haemoptysis requiring admission
subjects affected / exposed	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Infections and infestations
Respiratory tract infection
Additional description: Infective exacerbation of cystic fibrosis, requiring admission to hospital. This study is investigating whether iron may indirectly contribute to infective episodes (see primary outcome), but none was felt to be directly attributable to iron.
subjects affected / exposed	6 / 20 (30.00%)
occurrences causally related to treatment / all	0 / 8
deaths causally related to treatment / all	0 / 0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	All participants
Total subjects affected by non serious adverse events
subjects affected / exposed	20 / 20 (100.00%)
Nervous system disorders
Paraesthesia
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Headache
Additional description: Headache, new or worse than normal for participant.
subjects affected / exposed	6 / 20 (30.00%)
occurrences all number	6
General disorders and administration site conditions
Fatigue
Additional description: Fatigue, new or worse than usual for participant, and not felt to be attributable to infective exacerbation.
subjects affected / exposed	5 / 20 (25.00%)
occurrences all number	5
Flu-like symptoms
Additional description: Flu-like symptoms, not felt to be attributable to infective exacerbation (or other infection).
subjects affected / exposed	4 / 20 (20.00%)
occurrences all number	4
Myalgia
Additional description: Myalgia, new or worse than normal for participant, and not felt to be attributable to infective exacerbation.
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Fever
Additional description: Fever, not felt to be attributable to infection.
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Ear and labyrinth disorders
Ear infection
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Gastrointestinal disorders
Gastrointestinal upset
Additional description: Diarrhoea/gastrointestinal upset, new or worse than normal for participant.
subjects affected / exposed	4 / 20 (20.00%)
occurrences all number	4
Sore throat
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Respiratory, thoracic and mediastinal disorders
Respiratory tract infection
Additional description: Infective exacerbation not requiring admission (including those for which intravenous antibiotics were given at home).
subjects affected / exposed	12 / 20 (60.00%)
occurrences all number	15
Haemoptysis
Additional description: Haemoptysis not requiring admission, and not felt to be attributable to infective exacerbation.
subjects affected / exposed	5 / 20 (25.00%)
occurrences all number	6
Cough
Additional description: Cough, new or worse than normal for participant, and not felt to be attributable to infective exacerbation.
subjects affected / exposed	3 / 20 (15.00%)
occurrences all number	3
Chest tightness
Additional description: Chest tightness or wheeze, new or worse than normal for participant, and not felt to be attributable to infective exacerbation.
subjects affected / exposed	3 / 20 (15.00%)
occurrences all number	3
Chest pain
Additional description: Chest or rib pain, new or worse than normal for participant, and not felt to be attributable to infective exacerbation.
subjects affected / exposed	3 / 20 (15.00%)
occurrences all number	3
Dyspnoea
Additional description: Dyspnoea, new or worse than normal for participant, and not felt to be attributable to infective exacerbation.
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Sputum increased
Additional description: Increased sputum production, worse than normal for participant, and not felt to be attributable to infective exacerbation.
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Hepatobiliary disorders
High ALP
Additional description: Elevated alkaline phosphatase, not normal for patient.
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	2 / 20 (10.00%)
occurrences all number	2
Tongue blistering
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Musculoskeletal and connective tissue disorders
Muscle cramps
Additional description: Muscle cramps, new or worse than normal for participant.
subjects affected / exposed	3 / 20 (15.00%)
occurrences all number	3
Infections and infestations
Sputum culture positive
Additional description: Isolation of new organism in sputum culture (i.e. not identified in previous 12 months). Long term/recurrent isolates were not regarded as an adverse event, as this is normal finding in this patient group.
subjects affected / exposed	7 / 20 (35.00%)
occurrences all number	10
High CRP
Additional description: High c-reactive protein (CRP), not normal for participant, and not felt to be attributable to infective exacerbation.
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1
Metabolism and nutrition disorders
Hyperglycaemia
Additional description: Hyperglycaemia, worse than normal for participant, and not felt to be attributable to infective exacerbation.
subjects affected / exposed	1 / 20 (5.00%)
occurrences all number	1

More information

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Were there any global substantial amendments to the protocol? Yes

26 Nov 2019

The primary purpose of this substantial amendment was to update the list of foreseeable events, and clarify the procedure for recording/collections of these events. The amendment also included some changes to the wording of several other sections, including around safety monitoring and assessment of adverse events, to reflect changes to the standard wording used by the Sponsor for clinical studies.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
27 Mar 2020	Following the final study visit, the analysis and laboratory work associated with the study was paused due to the global COVID-19 pandemic.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The results of the primary outcome have been posted, along with baseline characteristics and adverse events. The analysis of secondary outcomes will be completed and published in due course.

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Clinical trials

Clinical Trial Results:
A pilot trial of intravenous iron for the treatment of iron deficiency in adult patients with cystic fibrosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: New infective events (4 weeks)

Primary: New infective events (4 weeks)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A pilot trial of intravenous iron for the treatment of iron deficiency in adult patients with cystic fibrosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: New infective events (4 weeks)

Primary: New infective events (4 weeks)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A pilot trial of intravenous iron for the treatment of iron deficiency in adult patients with cystic fibrosis