IV Iron Replacement for Iron Deficiency in Idiopathic Pulmonary Arterial Hypertension (IPAH) Patients

Phase 2

Completed

Conditions: Iron Deficiency
Pulmonary Arterial Hypertension

Interventions: Drug: Saline
Drug: Ferinject or CosmoFer

Registration Number: NCT01447628

Lead Sponsor: Imperial College London

Brief Summary: This study will establish whether intravenous iron replacement has clinical benefit in idiopathic pulmonary arterial hypertension.

A 24-week double-blind, randomised, placebo-controlled, crossover study will investigate whether a single dose of 1g of Ferinject® or CosmoFer improves cardiopulmonary haemodynamics, exercise capacity and quality of life and is well-tolerated.

IV iron formulation used in Europe - Ferinject IV iron formulation used in China - CosmoFer

Detailed Description: These results represent the outcome of two separate clinical trials which were conducted in collaboration, led by Imperial College and Fuwai, China respectively. The protocols were analogous, although in China Endurance Cardio-Pulmonary Exercise Testing (CPET) was not done and instead of Ferinject/Placebo being infused over 15 minutes, Cosmofer/Placebo was infused over 4-6 hours.

The study analyses were performed as Intention to Treat, except for patients 6009-6017 as described below. The study was a cross-over design and results are presented for 2 groups based on the participants' study timepoint, and presented separately for the two study datasets (Europe and Fuwai). A meta-analysis was conducted for the combined data where possible and the relevant p-values have been provided.

Iron results in the European dataset are taken from blood results which were collected centrally and analysed by one laboratory at Imperial College London. N-Terminal B-type natriuretic peptide (NT-PRO-BNP) and Soluble Transferrin Receptors (STFR) were not done at Fuwai.

The study was conducted according to Good Clinical Practice (GCP), but there were some missing data (imputed using multiple imputation techniques), and also some significant protocol deviations which are summarised below.

Six participants (2003, 3004, 4002-4005) had their endurance CPETs set at incorrect workloads which differed significantly from that achieved at the baseline incremental CPET. These data were therefore treated as missing, and relevant values imputed as per the statistical analysis plan.

Visit 5 CPETs for participants 1008 (Incremental CPET 12 weeks later) 1018 (Endurance CPET 13 days later) and 1019 (Incremental CPET 15 days later) were performed outside the protocol-specified window.

Participant 1014 received placebo at both treatment visits in error. Participant 6017 suffered a suspected allergic reaction to their first infusion and was withdrawn from the study. There was a systemic error where participants 6009-6016 received the opposite to their random-assigned treatment at each time point. These participants were analysed according to the treatment actually received, rather than that originally assigned by randomisation.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 56

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo followed by Ferinject or CosmoFer	Ferinject or CosmoFer	Placebo comparator Placebo (saline) given at Week 0, IV Iron given at Week 12.
Ferinject or CosmoFer followed by Placebo	Saline	IV iron formulation used in Europe - Ferinject - given over 15 minutes IV iron formulation used in China - CosmoFer - over a period of 4 to 6 hours IV Iron given at Week 0, Placebo (saline) given at Week 12.
Ferinject or CosmoFer followed by Placebo	Ferinject or CosmoFer	IV iron formulation used in Europe - Ferinject - given over 15 minutes IV iron formulation used in China - CosmoFer - over a period of 4 to 6 hours IV Iron given at Week 0, Placebo (saline) given at Week 12.
Placebo followed by Ferinject or CosmoFer	Saline	Placebo comparator Placebo (saline) given at Week 0, IV Iron given at Week 12.

Primary Outcome Measures

Name	Time	Method
Change in Resting Pulmonary Vascular Resistance (PVR)	12 weeks post study treatment	To be measured by cardiac catheterisation in wood units.
Change in Exercise Capacity - Endurance	12 Weeks post study treatment	Time measured in seconds from start to end of the endurance bicycle cardiopulmonary exercise testing at 80% of the peak work rate. Peak work rate is determined by that achieved at the baseline incremental cardiopulmonary exercise test (CPET). Note that this was the primary end-point of the European study. Endurance CPET was not done in China.

Secondary Outcome Measures

Name	Time	Method
Oxygen Consumption (VO2) at 3 Minutes	12 weeks post study treatment	Level of VO2 measured at 3 minutes into endurance cardio-pulmonary exercise test (CPET) Note that endurance CPET was not done in China, hence results are presented only for the European dataset.
Iron Indices: Ferritin	12 weeks post study treatment	Measured level of serum ferritin
Oxygen Consumption (VO2) / Work Rate (WR) Slope	12 weeks post study treatment	Level of VO2 / WR Slope measured during incremental cardio-pulmonary exercise testing
Oxygen Consumption (VO2) at the End of Endurance Cardio-pulmonary Exercise Test (CPET)	12 weeks post study treatment	Level of VO2 measured at end of endurance cardio-pulmonary exercise test. Note that endurance CPET was not done in China, so this is reported only for the European dataset.
Oxygen Consumption (VO2) Level at Peak 12 Weeks After Study Treatment	12 weeks post study treatment	Level of VO2 at peak measured during incremental cardio-pulmonary exercise testing
6 Minute Walk Test: Borg Dyspnoea Score After Test	12 weeks post study treatment	Participant reported score on the modified Borg Dyspnoea scale (0-10) following 6 minute walk test. Higher scores indicate worsened dyspnoea.
Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR Questionnaire): Activity Score	12 weeks post study treatment	Participants' self reported score of their own level of activity based on the CAMPHOR questionnaire. Activity scores range from 0-30, with higher scores indicating more physical limitations Note that this was not measured in China, hence is presented only for the European dataset.
Mean Right Atrial Pressure (Cardiac Catheter)	12 weeks post study treatment	Mean right atrial pressure at rest measured by cardiac catheter
Ventilation / Volume of Exhaled Carbon Dioxide (VE/VCO2 Slope)	12 weeks post study treatment	VE/VCO2 slope measured during incremental cardio-pulmonary exercise testing
Iron Indices: Serum Iron	12 weeks post study treatment	Measurement of serum iron
6 Minute Walk Test: Distance Walked	12 weeks post study treatment	Distance in metres walked during standardised and validated 6 minute walk test
Stroke Volume (Cardiac Catheter)	12 weeks post treatment	Measurement of stroke volume at rest by cardiac catheter at 12 weeks post treatment
Oxygen Consumption (VO2) at Metabolic Threshold	12 weeks post treatment	VO2 at Metabolic Threshold measured during incremental cardio-pulmonary exercise test
Peak Oxygen (O2) Pulse Rate	12 weeks post study treatment	O2 pulse rate (amount of oxygen consumed per heart beat) at peak measured during incremental cardio-pulmonary exercise test
Iron Indices: Transferrin Saturations	12 weeks post study treatment	Measurement of serum transferrin saturations. The saturation measures the iron concentration as a proportion of the iron binding capacity of transferrin.
Iron Indices: Soluble Transferrin Receptors (sTfR)	12 weeks post study treatment	Measure of serum sTfR level. Note that this was not measured in China, hence is reported only for the European dataset.
Iron Indices: N-terminal Pro B-type Natriuretic Peptide (NT-pro-BNP)	12 weeks post study treatment	Measured level of NT-pro-BNP in blood sample. Note that this was not measured in China, hence is presented only for the European dataset.
Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR Questionnaire): Symptom Score	12 weeks post study treatment	Participant self reported symptom score using the CAMPHOR questionnaire (0-25). Scores for symptoms range from 0-25, with higher scores indicating worse symptoms. Note that this was not measured in China, hence is presented only for the European dataset.
Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular End Systolic Volume (LVESV)	12 weeks	Cardiac MR: Left Ventricular End Systolic Volume
Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR Questionnaire): QoL Score	12 weeks post study treatment	Quality of Life score based on the Cambridge Pulmonary Hypertension Outcomes Review (CAMPHOR) questionnaire (0-25). Scores for QoL range from 0-25, with higher scores indicating worse quality of life Note that this was not measured in China, hence is presented only for the European dataset.
Oxygen Consumption (VO2) Level at Peak	12 weeks post study treatment	VO2 at peak of Incremental Cardio-pulmonary exercise test in ml/min/kg
Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular End Systolic Volume (RVESV)	12 weeks	Cardiac MR: Right ventricular end systolic volume
Cardiac Magnetic Resonance Imaging: Left Ventricular Mass	12 weeks	Cardiac MR: Left Ventricular Mass
Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular End-diastolic Volume	12 weeks	Cardiac MRI: Right ventricular end-diastolic volumes
Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular Stroke Volume (RVSV)	12 weeks	Right ventricular stroke volumes assessed by cardiac MRI scan
Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular Ejection Fraction (RVEF)	12 weeks	Cardiac MR: Right ventricular ejection fractions
Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular End Diastolic Volume (LVEDV)	12 weeks	Cardiac MR: Left Ventricular End Diastolic Volume
Cardiac Magnetic Resonance Imaging: Left Ventricular Stroke Volume (LVSV)	12 weeks	Cardiac MR: Left Ventricular Stroke Volume
Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular Ejection Fraction (LVEF)	12 weeks	Cardiac MR: Left Ventricular Ejection Fraction

Trial Locations

Locations (5): Fuwai Hospital
🇨🇳
Beijing, China
Justus-Liebig University
🇩🇪
Giessen, Germany
Papworth Hospital NHS Foundation Trust
🇬🇧
Cambridge, United Kingdom
Hammersmith Hospital, Imperial College NHS Trust
🇬🇧
London, United Kingdom
Royal Hallamshire Hospital
🇬🇧
Sheffield, United Kingdom