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

Study Overview
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Brief Summary
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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
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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.

Official Title
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What is the Effect of Intravenous Iron Supplementation on Cardiopulmonary Haemodynamics, Exercise Capacity and Quality of Life in Patients With IPAH and Iron Deficiency?

Conditions
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Pulmonary Arterial Hypertension, Iron Deficiency

Intervention / Treatment
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* Drug: Saline
* Drug: Ferinject or CosmoFer


Participation Criteria
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Eligibility Criteria
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Males or females aged between 16-75 years old Pulmonary Arterial Hypertension (PAH) which is idiopathic, heritable or associated with anorexigens. Iron deficiency (TfR levels > 28.1 nmol/l, where sTfR analysis is available, Ferritin < 37 ug/l; transferrin saturations < 16.4%; iron < 10.3 umol/l) Documented diagnosis of PAH by right heart catheterisation performed at any time prior to Screening showing: resting mean pulmonary artery pressure >25mmHg, pulmonary capillary wedge pressure =/< 15 mm Hg and normal or reduced cardiac output; 6 minute walking distance greater than 50m at entry; Stable on an unchanged PAH therapeutic regime (any combination of endothelin receptor antagonist, phosphodiesterase inhibitor or prostacyclin analogue) for at least 1 month. Able to provide written informed consent prior to any study-mandated procedures Female subjects of child-bearing potential are eligible to participate if they agree to use one of the following contraception methods: Abstinence Contraceptive methods with a failure rate of < 1%: Oral contraceptive, either combined or progestogen alone; Injectable progestogen; Implants of levonorgestrel; Estrogenic vaginal ring; Percutaneous contraceptive patches; Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure rate as stated in the product label; Male partner(s) sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study; Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus vaginal spermicidal agent (foam/gel/film/cream/suppository). Exclusion criteria Unable to provide informed consent. Clinically-significant renal disease (Creatinine clearance < 30 ml/min per 1.73 m2 calculated from Chronic Kidney Disease-Epidemiology Collaboration (CKD-Epi) http://www.qxmed.com/renal/Calculate-CKD-EPI-GFR.php) or liver disease (including serum transaminases > 3 times upper limit of normal). Haemoglobin concentration <10 g/dl. Patients will be excluded if any single parameter (iron, ferritin or transferrin saturation) exceeds 1x upper limit of normal (ULN) in the local lab reference range. Patients with moderate to severe hypophosphatemia as defined as <0.65mmol/L Known to have haemoglobinopathy e.g. sickle cell disease, thalassaemia. Admission to hospital related to PAH or change in PAH therapy within 1 month prior to Screening. Evidence of left ventricular disease or significant lung disease on high-resolution Computed Tomography (CT) scanning or lung function as judged by the investigator Acute or chronic infection or inflammation. Significant uncontrolled asthma as judged by the investigator, eczema or atopic allergies. Females who are lactating or pregnant. Individuals known to have Human Immunodeficiency Virus (HIV), Hepatitis B or C or Creutzfeld-Jakob disease. Known hypersensitivity to Ferinject® or any of its excipients. Evidence of disturbances in utilisation of iron. Significant blood loss (e.g. Gastro-intestinal bleed) within the last 3 months or history of menorrhagia. Unable to perform a Cardiopulmonary Exercise Test i.e. due to syncope or musculoskeletal factors. Patients who have received an investigational medicinal product within 30 days of entering the baseline visit

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ferinject or CosmoFer followed by Placebo<br>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. | Drug: Saline<br>* intravenous, no active drug<br>* Other names: Placebo;Drug: Ferinject or CosmoFer<br>* Intravenous, 1000 mg iron<br>* Other names: Intravenous Iron;|
| Placebo Comparator: Placebo followed by Ferinject or CosmoFer<br>Placebo comparator Placebo (saline) given at Week 0, IV Iron given at Week 12. | Drug: Saline<br>* intravenous, no active drug<br>* Other names: Placebo;Drug: Ferinject or CosmoFer<br>* Intravenous, 1000 mg iron<br>* Other names: Intravenous Iron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Exercise Capacity - Endurance | 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. | 12 Weeks post study treatment | 
| Change in Resting Pulmonary Vascular Resistance (PVR) | To be measured by cardiac catheterisation in wood units. | 12 weeks post study treatment | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Idiopathic pulmonary arterial hypertension (IPAH), Iron deficiency