Iron Deficiency, Pulmonary Arterial Hypertension
Conditions
Keywords
Idiopathic pulmonary arterial hypertension (IPAH), Iron deficiency
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.
Interventions
DRUGSaline
intravenous, no active drug
DRUGFerinject or CosmoFer
Intravenous, 1000 mg iron
Sponsors
Fu Wai Hospital, Beijing, China
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Change in Resting Pulmonary Vascular Resistance (PVR) | 12 weeks post study treatment | To be measured by cardiac catheterisation in wood units. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ventilation / Volume of Exhaled Carbon Dioxide (VE/VCO2 Slope) | 12 weeks post study treatment | VE/VCO2 slope measured during incremental cardio-pulmonary exercise testing |
| Oxygen Consumption (VO2) / Work Rate (WR) Slope | 12 weeks post study treatment | Level of VO2 / WR Slope measured during incremental cardio-pulmonary exercise testing |
| 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 |
| 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) 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: Serum Iron | 12 weeks post study treatment | Measurement of serum iron |
| 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: Ferritin | 12 weeks post study treatment | Measured level of serum ferritin |
| 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. |
| 6 Minute Walk Test: Distance Walked | 12 weeks post study treatment | Distance in metres walked during standardised and validated 6 minute walk test |
| 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. |
| 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. |
| 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 |
| 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. |
| Mean Right Atrial Pressure (Cardiac Catheter) | 12 weeks post study treatment | Mean right atrial pressure at rest measured by cardiac catheter |
| Oxygen Consumption (VO2) Level at Peak | 12 weeks post study treatment | VO2 at peak of Incremental Cardio-pulmonary exercise test in ml/min/kg |
| Stroke Volume (Cardiac Catheter) | 12 weeks post treatment | Measurement of stroke volume at rest by cardiac catheter at 12 weeks post treatment |
| 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 End Systolic Volume (RVESV) | 12 weeks | Cardiac MR: Right ventricular end systolic volume |
| 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 (MRI): Left Ventricular End Systolic Volume (LVESV) | 12 weeks | Cardiac MR: Left Ventricular End Systolic 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 |
| Cardiac Magnetic Resonance Imaging: Left Ventricular Mass | 12 weeks | Cardiac MR: Left Ventricular Mass |
| 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. |
| Oxygen Consumption (VO2) at Metabolic Threshold | 12 weeks post study treatment | Level of VO2 at metabolic threshold measured during incremental cardio-pulmonary exercise test |
Countries
China, Germany, United Kingdom
Participant flow
Pre-assignment details
The groups are separated into Europe and China, because a different Investigational Medicinal Product (IMP) was used and outcome measures were analysed separately.
Participants by arm
| Arm | Count |
|---|---|
| European Dataset IV iron (1000 mg) formulation used in Europe - Ferinject - given over 15 minutes
Saline: intravenous, no active drug | 39 |
| China Dataset IV iron (1000mg) formulation used in China - CosmoFer - over a period of 4 to 6 hours
Saline: intravenous, no active drug | 17 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Week 0 to Week 12 (1st Intervention) | Adverse Event | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | European Dataset | China Dataset | Total |
|---|---|---|---|
| Age, Continuous | 49.4 years | 32.58 years | 44.3 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 17 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 36 Participants | 0 Participants | 36 Participants |
| Region of Enrollment China | 0 participants | 17 participants | 17 participants |
| Region of Enrollment Germany | 5 participants | 0 participants | 5 participants |
| Region of Enrollment United Kingdom | 34 participants | 0 participants | 34 participants |
| Sex: Female, Male Female | 29 Participants | 15 Participants | 44 Participants |
| Sex: Female, Male Male | 10 Participants | 2 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 26 / 39 | 28 / 39 | 13 / 39 | 3 / 17 | 4 / 17 | 2 / 17 |
| other Total, other adverse events | 22 / 39 | 21 / 39 | 11 / 39 | 3 / 17 | 4 / 17 | 3 / 17 |
| serious Total, serious adverse events | 4 / 39 | 3 / 39 | 1 / 39 | 0 / 17 | 1 / 17 | 0 / 17 |
Outcome results
Primary
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.
Time frame: 12 Weeks post study treatment
Population: Intention to treat (ITT)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Change in Exercise Capacity - Endurance | 315.44 Seconds |
| Placebo Group (Europe) | Change in Exercise Capacity - Endurance | 302.89 Seconds |
p-value: 0.6039Mixed Models Analysis
Primary
Change in Resting Pulmonary Vascular Resistance (PVR)
To be measured by cardiac catheterisation in wood units.
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Change in Resting Pulmonary Vascular Resistance (PVR) | 7.69 Wood units |
| Placebo Group (Europe) | Change in Resting Pulmonary Vascular Resistance (PVR) | 5.15 Wood units |
| Cosmofer Group (China) | Change in Resting Pulmonary Vascular Resistance (PVR) | 11.70 Wood units |
| Placebo Group (China) | Change in Resting Pulmonary Vascular Resistance (PVR) | 9.5 Wood units |
p-value: 0.0747Mixed Models Analysis
p-value: 0.799Mixed Models Analysis
Comparison: This is a combination of the p-values from the separate analyses of each data set.p-value: 0.2111Mixed Models Analysis
Secondary
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.
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | 6 Minute Walk Test: Borg Dyspnoea Score After Test | 3.24 units on a scale |
| Placebo Group (Europe) | 6 Minute Walk Test: Borg Dyspnoea Score After Test | 3.68 units on a scale |
| Cosmofer Group (China) | 6 Minute Walk Test: Borg Dyspnoea Score After Test | 1.38 units on a scale |
| Placebo Group (China) | 6 Minute Walk Test: Borg Dyspnoea Score After Test | 1.28 units on a scale |
p-value: 0.0725Mixed Models Analysis
p-value: 0.8572Mixed Models Analysis
p-value: 0.2348Mixed Models Analysis
Secondary
6 Minute Walk Test: Distance Walked
Distance in metres walked during standardised and validated 6 minute walk test
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | 6 Minute Walk Test: Distance Walked | 426.03 Metres |
| Placebo Group (Europe) | 6 Minute Walk Test: Distance Walked | 424.3 Metres |
| Cosmofer Group (China) | 6 Minute Walk Test: Distance Walked | 478 Metres |
| Placebo Group (China) | 6 Minute Walk Test: Distance Walked | 474.19 Metres |
p-value: 0.8093Mixed Models Analysis
p-value: 0.63Mixed Models Analysis
p-value: 0.8533Mixed Models Analysis
Secondary
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.
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR Questionnaire): Activity Score | 9.12 units on a scale |
| Placebo Group (Europe) | Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR Questionnaire): Activity Score | 9.18 units on a scale |
p-value: 0.7702Mixed Models Analysis
Secondary
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.
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR Questionnaire): QoL Score | 7.58 units on a scale |
| Placebo Group (Europe) | Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR Questionnaire): QoL Score | 7 units on a scale |
p-value: 0.2219Mixed Models Analysis
Secondary
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.
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR Questionnaire): Symptom Score | 7.94 score on a scale |
| Placebo Group (Europe) | Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR Questionnaire): Symptom Score | 7.94 score on a scale |
p-value: 0.979Mixed Models Analysis
Secondary
Cardiac Magnetic Resonance Imaging: Left Ventricular Mass
Cardiac MR: Left Ventricular Mass
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Cardiac Magnetic Resonance Imaging: Left Ventricular Mass | 72.82 Grams |
| Placebo Group (Europe) | Cardiac Magnetic Resonance Imaging: Left Ventricular Mass | 73.53 Grams |
p-value: 0.2651Mixed Models Analysis
Secondary
Cardiac Magnetic Resonance Imaging: Left Ventricular Stroke Volume (LVSV)
Cardiac MR: Left Ventricular Stroke Volume
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Cardiac Magnetic Resonance Imaging: Left Ventricular Stroke Volume (LVSV) | 43.90 Mililitres |
| Placebo Group (Europe) | Cardiac Magnetic Resonance Imaging: Left Ventricular Stroke Volume (LVSV) | 73.96 Mililitres |
p-value: 0.7721Mixed Models Analysis
Secondary
Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular Ejection Fraction (LVEF)
Cardiac MR: Left Ventricular Ejection Fraction
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular Ejection Fraction (LVEF) | 63.10 Percentage |
| Placebo Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular Ejection Fraction (LVEF) | 62.94 Percentage |
p-value: 0.8332Mixed Models Analysis
Secondary
Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular End Diastolic Volume (LVEDV)
Cardiac MR: Left Ventricular End Diastolic Volume
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular End Diastolic Volume (LVEDV) | 117.36 Mililitres |
| Placebo Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular End Diastolic Volume (LVEDV) | 118.33 Mililitres |
p-value: 0.585Mixed Models Analysis
Secondary
Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular End Systolic Volume (LVESV)
Cardiac MR: Left Ventricular End Systolic Volume
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular End Systolic Volume (LVESV) | 43.90 Mililitres |
| Placebo Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular End Systolic Volume (LVESV) | 44.43 Mililitres |
p-value: 0.4619Mixed Models Analysis
Secondary
Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular Ejection Fraction (RVEF)
Cardiac MR: Right ventricular ejection fractions
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular Ejection Fraction (RVEF) | 39.89 percentage |
| Placebo Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular Ejection Fraction (RVEF) | 39.64 percentage |
p-value: 0.6944Mixed Models Analysis
Secondary
Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular End-diastolic Volume
Cardiac MRI: Right ventricular end-diastolic volumes
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular End-diastolic Volume | 201.35 mililitres |
| Placebo Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular End-diastolic Volume | 203.06 mililitres |
p-value: 0.4478Mixed Models Analysis
Secondary
Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular End Systolic Volume (RVESV)
Cardiac MR: Right ventricular end systolic volume
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular End Systolic Volume (RVESV) | 124.99 mililitres |
| Placebo Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular End Systolic Volume (RVESV) | 126.31 mililitres |
p-value: 0.459Mixed Models Analysis
Secondary
Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular Stroke Volume (RVSV)
Right ventricular stroke volumes assessed by cardiac MRI scan
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular Stroke Volume (RVSV) | 76.46 mililitres |
| Placebo Group (Europe) | Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular Stroke Volume (RVSV) | 76.84 mililitres |
p-value: 0.8086Mixed Models Analysis
Secondary
Iron Indices: Ferritin
Measured level of serum ferritin
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Iron Indices: Ferritin | 150.32 ug/L |
| Placebo Group (Europe) | Iron Indices: Ferritin | 92.74 ug/L |
| Cosmofer Group (China) | Iron Indices: Ferritin | 135.06 ug/L |
| Placebo Group (China) | Iron Indices: Ferritin | 65.5 ug/L |
p-value: 0.0003Mixed Models Analysis
p-value: 0.0001Mixed Models Analysis
p-value: <0.0001Mixed Models Analysis
Secondary
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.
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Iron Indices: N-terminal Pro B-type Natriuretic Peptide (NT-pro-BNP) | 307.64 fmol/ml |
| Placebo Group (Europe) | Iron Indices: N-terminal Pro B-type Natriuretic Peptide (NT-pro-BNP) | 394.94 fmol/ml |
p-value: 0.1115Mixed Models Analysis
Secondary
Iron Indices: Serum Iron
Measurement of serum iron
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Iron Indices: Serum Iron | 17.15 umol/L |
| Placebo Group (Europe) | Iron Indices: Serum Iron | 15.48 umol/L |
| Cosmofer Group (China) | Iron Indices: Serum Iron | 15.81 umol/L |
| Placebo Group (China) | Iron Indices: Serum Iron | 14.31 umol/L |
p-value: 0.205Mixed Models Analysis
p-value: 0.1993Mixed Models Analysis
p-value: 0.1993Mixed Models Analysis
Secondary
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.
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Iron Indices: Soluble Transferrin Receptors (sTfR) | 28.37 nmol/L |
| Placebo Group (Europe) | Iron Indices: Soluble Transferrin Receptors (sTfR) | 37.25 nmol/L |
p-value: <0.0001Mixed Models Analysis
Secondary
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.
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Iron Indices: Transferrin Saturations | 26.2 percentage of iron occupied transferrin |
| Placebo Group (Europe) | Iron Indices: Transferrin Saturations | 22 percentage of iron occupied transferrin |
| Cosmofer Group (China) | Iron Indices: Transferrin Saturations | 26.81 percentage of iron occupied transferrin |
| Placebo Group (China) | Iron Indices: Transferrin Saturations | 22.88 percentage of iron occupied transferrin |
p-value: 0.061Mixed Models Analysis
p-value: 0.0641Mixed Models Analysis
Secondary
Mean Right Atrial Pressure (Cardiac Catheter)
Mean right atrial pressure at rest measured by cardiac catheter
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Mean Right Atrial Pressure (Cardiac Catheter) | 6.56 mmHg |
| Placebo Group (Europe) | Mean Right Atrial Pressure (Cardiac Catheter) | 10.12 mmHg |
| Cosmofer Group (China) | Mean Right Atrial Pressure (Cardiac Catheter) | 6.67 mmHg |
| Placebo Group (China) | Mean Right Atrial Pressure (Cardiac Catheter) | 4.5 mmHg |
p-value: 0.1777Mixed Models Analysis
p-value: 0.7889Mixed Models Analysis
p-value: 0.4156Mixed Models Analysis
Secondary
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.
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Oxygen Consumption (VO2) at 3 Minutes | 1.29 Litres per minute |
| Placebo Group (Europe) | Oxygen Consumption (VO2) at 3 Minutes | 1.14 Litres per minute |
p-value: 0.4758Mixed Models Analysis
Secondary
Oxygen Consumption (VO2) at Metabolic Threshold
VO2 at Metabolic Threshold measured during incremental cardio-pulmonary exercise test
Time frame: 12 weeks post treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Oxygen Consumption (VO2) at Metabolic Threshold | 10.01 ml/min/kg |
| Placebo Group (Europe) | Oxygen Consumption (VO2) at Metabolic Threshold | 9.99 ml/min/kg |
| Cosmofer Group (China) | Oxygen Consumption (VO2) at Metabolic Threshold | 10.91 ml/min/kg |
| Placebo Group (China) | Oxygen Consumption (VO2) at Metabolic Threshold | 11.2 ml/min/kg |
p-value: 0.7711Mixed Models Analysis
p-value: 0.7806Mixed Models Analysis
p-value: 0.9074Mixed Models Analysis
Secondary
Oxygen Consumption (VO2) at Metabolic Threshold
Level of VO2 at metabolic threshold measured during incremental cardio-pulmonary exercise test
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Oxygen Consumption (VO2) at Metabolic Threshold | 0.78 Litres per minute |
| Placebo Group (Europe) | Oxygen Consumption (VO2) at Metabolic Threshold | 0.77 Litres per minute |
| Cosmofer Group (China) | Oxygen Consumption (VO2) at Metabolic Threshold | 0.66 Litres per minute |
| Placebo Group (China) | Oxygen Consumption (VO2) at Metabolic Threshold | 0.69 Litres per minute |
p-value: 0.4039Mixed Models Analysis
p-value: 0.9144Mixed Models Analysis
p-value: 0.9959Mixed Models Analysis
Secondary
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.
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Oxygen Consumption (VO2) at the End of Endurance Cardio-pulmonary Exercise Test (CPET) | 4.25 Litres per minute |
| Placebo Group (Europe) | Oxygen Consumption (VO2) at the End of Endurance Cardio-pulmonary Exercise Test (CPET) | 4.49 Litres per minute |
Comparison: Note that Endurance CPET was not done in China, hence only European data provided.p-value: 0.6241Mixed Models Analysis
Secondary
Oxygen Consumption (VO2) Level at Peak
VO2 at peak of Incremental Cardio-pulmonary exercise test in ml/min/kg
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Oxygen Consumption (VO2) Level at Peak | 15.10 ml/min/kg |
| Placebo Group (Europe) | Oxygen Consumption (VO2) Level at Peak | 14.67 ml/min/kg |
| Cosmofer Group (China) | Oxygen Consumption (VO2) Level at Peak | 14.53 ml/min/kg |
| Placebo Group (China) | Oxygen Consumption (VO2) Level at Peak | 14.36 ml/min/kg |
p-value: 0.7625Mixed Models Analysis
p-value: 0.2262Mixed Models Analysis
p-value: 0.4756Mixed Models Analysis
Secondary
Oxygen Consumption (VO2) Level at Peak 12 Weeks After Study Treatment
Level of VO2 at peak measured during incremental cardio-pulmonary exercise testing
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Oxygen Consumption (VO2) Level at Peak 12 Weeks After Study Treatment | 1.17 Litres per minute |
| Placebo Group (Europe) | Oxygen Consumption (VO2) Level at Peak 12 Weeks After Study Treatment | 1.13 Litres per minute |
| Cosmofer Group (China) | Oxygen Consumption (VO2) Level at Peak 12 Weeks After Study Treatment | 0.93 Litres per minute |
| Placebo Group (China) | Oxygen Consumption (VO2) Level at Peak 12 Weeks After Study Treatment | 0.94 Litres per minute |
p-value: 0.6583Mixed Models Analysis
p-value: 0.9166Mixed Models Analysis
p-value: 0.6631Mixed Models Analysis
Secondary
Oxygen Consumption (VO2) / Work Rate (WR) Slope
Level of VO2 / WR Slope measured during incremental cardio-pulmonary exercise testing
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Oxygen Consumption (VO2) / Work Rate (WR) Slope | 8.12 ml/min/watt |
| Placebo Group (Europe) | Oxygen Consumption (VO2) / Work Rate (WR) Slope | 8.04 ml/min/watt |
| Cosmofer Group (China) | Oxygen Consumption (VO2) / Work Rate (WR) Slope | 5.97 ml/min/watt |
| Placebo Group (China) | Oxygen Consumption (VO2) / Work Rate (WR) Slope | 6.04 ml/min/watt |
p-value: 0.8688Mixed Models Analysis
p-value: 0.9999Mixed Models Analysis
p-value: 0.991Mixed Models Analysis
Secondary
Peak Oxygen (O2) Pulse Rate
O2 pulse rate (amount of oxygen consumed per heart beat) at peak measured during incremental cardio-pulmonary exercise test
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Peak Oxygen (O2) Pulse Rate | 13.30 ml/beat |
| Placebo Group (Europe) | Peak Oxygen (O2) Pulse Rate | 11.92 ml/beat |
| Cosmofer Group (China) | Peak Oxygen (O2) Pulse Rate | 6.55 ml/beat |
| Placebo Group (China) | Peak Oxygen (O2) Pulse Rate | 6.36 ml/beat |
p-value: 0.5465Mixed Models Analysis
p-value: 0.4298Mixed Models Analysis
p-value: 0.5451Mixed Models Analysis
Secondary
Stroke Volume (Cardiac Catheter)
Measurement of stroke volume at rest by cardiac catheter at 12 weeks post treatment
Time frame: 12 weeks post treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Stroke Volume (Cardiac Catheter) | 77.87 mililitres |
| Placebo Group (Europe) | Stroke Volume (Cardiac Catheter) | 99.71 mililitres |
| Cosmofer Group (China) | Stroke Volume (Cardiac Catheter) | 55.11 mililitres |
| Placebo Group (China) | Stroke Volume (Cardiac Catheter) | 54.65 mililitres |
p-value: 0.9504Mixed Models Analysis
p-value: 0.8666Mixed Models Analysis
p-value: 0.8104Mixed Models Analysis
Secondary
Ventilation / Volume of Exhaled Carbon Dioxide (VE/VCO2 Slope)
VE/VCO2 slope measured during incremental cardio-pulmonary exercise testing
Time frame: 12 weeks post study treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ferinject Group (Europe) | Ventilation / Volume of Exhaled Carbon Dioxide (VE/VCO2 Slope) | 41.15 l/min/l/min |
| Placebo Group (Europe) | Ventilation / Volume of Exhaled Carbon Dioxide (VE/VCO2 Slope) | 42.35 l/min/l/min |
| Cosmofer Group (China) | Ventilation / Volume of Exhaled Carbon Dioxide (VE/VCO2 Slope) | 35.06 l/min/l/min |
| Placebo Group (China) | Ventilation / Volume of Exhaled Carbon Dioxide (VE/VCO2 Slope) | 36.27 l/min/l/min |
p-value: 0.1788Mixed Models Analysis
p-value: 0.7795Mixed Models Analysis
p-value: 0.414Mixed Models Analysis