IV Iron Replacement for Iron Deficiency in Idiopathic Pul... | NCT01447628

Status Module

Name	Class
Fu Wai Hospital, Beijing, China	OTHER

Description Module

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 Participant 6017 suffered a suspected allergic reaction to their first infusion and was withdrawn from the study.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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Ferinject or CosmoFer followed by Placebo	Active Comparator	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 Drug: Ferinject or CosmoFer
Placebo followed by Ferinject or CosmoFer	Placebo Comparator	Placebo comparator Placebo (saline) given at Week 0, IV Iron given at Week 12.	Drug: Saline Drug: Ferinject or CosmoFer

Name	Type	Description	Arm Group Labels	Other Names
Saline	Drug	intravenous, no active drug	Ferinject or CosmoFer followed by Placebo Placebo followed by Ferinject or CosmoFer

Outcomes Module

Primary Outcomes

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 Outcomes

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

Eligibility Module

Eligibility 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

Name	Affiliation	Role
Luke Howard, DPhil, FRCP	Imperial College London	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Fuwai Hospital		Beijing			China
Justus-Liebig University

PubMed Identifier	Type	Citation	Retractions
33735594	Derived	Howard LSGE, He J, Watson GMJ, Huang L, Wharton J, Luo Q, Kiely DG, Condliffe R, Pepke-Zaba J, Morrell NW, Sheares KK, Ulrich A, Quan R, Zhao Z, Jing X, An C, Liu Z, Xiong C, Robbins PA, Dawes T, de Marvao A, Rhodes CJ, Richter MJ, Gall H, Ghofrani HA, Zhao L, Huson L, Wilkins MR. Supplementation with Iron in Pulmonary Arterial Hypertension. Two Randomized Crossover Trials. Ann Am Thorac Soc. 2021 Jun;18(6):981-988. doi: 10.1513/AnnalsATS.202009-1131OC.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Ferinject Followed by Placebo (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes followed by Placebo given as 1000mg saline according to randomisation. Ferinject administered at week 0, placebo (saline) administered at week 12.
FG001

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Oct 24, 2016	Dec 15, 2017

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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.

Intention to treat (ITT)

Posted

Least Squares Mean

95% Confidence Interval

Seconds

12 Weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo whether at the first or second timepoint

Units	Counts
Participants	OG00039 OG00139

Title

Denominators

Categories

Title	Measurements
	OG000315.44(274.68 to 356.20) OG001302.89(260.09 to 345.69)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Mixed Models Analysis		0.6039														Superiority

Primary

Change in Resting Pulmonary Vascular Resistance (PVR)

To be measured by cardiac catheterisation in wood units.

Posted

Mean

95% Confidence Interval

Wood units

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003	Placebo Group (China)

Secondary

Oxygen Consumption (VO2) Level at Peak 12 Weeks After Study Treatment

Level of VO2 at peak measured during incremental cardio-pulmonary exercise testing

Posted

Mean

95% Confidence Interval

Litres per minute

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003	Placebo Group (China)

Secondary

Oxygen Consumption (VO2) at Metabolic Threshold

Level of VO2 at metabolic threshold measured during incremental cardio-pulmonary exercise test

Posted

Mean

95% Confidence Interval

Litres per minute

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003	Placebo Group (China)

Secondary

Ventilation / Volume of Exhaled Carbon Dioxide (VE/VCO2 Slope)

VE/VCO2 slope measured during incremental cardio-pulmonary exercise testing

Posted

Mean

95% Confidence Interval

l/min/l/min

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003	Placebo Group (China)

Secondary

Oxygen Consumption (VO2) / Work Rate (WR) Slope

Level of VO2 / WR Slope measured during incremental cardio-pulmonary exercise testing

Posted

Mean

95% Confidence Interval

ml/min/watt

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003	Placebo Group (China)

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

Posted

Least Squares Mean

95% Confidence Interval

ml/beat

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003	Placebo Group (China)

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.

Posted

Least Squares Mean

95% Confidence Interval

Litres per minute

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint

Units	Counts
Participants	OG000

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.

Posted

Least Squares Mean

95% Confidence Interval

Litres per minute

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint

Units	Counts
Participants	OG000

Secondary

Iron Indices: Serum Iron

Measurement of serum iron

Posted

Mean

95% Confidence Interval

umol/L

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003	Placebo Group (China)	This group provides the outcome measurements for participants from the Fuwai site following their infusion of Placebo (saline, infused over 4-6hrs), whether this was at the first or second timepoint.

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.

Posted

Mean

95% Confidence Interval

percentage of iron occupied transferrin

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject European Dataset: Active IMP	Measure of transferrin saturations in European patients receiving active treatment.
OG001	Ferinject European Dataset: Placebo Arm	Measure of transferrin saturations at 12 weeks in European patients receiving placebo
OG002	Cosmofer: China Dataset Active	Measure of transferrin saturations in China patients receiving Cosmofer
OG003	Placebo: China Dataset	Measure of transferrin saturations in China patients receiving Placebo

Secondary

Iron Indices: Ferritin

Measured level of serum ferritin

Posted

Mean

95% Confidence Interval

ug/L

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003	Placebo Group (China)	This group provides the outcome measurements for participants from the Fuwai site following their infusion of Placebo (saline, infused over 4-6hrs), whether this was at the first or second timepoint.

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.

Posted

Mean

95% Confidence Interval

nmol/L

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint

Units	Counts
Participants	OG000

Secondary

6 Minute Walk Test: Distance Walked

Distance in metres walked during standardised and validated 6 minute walk test

Posted

Mean

95% Confidence Interval

Metres

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003	Placebo Group (China)

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.

Posted

Mean

95% Confidence Interval

units on a scale

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003

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.

Posted

Mean

95% Confidence Interval

fmol/ml

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint

Units	Counts
Participants	OG000

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.

Posted

Mean

95% Confidence Interval

score on a scale

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint

Units	Counts
Participants

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.

Posted

Mean

95% Confidence Interval

units on a scale

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint

Units	Counts
Participants

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.

Posted

Mean

95% Confidence Interval

units on a scale

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint

Units	Counts
Participants

Secondary

Mean Right Atrial Pressure (Cardiac Catheter)

Mean right atrial pressure at rest measured by cardiac catheter

Posted

Mean

95% Confidence Interval

mmHg

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003	Placebo Group (China)

Secondary

Oxygen Consumption (VO2) Level at Peak

VO2 at peak of Incremental Cardio-pulmonary exercise test in ml/min/kg

Posted

Mean

95% Confidence Interval

ml/min/kg

12 weeks post study treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003	Placebo Group (China)

Secondary

Oxygen Consumption (VO2) at Metabolic Threshold

VO2 at Metabolic Threshold measured during incremental cardio-pulmonary exercise test

Posted

Mean

95% Confidence Interval

ml/min/kg

12 weeks post treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003	Placebo Group (China)

Secondary

Stroke Volume (Cardiac Catheter)

Measurement of stroke volume at rest by cardiac catheter at 12 weeks post treatment

Posted

Mean

95% Confidence Interval

mililitres

12 weeks post treatment

ID	Title	Description
OG000	Ferinject Group (Europe)	IV iron formulation used in Europe - Ferinject (Intravenous, 1000 mg iron)- given over 15 minutes This group provides the outcome measurements for participants following their infusion of Ferinject, whether this was at the first or second timepoint
OG001	Placebo Group (Europe)	Placebo (saline) given intravenously over 15 minutes. This group provides the outcome measurements for participants following their infusion of Placebo, whether this was at the first or second timepoint
OG002	Cosmofer Group (China)	This group provides the outcome measurements for participants following their infusion of CosmoFer, whether this was at the first or second timepoint. IV iron formulation used in China was CosmoFer - given intravenously over a period of 4 to 6 hours
OG003	Placebo Group (China)

Secondary

Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular End-diastolic Volume

Cardiac MRI: Right ventricular end-diastolic volumes

Posted

Mean

95% Confidence Interval

mililitres

12 weeks

ID	Title	Description
OG000	Cardiac MR Dataset: Active Treatment	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received active treatment
OG001	Cardiac MR Dataset: Placebo	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received Placebo

Units	Counts
Participants	OG000

Secondary

Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular End Systolic Volume (RVESV)

Cardiac MR: Right ventricular end systolic volume

Posted

Mean

95% Confidence Interval

mililitres

12 weeks

ID	Title	Description
OG000	Cardiac MR Dataset: Active Treatment	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received active treatment
OG001	Cardiac MR Dataset: Placebo	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received Placebo

Units	Counts
Participants	OG000

Secondary

Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular Stroke Volume (RVSV)

Right ventricular stroke volumes assessed by cardiac MRI scan

Posted

Mean

95% Confidence Interval

mililitres

12 weeks

ID	Title	Description
OG000	Cardiac MR Dataset: Active Treatment	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received active treatment
OG001	Cardiac MR Dataset: Placebo	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received Placebo

Units	Counts
Participants	OG000

Secondary

Cardiac Magnetic Resonance Imaging (MRI): Right Ventricular Ejection Fraction (RVEF)

Cardiac MR: Right ventricular ejection fractions

Posted

Mean

95% Confidence Interval

percentage

12 weeks

ID	Title	Description
OG000	Cardiac MR Dataset: Active Treatment	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received active treatment
OG001	Cardiac MR Dataset: Placebo	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received Placebo

Units	Counts
Participants	OG000

Secondary

Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular End Diastolic Volume (LVEDV)

Cardiac MR: Left Ventricular End Diastolic Volume

Posted

Mean

95% Confidence Interval

Mililitres

12 weeks

ID	Title	Description
OG000	Cardiac MR Dataset: Active Treatment	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received active treatment
OG001	Cardiac MR Dataset: Placebo	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received Placebo

Units	Counts
Participants	OG000

Secondary

Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular End Systolic Volume (LVESV)

Cardiac MR: Left Ventricular End Systolic Volume

Posted

Mean

95% Confidence Interval

Mililitres

12 weeks

ID	Title	Description
OG000	Cardiac MR Dataset: Active Treatment	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received active treatment
OG001	Cardiac MR Dataset: Placebo	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received Placebo

Units	Counts
Participants	OG000

Secondary

Cardiac Magnetic Resonance Imaging: Left Ventricular Stroke Volume (LVSV)

Cardiac MR: Left Ventricular Stroke Volume

Posted

Mean

95% Confidence Interval

Mililitres

12 weeks

ID	Title	Description
OG000	Cardiac MR Dataset: Active Treatment	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received active treatment
OG001	Cardiac MR Dataset: Placebo	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received Placebo

Units	Counts
Participants	OG000

Secondary

Cardiac Magnetic Resonance Imaging (MRI): Left Ventricular Ejection Fraction (LVEF)

Cardiac MR: Left Ventricular Ejection Fraction

Posted

Mean

95% Confidence Interval

Percentage

12 weeks

ID	Title	Description
OG000	Cardiac MR Dataset: Active Treatment	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received active treatment
OG001	Cardiac MR Dataset: Placebo	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received Placebo

Units	Counts
Participants	OG000

Secondary

Cardiac Magnetic Resonance Imaging: Left Ventricular Mass

Cardiac MR: Left Ventricular Mass

Posted

Mean

95% Confidence Interval

Grams

12 weeks

ID	Title	Description
OG000	Cardiac MR Dataset: Active Treatment	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received active treatment
OG001	Cardiac MR Dataset: Placebo	This group includes all participants in the Europe and China Dataset that volunteered to the optional cardiac MR that received Placebo

Units	Counts
Participants	OG000

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	European Dataset: Iron	IV iron formulation used in Europe - Ferinject - given over 15 minutes Ferinject or CosmoFer: Intravenous, 1000 mg iron Time scale is within 12 weeks from Ferinject administration	26	39	4	39	22	39
EG001	European Dataset: Placebo	Placebo was 1000mg saline: intravenous, no active drug Time scale is within 12 weeks from saline administration	28	39	3	39	21	39
EG002	European Dataset: Outside Window	AEs reported before intervention or more than 12 weeks following both Iron and Placebo.	13	39	1	39	11	39
EG003	China Dataset: Iron	IV iron formulation used in China - CosmoFer - over a period of 4 to 6 hours Ferinject or CosmoFer: Intravenous, 1000 mg iron Time scale is within 12 weeks from Ferinject administration	3	17	0	17	3	17
EG004	China Dataset: Placebo	Placebo was 1000mg saline: intravenous, no active drug Time scale is within 12 weeks from saline administration	4	17	1	17	4	17
EG005	China Dataset: Outside Window	AEs reported before intervention or more than 12 weeks following both Iron and Placebo.	2	17	0	17	3	17

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Device related infection	Infections and infestations	MedDRA (10.0)	Systematic Assessment	Line infection from Groshong line (Presented with pyrexia 39.7 degrees C. patient hospitalised, treated with antibiotics and fully recovered)	EG0000 events0 affected39 at risk EG0010 events0 affected39 at risk EG0021 events1 affected39 at risk EG0030 events0 affected17 at risk
Hypophosphatemia	Blood and lymphatic system disorders	MedDRA (10.0)	Systematic Assessment	Required hospitalisation	EG0002 events2 affected39 at risk EG0010 events0 affected39 at risk EG0020 events0 affected39 at risk EG003
Haemorrhagic Ovarian Cyst	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (10.0)	Systematic Assessment		EG0000 events0 affected39 at risk EG0011 events1 affected39 at risk EG0020 events0 affected39 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA (10.0)	Systematic Assessment	Patient fell and cut their face and nose which bled heavily. Patient on Warfarin at the time. Hospitalised and given CT scan and stiches.	EG0001 events1 affected39 at risk EG0010 events0 affected39 at risk EG0020 events0 affected39 at risk EG003
Disease Progression	Cardiac disorders	MedDRA (10.0)	Systematic Assessment		EG0000 events0 affected39 at risk EG0011 events1 affected39 at risk EG0020 events0 affected39 at risk EG003
Para-spinal haematoma	Vascular disorders	MedDRA (10.0)	Systematic Assessment		EG0000 events0 affected39 at risk EG0011 events1 affected39 at risk EG0020 events0 affected39 at risk EG003
Infection: Tonsillitis	Infections and infestations	MedDRA (10.0)	Systematic Assessment		EG0001 events1 affected39 at risk EG0010 events0 affected39 at risk EG0020 events0 affected39 at risk EG003
Allergic reaction	Immune system disorders	MedDRA (10.0)	Systematic Assessment	Believed to be allergic-type reaction to IMP / placebo infusion. Patient suffered a rash and itchiness after 10 minutes of starting infusion. Recovered after administration of anti-allergic medications.	EG0000 events0 affected39 at risk EG0010 events0 affected39 at risk EG0020 events0 affected39 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Upper Respiratory Infection	Infections and infestations	MedDRA (10.0)	Systematic Assessment	EG0001 events1 affected39 at risk EG0011 events1 affected39 at risk EG0021 events1 affected39 at risk EG0031 events1 affected17 at risk EG0043 events3 affected17 at risk EG0051 events1 affected17 at risk
Flu like symptoms	General disorders	MedDRA (10.0)	Systematic Assessment	EG0009 events7 affected39 at risk EG0016 events5 affected39 at risk EG0020 events0 affected39 at risk EG003
Fatigue	General disorders	MedDRA (10.0)	Systematic Assessment	EG0005 events4 affected39 at risk EG0012 events2 affected39 at risk EG0023 events3 affected39 at risk EG003
Headache	General disorders	MedDRA (10.0)	Systematic Assessment	EG0000 events0 affected39 at risk EG0015 events5 affected39 at risk EG0023 events1 affected39 at risk EG003
Palpitations	Cardiac disorders	MedDRA (10.0)	Systematic Assessment	EG0000 events0 affected39 at risk EG0013 events3 affected39 at risk EG0021 events1 affected39 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA (10.0)	Systematic Assessment	EG0003 events2 affected39 at risk EG0010 events0 affected39 at risk EG0020 events0 affected39 at risk EG003
Vertigo	Ear and labyrinth disorders	MedDRA (10.0)	Systematic Assessment	EG0000 events0 affected39 at risk EG0012 events2 affected39 at risk EG0020 events0 affected39 at risk EG003
Abdominal pain	General disorders	MedDRA (10.0)	Systematic Assessment	EG0003 events3 affected39 at risk EG0010 events0 affected39 at risk EG0020 events0 affected39 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA (10.0)	Systematic Assessment	EG0005 events4 affected39 at risk EG0012 events2 affected39 at risk EG0021 events1 affected39 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (10.0)	Systematic Assessment	EG0001 events1 affected39 at risk EG0012 events2 affected39 at risk EG0022 events2 affected39 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA (10.0)	Systematic Assessment	EG0000 events0 affected39 at risk EG0010 events0 affected39 at risk EG0023 events2 affected39 at risk EG003
Hypophosphataemia	Investigations	MedDRA (10.0)	Systematic Assessment	EG0008 events7 affected39 at risk EG0011 events1 affected39 at risk EG0020 events0 affected39 at risk EG003
Cardiac chest pain	Cardiac disorders	MedDRA (10.0)	Systematic Assessment	EG0000 events0 affected39 at risk EG0011 events1 affected39 at risk EG0020 events0 affected39 at risk EG003
Periodontal disease	Gastrointestinal disorders	MedDRA (10.0)	Systematic Assessment	EG0000 events0 affected39 at risk EG0010 events0 affected39 at risk EG0020 events0 affected39 at risk EG003
Non-cardiac chest pain	General disorders	MedDRA (10.0)	Systematic Assessment	EG0000 events0 affected39 at risk EG0012 events2 affected39 at risk EG0020 events0 affected39 at risk EG003
Allergic reaction	General disorders	MedDRA (10.0)	Systematic Assessment	EG0000 events0 affected39 at risk EG0010 events0 affected39 at risk EG0020 events0 affected39 at risk EG003
Elevated NT-Pro BNP	Investigations	MedDRA (10.0)	Systematic Assessment	EG0000 events0 affected39 at risk EG0010 events0 affected39 at risk EG0020 events0 affected39 at risk EG003
Bruising	Injury, poisoning and procedural complications	MedDRA (10.0)	Systematic Assessment	EG0001 events1 affected39 at risk EG0012 events2 affected39 at risk EG0022 events2 affected39 at risk EG003
Dysguesia	Nervous system disorders	MedDRA (10.0)	Systematic Assessment	EG0002 events2 affected39 at risk EG0010 events0 affected39 at risk EG0020 events0 affected39 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (10.0)	Systematic Assessment	EG0002 events2 affected39 at risk EG0011 events1 affected39 at risk EG0020 events0 affected39 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA (10.0)	Systematic Assessment	EG0001 events1 affected39 at risk EG0012 events2 affected39 at risk EG0020 events0 affected39 at risk EG003
Productive cough	Infections and infestations	MedDRA (10.0)	Systematic Assessment	EG0000 events0 affected39 at risk EG0011 events1 affected39 at risk EG0022 events2 affected39 at risk EG003
Lung infection	Infections and infestations	MedDRA (10.0)	Systematic Assessment	EG0002 events2 affected39 at risk EG0011 events1 affected39 at risk EG0020 events0 affected39 at risk EG003

ID	Title	Description
BG000	European Dataset	IV iron (1000 mg) formulation used in Europe - Ferinject - given over 15 minutes Saline: intravenous, no active drug
BG001	China Dataset	IV iron (1000mg) formulation used in China - CosmoFer - over a period of 4 to 6 hours Saline: intravenous, no active drug
BG002	Total	Total of all reporting groups

ID	Term
D000081029	Pulmonary Arterial Hypertension
D000090463	Iron Deficiencies
D065627	Familial Primary Pulmonary Hypertension

ID	Term
D006976	Hypertension, Pulmonary
D008171	Lung Diseases
D012140	Respiratory Tract Diseases
D019189	Iron Metabolism Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases

ID	Term
D012965	Sodium Chloride
C522335	ferric carboxymaltose

ID	Term
D002712	Chlorides
D006851	Hydrochloric Acid
D017606	Chlorine Compounds
D007287	Inorganic Chemicals
D017670	Sodium Compounds