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

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 Participant 6017 suffered a suspected allergic reaction to their first infusion and was withdrawn from the study.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

• 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