Brief Title
Intravenous Iron Supplement for Iron Deficiency in Patients With Severe Aortic Stenosis
Official Title
Intravenous Iron Supplement for Iron Deficiency in Patients With Severe Aortic Stenosis: The IIISAS Trial
Brief Summary
Iron deficiency is a prevalent nutritional deficiency and a common cause of anemia. Although
iron deficiency is traditionally linked to anemia, iron deficiency is prevalent even in the
absence of anaemia and in itself limits function and survival. Iron deficiency is a common
feature of various chronic diseases, and up to 50% of patients with heart failure have iron
deficiency. Iron deficiency is more prevalent the more advanced the disease is and occurs
more frequently in women. Iron deficiency comprises absolute iron deficiency (usually defined
as ferritin < 100 ng/ml) as well as functional iron deficiency, in which iron supply is
inadequate to meet the demand for the production of red blood cells and other cellular
functions despite normal or abundant body iron stores. Iron deficiency is associated with
poor exercise capacity, lethargy and reduced quality of life. Results from our studies have
shown that iron deficiency is prevalent in patients with aortic stenosis. Some of the
symptoms associated with aortic stenosis, such as fatigue, reduced exercise capacity,
dyspnoea and cognitive dysfunction, have traditionally been thought to be caused by the
haemodynamic derangements precipitated by the valvular stenosis. However, similar symptoms
can be brought about by iron deficiency, and the investigators hypothesize that intravenous
iron supplement will improve exercise capacity, muscle strength, cognition, health-related
quality of life and myocardial function in patients with severe aortic stenosis and iron
deficiency. This is a phase 2, double blind, randomised, placebo-controlled trial.
Participants will be randomised in a 1:1 fashion to receive a single intravenous dose of iron
isomaltoside (50 patients) or matching placebo (50 patients). The study is designed to show
superiority with regard to the primary endpoint in patients assigned to active treatment
versus patients allocated to the placebo arm. The main goal is to evaluate the effect of a
single dose of intravenous iron isomaltoside on exercise capacity after transcatheter aortic
valve implantation in patients with severe aortic stenosis and iron deficiency. For this
study, the investigators have defined as serum ferritin < 100 µg/l or ferritin between 100
and 300 µg/l in combination with a transferrin saturation < 20 %.
Detailed Description
Written informed consent must have been provided voluntarily by each subject before any study
specific procedure is initiated.
A physical examination (including examination of heart, lungs, abdomen, neck and assessment
of peripheral circulation and oedema) must be performed; vital signs (blood pressure, and
heart rate); and height and weight must be recorded. A medical history must be obtained, and
age; gender; New York Heart Association (NYHA) functional status; risk factors (hypertension,
smoking, and diabetes); symptom duration, and concomitant disease must be recorded. All
concomitant medication (incl. vitamins, herbal preparation and other "over-the-counter"
drugs) used by the participant within 28 days of treatment start must be recorded in the CRF
by generic name and dose. Blood samples will be obtained to determine haemoglobin; white
blood cell count, platelet count; serum potassium; serum sodium; glucose, glycosylated
haemoglobin; creatinine; ALT; bilirubin; albumin; INR; CRP; N-terminal pro-B-type natriuretic
peptide; total cholesterol; ferritin; transferrin, serum iron and total iron binding
capacity. Blood for efficacy analyses must be drawn and appropriately labelled and stored for
later analysis. A 6 min walk test will be performed in accordance with current guidelines at
baseline. The results of this test will be used for adjustment of the test-result six months
after study drug infusion. The latter result, with adjustment for the baseline result,
constitutes the primary endpoint of the IIISAS trial. Right and left hand grip strengths will
be measured by a hand-held dynamometer. Body composition (weight, total water, total fat,
percent fat, the ratio of extracellular water to intracellular water [measuring oedema], and
visceral fat) will be measured at baseline and after 6 months with the InBody 770 body
composition analyser. Self-reported, health-related quality of life will be gauged with the
SF-36, EQ 5D 3L, EQ-VAS, HAD and the Kansas City Cardiomyopathy Questionnaires. Cognitive
function will be assessed with the Cambridge Neuropsychological Test Automated Battery
(CANTAB).
A physical examination, medical history, all concomitant medication, blood samples, 6 min
walk test, right and left hand grip strengths, body composition, and self-reported,
health-related quality of life as well as cognitive function will be conducted again on
average approximately 3 months after study drug administration, and it is designed to assess
initial efficacy and safety. This will be conducted again 3 months after transcatheter aortic
valve implantation (TAVI).
Patients will be followed for the first year after the TAVI procedure for safety assessment,
including MACE, and all-cause mortality. At 12 months after that TAVI procedure,
approximately 15 months after study drug infusion, a visit to Oslo University hospital, the
local hospital or a telephone interview will be performed to assess NYHA functional class,
adverse events and clinical events.
Patients may be discontinued from study treatment and assessments at any time. Specific
reasons for discontinuing patient follow-up are:
- Voluntary discontinuation: participating patients are free to discontinue his/her
participation in the study at any point in time, without prejudice to further treatment.
- Major protocol deviation
- Incorrect randomisation, i.e. the patient does not meet the required inclusion/exclusion
criteria for the study
- Patient lost to follow-up
- Patient's non-compliance to study treatment and/or procedures
Patient withdrawal must be documented in the CRF as well as in hospital records. If possible,
a final assessment should be obtained (end of study visit). The reason for discontinuation is
recorded. The investigator is obliged to follow up any significant adverse events until the
outcome either is recovered or resolved, recovering/resolving, not recovered/not resolved,
recovered/resolved with sequelae, fatal or unknown. Patients who withdraw will be included in
the intention-to treat analysis.
The whole trial may be discontinued at the discretion of the primary investigator or the
sponsor in the event of any of the following:
- Occurrence of AEs unknown to date in respect of their nature, severity and duration
- Medical or ethical reasons affecting the continued performance of the trial
- Difficulties in the recruitment of patients
- Cancellation of drug development The sponsor and principal investigator will inform all
investigators, the relevant Competent Authorities and Ethics Committees of the
termination of the trial along with the reasons for such action. If the study is
terminated early on grounds of safety, the Competent Authorities and Ethics Committees
will be informed within 15 days.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Submaximal Exercise Test
Secondary Outcome
Iron deficiency
Condition
Severe Aortic Stenosis
Intervention
Intravenous iron isomaltoside
Study Arms / Comparison Groups
Active treatment
Description: Active drug: Intravenous iron isomaltoside dissolved in 100 ml NaCl 0.9 %
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
100
Start Date
January 2, 2020
Completion Date
March 2022
Primary Completion Date
March 2021
Eligibility Criteria
Inclusion Criteria:
- Aortic stenosis patients with peak flow velocity (>3.5 m/s) scheduled for aortic valve
replacement with TAVI
- Iron deficiency defined as serum ferritin < 100 µg/l or ferritin between 100 and 300
µg/l in combination with a transferrin saturation < 20 %.
- Age > 18 years.
- Signed informed consent and expected compliance with protocol.
Exclusion Criteria:
Patients will be excluded from the study if they meet any of the following criteria:
- Anaemia (Haemoglobin < 100 mg/l)
- Haemochromatosis
- Haemosiderosis
- Porphyria cutanea tarda
- Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells
- Decompensated liver disease (Child-Pugh score 7 or higher)
- End-stage renal failure, i.e. eGFR < 15 ml/min or on renal replacement therapy
- Planned major surgery within 6 months
- On erythropoietin analogues
- Known sensitivity or intolerance to iron isomaltoside or other parenteral iron
preparations
- Intravenous iron supplement within 6 months prior to inclusion
- A clear indication for intravenous iron supplement
- On oral iron substitution (unless the subject agrees to stop treatment prior to
randomisation)
- Alcohol or drug abuse within 3 months of informed consent that would interfere with
trial participation or any ongoing condition leading to decreased compliance with
study procedures or study drug intake
- Intake of an investigational drug in another trial within 30 days prior to intake of
study medication in this trial or participating in another trial involving an
investigational drug and/or follow-up
- Failure to obtain written informed consent
- Inability to walk at least 100 meters over 6 minutes
- Women of child-bearing potential (1)
1. A woman is considered of childbearing potential, i.e. fertile, following menarche
and until becoming post-menopausal unless permanently sterile. Permanent
sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral
oophorectomy. Menopause is defined as 12 months continuous amenorrhea without an
alternative medical cause in a female ≥ 55 years old or 12 months of spontaneous
and continuous amenorrhea with a follicle stimulating hormone (FSH) level > 40
IU/L (or according to the definition of "postmenopausal range" for the laboratory
involved) in a female < 55 years old unless the subject has undergone bilateral
oophorectomy.
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Lars Gullestad, MD, PhD, +4723070641, [email protected]
Location Countries
Norway
Location Countries
Norway
Administrative Informations
NCT ID
NCT04206228
Organization ID
2019-002037-11
Responsible Party
Principal Investigator
Study Sponsor
Oslo University Hospital
Study Sponsor
Lars Gullestad, MD, PhD, Principal Investigator, Oslo University Hospital
Verification Date
April 2020