Severe Aortic StenosisPhase 2IIISASNCT04206228
Intravenous Iron Supplement for Iron Deficiency in Patients With Severe Aortic Stenosis
A Phase 2 study testing Intravenous iron isomaltoside in people with Severe Aortic Stenosis and Iron-deficiency, run by Oslo University Hospital at 1 site in Norway.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Severe Aortic Stenosis, Iron-deficiency
- What is being tested?
- Intravenous iron isomaltoside
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 149 participants
- Where
- 1 siteNorway
- Study dates
- 13 Jan 2020to 15 Feb 2022
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
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- 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
- Unresolved cancer predisposing to chronic bleeding or associated with life expectancy < 2 years
- 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)
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Intravenous Iron Supplement for Iron Deficiency in Patients With Severe Aortic Stenosis: The IIISAS Trial
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 %.
Read the 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.
- Conditions
- Severe Aortic Stenosis, Iron-deficiency
- Being tested
- Intravenous iron isomaltoside, Placebo
- Keywords
- Severe Aortic Stenosis, Iron-deficiency, Iron Isomaltoside, Exercise Capacity
- Medical subject headings
- Aortic Valve Stenosis, Anemia, Iron-Deficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Intravenous iron isomaltosideDrug
Also called Monofer®
The active drug, iron isomaltoside, will be administered as a single, intravenous infusion of 20 mg/kg body weight (rounded off to the nearest 100 mg) dissolved in 100 ml NaCl as recommended by the drug manufacturer ("on-label" treatment), over 30 minutes only (1,67 ml/min).
PlaceboDrug
Also called Intravenous sodium chloride 0.9%
The placebo will be prepared according to the randomisation code, and administered as a single intravenous infusion over 30 minutes only (1,67 ml/min).
| Study group | Role | What they receive |
|---|---|---|
| Active treatment | Active comparator | Active drug: Intravenous iron isomaltoside dissolved in 100 ml NaCl 0.9 % Receives: Drug: Intravenous iron isomaltoside |
| Placebo | Placebo comparator | Placebo: Intravenous NaCl 0.9 % dissolved in 100 ml Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Submaximal Exercise Test
The distance walked on a 6 min walk test performed 6 months after the trial intervention.
Measured: 6 months
Secondary outcomes (9)
Iron Deficiency
Iron deficiency defined as serum ferritin < 100 µg/l or ferritin between 100 and 300 µg/l in combination with a transferrin saturation < 20 %.
Measured: 6 months
Muscle Strength
Grip strength will be measure using a hand-held dynamometer (hand-grip device).
Measured: 6 months
The 36-item Short Health Survey Questionnaire (SF-36) Summary PCS
The SF-36 Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.
Measured: 6 months
The 3-level Version of EQ-5D (EQ-5D-3L) Questionnaire
Scores on a scale. The results are reported as the EQ-5D summary index which is a standardized, single-index score representing health-related quality of life (HRQoL) ranging from 0 to 1, where 1 is perfect health.
Measured: 6 months
EuroQol-visual Analogue Scales (EQ-VAS)
EQ-VAS is an instrument to measure overall health on a vertical visual analogue scale, ranging from "worst possible" (zero) to "best possible" (100)health.
Measured: 6 months
The Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score
The KCCQ Overall Summary Score (OSS) is a 0-100 scale measuring heart failure health status, where higher scores indicate better quality of life and fewer symptoms.
Measured: 6 months
N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP)
NT-proBNP is measured as a simple blood test and used as diagnostic biomarker for heart failure and cardiac dysfunction in clinical medicine.
Measured: 6 months
Cardiac Troponin T (TnT)
TnT is measured as a simple blood test and used as a standard biomarker of myocardial injury.
Measured: 6 months
New York Heart Association Functional Class
The NYHA (New York Heart Association) Functional Classification is a 4-stage system that ranks the severity of heart failure based on a patient's physical limitations and symptoms from 1 (no symptoms) to 4 (worst, symptoms at rest).
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Dec 2019
- Study start13 Jan 2020
- Primary completion15 Feb 2022
- Study completion15 Feb 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Severe Aortic StenosisStudies of the same condition, open and under way.
- More trials run by Oslo University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 149 participants (actual)
Sponsor and investigators
- Lead sponsor
- Oslo University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Lars Gullestad, Oslo University Hospital
- Investigators
- Lars Gullestad, MD, PhD, Principal investigator, Oslo University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04206228
- Sponsor's protocol ID
- 2019-002037-11
- Other IDs
- 2019
- Acronym
- IIISAS
- Status last verified
- Mar 2026
- First submitted
- 18 Dec 2019
- Last updated
- 15 Apr 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Bardan S, Kvaslerud AB, Andresen K, Klove SF, Edvardsen T, Gullestad L, Broch K. Intravenous ferric derisomaltose in iron-deficient patients undergoing transcatheter aortic valve implantation due to severe aortic stenosis: study protocol of the randomised controlled IIISAS trial. BMJ Open. 2022 Sep 2;12(9):e059546. doi: 10.1136/bmjopen-2021-059546.
PubMed 36691165Kvaslerud AB, Bardan S, Andresen K, Klove SF, Fagerland MW, Edvardsen T, Gullestad L, Broch K. Intravenous iron supplement for iron deficiency in patients with severe aortic stenosis scheduled for transcatheter aortic valve implantation: results of the IIISAS randomised trial. Eur J Heart Fail. 2022 Jul;24(7):1269-1279. doi: 10.1002/ejhf.2557. Epub 2022 Jun 3.
PubMed 35579454