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Desferal Administration to Improve the Impaired Reaction to Hypoxia in Diabetes (DESIRED)

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ClinicalTrials.gov Identifier: NCT03085771
Recruitment Status : Recruiting
First Posted : March 21, 2017
Last Update Posted : August 9, 2018
Sponsor:
Information provided by (Responsible Party):
Sergiu Catrina, Karolinska University Hospital

Tracking Information
First Submitted Date  ICMJE March 7, 2017
First Posted Date  ICMJE March 21, 2017
Last Update Posted Date August 9, 2018
Actual Study Start Date  ICMJE January 1, 2017
Estimated Primary Completion Date December 12, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 15, 2017)
Endothelial precursor cell account (EPC) [ Time Frame: 24 hours ]
The absolute amount of endothelial precursor cells in 10 ml of blood
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03085771 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Desferal Administration to Improve the Impaired Reaction to Hypoxia in Diabetes
Official Title  ICMJE Desferal Administration to Improve the Impaired Reaction to Hypoxia in Diabetes
Brief Summary

The general aim of this study is to investigate the influence of systemic administration of Desferal (Deferoxamine [DFO]) on the response to hypoxic challenge in patients with diabetes mellitus (DM).

The investigation will elucidate if DFO can restore:

  • the impaired angiogenetic response to hypoxia in patients with type 1 DM.
  • the disturbed respiratory and cardiovascular regulation in response to hypoxia in patients with DM type 1
Detailed Description

Background Complications of diabetes represent the main concern for modern diabetes therapy, and it has become a priority to further characterize the pathophysiological mechanisms of these complications to ensure the development of novel rational therapeutic strategies.

Although the prolonged exposure of tissues to hyperglycemia is the primary causative factor for chronic diabetes complications, it has recently become increasingly evident that hypoxia also plays an important role in all diabetes complication. A low tissue concentration of oxygen in diabetes is the consequence of several mechanisms (e.g., deficient blood supply secondarily to micro- and macro-vascular disease, poor local oxygen diffusion secondarily to local edema or as a result of increased oxygen consumption).

Adaptive responses of the cells to hypoxia are mediated by Hypoxia-Inducible Factor 1 (HIF), which is a heterodimeric transcription factor, composed of two subunits (alfa and beta subunit) both constitutively expressed in mammalian cells. In normoxia, HIF-1α is continually degraded by the ubiquitin-proteasome system as a consequence of the oxygen-dependent hydroxylation of two key proline residues catalyzed by a group of enzymes called prolyl-hydroxylases (PHDs). Under hypoxia when the degradation pathway is suppressed and HIF-1α is stabilized, it translocates in the nucleus where it induces more than 800 genes that are

involved in angiogenesis, glycolytic energy metabolism, cell proliferation and survival that enable the cells to adapt to reduced oxygen availability. HIF-1 is central for expression of several angiogenic growth factors (ex. as Vascular Endothelial Growth Factor (VEGF), erythropoietin (EPO), and stromal cell-derived factor-1α (SDF-1α) and for endothelial progenitor cells (EPC) recruitment. Recently, it has been proposed that microRNAs (ex. mir210) also mediate a part of the HIF-1 functions.

PHDs that control the HIF 1 α stability and function are Fe 2+ and/or O2 -dependent enzymes and their activity could be inhibited by depleting the iron. Deferoxamine (DFO), which is an iron chelator induces therefore HIF-1α accumulation and hypoxia-response genes in normoxia both in vitro and in vivo being able to restore the repressed adaptative reaction to hypoxia different animal models of diabetes. DFO has been in clinical use for decades for treating excessive iron deposition secondary to different pathologies (thalassemia, myelosclerosis etc) and was used as pharmacological tool to induce HIF dependent responses.

In the last decade several pieces of evidence have gathered, point out that in diabetes there is a defective cellular response to hypoxia. An impaired hypoxia response is present in all tissues that develop complications both in animal models for diabetes and in patients with diabetes as a consequence of a defective HIF signaling. It is a direct effect of hyperglycemia that directly represses HIF stability and function at multiple levels.

The recently described impaired reaction to hypoxia in diabetes have potentially important consequences in acute hypoxic challenges as acute heart infarction, stroke, limb ischemia (known to have a worse prognosis in diabetes) but also in subtle regulation of cardiovascular and respiratory system as a consequence of autonomic neuropathy with potential severe prognostic effect on late cardiovascular events. Different studies have addressed the cardiovascular responses to intermittent hypoxia (IH) compared with normoxia exposure in patients with diabetes. In order to establish the appropriateness of the cardiovascular reaction to hypoxia in diabetes the cardiorespiratory and angiogenetic responses towards IH in patients with diabetes compared with matched non- diabetic control subjects has recently been investigated(HYKRAND ethical approval number 2015/1182-31/4). The preliminary results (not published) showed several defects in both acute and delayed reaction of the patients with diabetes compared with controls. The baroreflex sensitivity (BRS) which is a marker of cardiovascular risk and survival prognosis after cardiovascular events was decreased in patients with diabetes after IH compared with non-diabetic subjects. Both the Endothelial Precursors Cells (EPC) number and the levels of their main stimulator Stromal derived factor (SDF-1α) were decreased in in response to IH in diabetics compared with non- diabetic subjects confirming the worse capacity to repair ischemic lesions in diabetes.

The project proposed here investigate the potential of DFO (known to improve the HIF dependent hypoxic signaling) to reverse the impaired cardiorespiratory and angiogenetic response in diabetic patients.

Research design. It is a blinded randomized cross-over study that investigates the efficacy of DFO (50mg/kg) vs isotonic saline given i.v before intermittent hypoxia (IH) to improve the cardiorespiratory and angiogenetic response in patients with diabetes. IH will consist in five hypoxic periods (13% O2 inspired fraction of oxygen) each lasting 6 min, with five normoxic intervals of same duration (as used in HYKRAND study) in 30 patients with type 1 diabetes without clinical signs of any complication. The study will be performed during 4 days with minimum 2 months separation between the 2 admissions to ensure sufficient wash-out and to restore iron deposits.

Methods Study design This is a randomized, double blind study conducted in patients with diabetes type 1 without chronic complications.

Patients will be randomized (by block randomization) (httpps://www.sealedenvelope.com/ simple-randomiser/v1/lists) to (A) Desferal (DFO) treatment or (B) isotonic saline treatment.

Both the patients and the personnel will be blinded to the patient's treatment group.

Subjects will be advised to abstain from caffeinated beverages for 12 h and from alcohol for 36h prior to testing

Day 1: Baseline blood samples will be collected in the morning and afterwards the patients will receive Desferal (50 mg/kg) / Saline infusion s.c during 6hs. During the last hour of infusion the subjects will be exposed to intermittent hypoxia (IH). Blood samples and cardiovascular and respiratory (CR) measurements will be performed (as detailed below) immediately before and at several time points after IH.

Day 2: Blood samples will be collected in the morning. IH exposure consists of five hypoxic periods (13% O2 inspired fraction of oxygen) each lasting 6 min, with five normoxic intervals of same duration (totally 1 hour).

Day 1: blood pressure, heart rate and arterial oxygen saturation are continuously measured. In case of a decrease in oxygen saturation 80% or the occurrence of symptoms, hypoxia is discontinued until oxygen levels reached at least 80%. A technician regulates and control the breathing periods under supervision of a medical doctor in a way that the intervention could not be observed by the patient. Thereafter, three measurement sessions will be performed: immediately after (t2), after 3 h (t3), and after 6 h (t4). After t2, each patient obtained an individual meal according to diet requirement.

Cardiovascular and respiratory testing.

Assessment of baroreflex sensitivity. All patients will be tested in the supine position in a silent room at comfortable temperature. Before participants will be connected to a rebreathing circuit through a mouthpiece with an antibacterial filter, spontaneous breathing of room air at rest will be performed for 4 min in order to obtain baseline data.

During each condition, continuous measurement of oxygen saturation (SaO2) by a pulse oximeter and end-tidal CO2 (CO2-et) using a capnograph connected to a mouthpiece will be performed. Recordings of electrocardiogram will be performed by chest leads, and continuous noninvasive blood pressure will be recorded using the cuff method. Two belts (positioned around the chest and the abdomen) will monitor respiratory movements of the chest. A pneumotachograph will be connected to a differential pressure transducer and inserted in series to the expiratory component of the rebreathing system to measure airway flow.

The baroreflex sensitivity (BRS) will be measured during spontaneous breathing at each measurement session. Since previous studies did not document a better performance of one method over the others, the average of seven different methods: positive and negative sequences, the a-coefficient in the low- and high-frequency bands and its average, the transfer function technique, and the ratio of SDs of R-R interval and systolic blood pressure variabilities will be calculated. Besides BRS, SD of the R-R interval (SDNN) was applied to determine a global index of heart rate variability. This selection is done based on the fact that normal distribution is more pronounced in this variable compared with other indices of variability (e.g., variance).

Hypoxic ventilatory response (HVR) and hypercapnic ventilatory response (HCVR) will be evaluated to determine respiratory system activity.

Cardiovascular autonomic function will be determined performing four tests according to recent guidelines: deep-breathing, 30:15 ratio, Valsalva maneuver and systolic blood pressure response to standing. Cardiovascular autonomic neuropathy will be defined as the "presence of two or more abnormal tests".

The baroreflex sensitivity (BRS) will be evaluated before (t1), immediately after (t2), 3 h (t3), and 6 h (t4) after IH.

The angiogenetic potential will be evaluated at the same endpoints and after 24 H (Day N3) by measuring in serum relevant cytokines that are gene targets for HIF-1 (i.e. Vascular endothelial growth factor (AVEGFA), stromal cell-derived factor 1a (SDF-1a), erythropoietin etc.). The direct response of HIF signaling will be evaluated by the serum levels of mir210 which exclusively regulated by HIF.

The EPC response will be evaluated at the same time points by Fluorescence-activated Cell Sorting (FACS) analysis of the number of Hematopoietic progenitor cell antigen (CD34+)/ CD133 antigen/Kinase insert domain receptor (KDR +)

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
This is a randomised, double-blind, placebo-controlled, cross-over, single center study of patients with diabetes mellitus type 1 without chronic complications.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
This is a double-blind study.
Primary Purpose: Treatment
Condition  ICMJE Diabetes Mellitus, Type 1
Intervention  ICMJE
  • Drug: desferal
    It is a blinded randomized cross-over study that investigates the efficacy of DFO (50mg/kg) given i.v before intermittent hypoxia (IH) to improve the cardiorespiratory and angiogenetic response in patients with diabetes.
    Other Name: deferoxamine
  • Drug: Isotonic saline
    It is a blinded randomized cross-over study that investigates the efficacy of isotonic saline given i.v before intermittent hypoxia (IH) to improve the cardiorespiratory and angiogenetic response in patients with diabetes.
    Other Name: Isotonic solution
Study Arms  ICMJE
  • Placebo Comparator: Desferal treatment
    Patients will be randomized (by block randomization) to Desferal (DFO) treatment.
    Intervention: Drug: desferal
  • Placebo Comparator: Isotonic saline treatment
    Patients will be randomized (by block randomization) to isotonic saline treatment.
    Intervention: Drug: Isotonic saline
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 15, 2017)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 12, 2022
Estimated Primary Completion Date December 12, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients with type1 diabetes with a duration of the disease between 10-20 years (HbA1c ≥ 55 mmol/mol)
  2. Age 18-55
  3. Diabetes duration 5-40 years
  4. Contraception: Female subjects must be postmenopausal, surgically sterile, or if premenopausal (and not surgically sterile), be prepared to use more than 1 effective method of contraception during the study and for 30 days after the last visit. Effective methods of contraception are considered to be those listed below:

    1. Double barrier method, i.e. (a) condom (male or female) or (b) diaphragm, with spermicide; or
    2. Intrauterine device; or
    3. Vasectomy (partner); or
    4. Hormonal (e.g. contraceptive pill, patch, intramuscular implant or injection); or
    5. Abstinence, if in line with the preferred and usual lifestyle of the subject.
  5. Signed informed consent

Exclusion Criteria:

  1. Smoking
  2. Infections during the last month
  3. Major cardiovascular complications such as coronary heart disease, unstable or stable angina, myocardial infarction, ventricular arrhythmias, and atrial fibrillation in the last 3 months
  4. Decompensated congestive heart failure or functional class 3-4.
  5. therapy with beta-blockers
  6. severe hypertension (180 mmHg systolic or 110 mmHg diastolic blood pressure
  7. proliferative retinopathy.
  8. Sign for peripheral diabetic neuropathy (decreased/absent sensitivity to 10 g monofilament, vibration, plantar reflex)
  9. definite autonomic dysfunction
  10. HbA1c > 100 mmol/l
  11. Any concomitant disease or condition that may interfere with the possibility for the patient to comply with or complete the study protocol
  12. Malignancy
  13. History of alcohol or drug abuse
  14. Participant in another ongoing pharmacological study
  15. If female: plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
  16. Unwillingness to participate following oral and written information
  17. Subjects with any other severe acute or chronic medical or psychiatric condition that make the subject inappropriate for the study in the judgment of the investigator
  18. History of anemia, bleeding gastric ulcer, abundant menstruation
  19. Treatment with prochlorperazine
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sergiu Catrina, Ass. prof. +46-8-517 700 00 sergiu.catrina@ki.se
Contact: Neda Rajamand Ekberg, M.D./Ph.D. +46-8-51772769 neda.ekberg@ki.se
Listed Location Countries  ICMJE Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03085771
Other Study ID Numbers  ICMJE 2016/1925-31
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sergiu Catrina, Karolinska University Hospital
Study Sponsor  ICMJE Karolinska University Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sergiu Catrina, Ass. prof. Karolinska University Hospital
PRS Account Karolinska University Hospital
Verification Date August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP