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

Primary Purpose

Diabetes Mellitus, Type 1

Status
Recruiting
Phase
Phase 2
Locations
Sweden
Study Type
Interventional
Intervention
desferal
Isotonic saline
Sponsored by
Karolinska University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 1

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Karolinska University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Desferal treatment

Isotonic saline treatment

Arm Description

Patients will be randomized (by block randomization) to Desferal (DFO) treatment.

Patients will be randomized (by block randomization) to isotonic saline treatment.

Outcomes

Primary Outcome Measures

Endothelial precursor cell account (EPC)
The absolute amount of endothelial precursor cells in 10 ml of blood

Secondary Outcome Measures

Full Information

First Posted
March 7, 2017
Last Updated
May 25, 2022
Sponsor
Karolinska University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT03085771
Brief Title
Desferal Administration to Improve the Impaired Reaction to Hypoxia in Diabetes
Acronym
DESIRED
Official Title
Desferal Administration to Improve the Impaired Reaction to Hypoxia in Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Recruiting
Study Start Date
January 1, 2017 (Actual)
Primary Completion Date
December 12, 2023 (Anticipated)
Study Completion Date
December 12, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Karolinska University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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 +)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 1

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
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
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
This is a double-blind study.
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Desferal treatment
Arm Type
Active Comparator
Arm Description
Patients will be randomized (by block randomization) to Desferal (DFO) treatment.
Arm Title
Isotonic saline treatment
Arm Type
Placebo Comparator
Arm Description
Patients will be randomized (by block randomization) to isotonic saline treatment.
Intervention Type
Drug
Intervention Name(s)
desferal
Other Intervention Name(s)
deferoxamine
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Isotonic saline
Other Intervention Name(s)
Isotonic solution
Intervention Description
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.
Primary Outcome Measure Information:
Title
Endothelial precursor cell account (EPC)
Description
The absolute amount of endothelial precursor cells in 10 ml of blood
Time Frame
24 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with type1 diabetes with a duration of the disease between 10-20 years (HbA1c ≥ 55 mmol/mol) Age 18-55 Diabetes duration 5-40 years 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: Double barrier method, i.e. (a) condom (male or female) or (b) diaphragm, with spermicide; or Intrauterine device; or Vasectomy (partner); or Hormonal (e.g. contraceptive pill, patch, intramuscular implant or injection); or Abstinence, if in line with the preferred and usual lifestyle of the subject. Signed informed consent Exclusion Criteria: Smoking Infections during the last month Major cardiovascular complications such as coronary heart disease, unstable or stable angina, myocardial infarction, ventricular arrhythmias, and atrial fibrillation in the last 3 months Decompensated congestive heart failure or functional class 3-4. therapy with beta-blockers severe hypertension (180 mmHg systolic or 110 mmHg diastolic blood pressure proliferative retinopathy. Sign for peripheral diabetic neuropathy (decreased/absent sensitivity to 10 g monofilament, vibration, plantar reflex) definite autonomic dysfunction HbA1c > 100 mmol/l Any concomitant disease or condition that may interfere with the possibility for the patient to comply with or complete the study protocol Malignancy History of alcohol or drug abuse Participant in another ongoing pharmacological study If female: plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating Unwillingness to participate following oral and written information 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 History of anemia, bleeding gastric ulcer, abundant menstruation Treatment with prochlorperazine
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sergiu Catrina, Ass. prof.
Phone
+46-8-517 700 00
Email
sergiu.catrina@ki.se
First Name & Middle Initial & Last Name or Official Title & Degree
Neda Rajamand Ekberg, M.D./Ph.D.
Phone
+46-8-51772769
Email
neda.ekberg@ki.se
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sergiu Catrina, Ass. prof.
Organizational Affiliation
Karolinska University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Karolinska University Hospital
City
Stockholm
ZIP/Postal Code
17176
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sergiu Catrina, ass prof MD
Phone
+46-8-51770000
Email
sergiu-bogdan.Catrina@ki.se
First Name & Middle Initial & Last Name & Degree
Neda Ekberg, PhD, MD
Phone
+46-(0)8 51775449
Email
Neda.Ekberg@ki.se

12. IPD Sharing Statement

Plan to Share IPD
No
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Desferal Administration to Improve the Impaired Reaction to Hypoxia in Diabetes

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