RISCAID Study: Remote ISchemic Conditioning for Angiopathy In Diabetes
Condition: Peripheral Arterial Disease
MeSH terms: Peripheral Arterial Disease; Peripheral Vascular Diseases
Study type: Interventional

Summary: 
      Objective The objective of this study is to investigate if long-term ambulatory remote
      ischemic conditioning can improve symptoms and signs of peripheral arterial disease in
      patients with type 2 diabetes.

      Background Peripheral arterial disease (PAD) is a vast socioeconomic challenge in the
      community of diabetes patients, causing foot ulcers and lower extremity amputations. The main
      treatment option for the complication is operative revascularisation. Thus there is a need
      for new treatment modalities for diabetes patients with PAD.

      Remote ischemic conditioning (RIC) is at non-invasive non-pharmacological treatment which has
      been shown to attenuate tissue damage caused by ischemia e.g. in hearts subjected to
      ischemia. RIC treatment consists of brief repetitive periods of ischemia induced in an
      extremity e.g. an arm. Recent findings show that six week RIC treatment improves healing of
      diabetic foot ulcers, suggesting a possible effect on the underlying pathological causes of
      ulcers e.g. PAD.

      Hypothesis The investigators hypothesize that RIC treatment can improve markers of
      inflammation, vascular and neuronal function and the sense of empowerment in type 2 diabetes
      patients with reduced peripheral blood supply.

      Aim to conduct a single center double-blinded randomized placebo controlled study
      investigating the efficacy of home based 12-week RIC treatment on markers of vascular,
      neuronal function, inflammation and serum lipid composition in 40 type 2 diabetes patients
      from Steno Diabetes Center with non-critical PAD.

      to qualitatively investigate the experience of empowerment related to the use of Remote
      Ischemic Conditioning (RIC) treatment and the mechanisms affecting if and how participants
      take up the RIC treatment.
    

Detailed description: 
      Objective The driving objective of this study is to investigate if long-term ambulatory
      remote ischemic conditioning can improve symptoms and signs of peripheral arterial disease
      and the sense of empowerment in patients with type 2 diabetes.

      Background Peripheral arterial disease (PAD) is vast challenge in the community of diabetes
      patients. The prevalence of PAD in diabetes patients exceeds that of non-diabetic individuals
      and is estimated to be about 26% in diabetes patients over 65 years of age and 71% in
      patients over 70 years . PAD is the major cause of foot ulcers and lower extremity
      amputations, which has great socioeconomic implications . The main treatment option for the
      complication is operative revascularisation which in diabetes patient is associated with
      increased rates of complication and mortality compared to non-diabetes patients .
      Pharmacological treatment with e.g. anti-platelet drugs in patients with PAD has shown effect
      on walking distance has not been indorsed as standard treatment.

      Thus there is a need for new treatment options for diabetes patients with PAD. Remote
      ischemic conditioning (RIC) is a non-invasive non-pharmacological treatment that has been
      shown to attenuate tissue damage caused by ischemia, reducing infarct size in patients with
      acute myocardial infarction , reducing organ damage in patient undergoing transplantation and
      having neuroprotective effects in patients with stroke .

      RIC treatment consists of brief repetitive periods of ischemia induced in an extremity e.g.
      an arm. It is believed that the effect of RIC is mediated through both neuronal and humoral
      pathways, however the mechanisms behind are not fully understood.

      RIC has been shown to have beneficial effects by attenuating platelet activation and
      aggregation, improving endothelial function , improvement of microcirculation ,
      down-regulation of neutrophil function , down-regulation of inflammatory gene expression ,
      improving mitochondrial function and inducing changes in serum lipid composition One of few
      long-term RIC treatment studies has shown that twice daily RIC treatment for 300 days is
      feasible. The study showed that RIC could reduce the recurrence of stroke

      . No studies are presently investigating the effect of long-term RIC on PAD in diabetes
      patients (Clinicaltrials.gov search 22nd of October 2015), the concept has however recently
      been presented in the literature . Two studies have addressed the acute effect of one RIC
      treatment on walking distance in non-diabetic patients with claudication. The results were
      inconclusive due to small sample sizes, but a trend towards improvement was shown. It is
      however likely that long-term RIC treatment is needed to show a beneficial effect of RIC on
      the pathology behind claudication - vascular and neuronal damage.

      Hypothesis We hypothesize that the long-term RIC treatment can improve PAD. PAD is caused by
      both micro- and macrovascular deficits. Reduced microvascular circulation can lead to distal
      nerve damage which in turn can both reduce peripheral circulation and cause tissue
      degeneration. Reduced macro vascular function is a direct cause of peripheral ischemia (2).
      It is possible that RIC could attenuate the pathophysiological processes in the micro- and
      microvasculature related to PAD by the abovementioned mechanisms and thereby improving of
      both neuronal and vascular function.

      Thus the present clinical evidence of the beneficial effects of RIC may be translated into a
      new safe and simple non-invasive non-pharmacological treatment of PAD in diabetes patients,
      preventing progression to critical ischemia and amputation.

      We also hypothesize that home-based and self-administered RIC treatment can improve the sense
      of empowerment in patients with non-critical peripheral arterial disease and type 2 diabetes.

      Aims and Methods

      Primary aim:

      to study the underlying mechanisms of the effects of long-term ambulatory RIC by
      investigating the effect on vascular function, neuronal function, markers of inflammation,
      oxidative stress and endothelial dysfunction and lipidomic profiles.

      Secondary aim to study the the experience of the use of RIC treatment and with focus on
      barriers that affect the uptake of the RIC treatment, and the effects of treatment on life
      quality and empowerment.

      Study design The study will consist of a single-center randomised double blinded placebo
      controlled trial.

      The trial will be performed to investigate the beneficial effects of RIC treatment on the
      study outcomes described below. The RIC treatment duration will be 12 weeks and 40 patients
      from the Steno Diabetes Center will be included in the trial. All tests and analyses will
      performed at Steno Diabetes Center expect for markers of inflammation and oxidative stress
      which will be performed at Dept. of inflammation, German Diabetes Center and institute of
      Clinical Diabetology, German Diabetes Center. All necessary facilities are available at the
      study sites.

      Most present knowledge of the beneficial effects of RIC listed above has come from short term
      trials (duration = 1 day. 20 days for one study) with small populations (n ≤ 40). Thus it is
      plausible that the study setup will yield significant differences in outcomes between the
      study arms. The study may also indicate if changes in outcomes will occur post RIC treatment.

      For the qualitative part of the study relevant questionnaires will be filled out at baseline
      and end-of trial. In addition 15 random patients will be asked to attend "think-aloud"
      interviews within the last 4 weeks of treatment.

      Power calculation RIC has shown to increase tissue oxygen tension (a measure of
      microcirculation) in a short-term study we hypothesize that RIC treatment will increase
      tissue oxygen tension in the feet (Primary outcome) by 13% (SD = 10%). With 90% power and a
      two sided significance level of 0.05 the sample size needed to detect this change is 16 in
      each group - 32 participants in total. Taking a drop-out ratio of 10% into account and given
      the inaccurate nature of this power calculation the sample size of the study will be 20
      patients in each group.

      Statistics The effects of treatment on outcome measures will be estimated by using
      complete-case logistic regression analyses. If needed outcome variables will be
      log-transformed using the natural logarithm to meet model assumptions of the distribution of
      the model residuals if necessary. Interactions between sex and all determinants will be
      investigated in all models to investigate possible sex interactions differences. A level of
      significance of 5% will be used.

      Analyses will be performed using SAS version 9.3 (SAS Institute, Cary, NC). Discontinuation
      of single person participation in study or cancellation of whole study The doctor responsible
      for the study can at any time discontinue the study for any reason e.g. for safety concerns.
      The responsible doctor can discontinue the participation of any single participant if
      informed consent is withdrawn, the a participant wants to get pregnant or get pregnant, if a
      participant does not follow the study protocol. A participant can withdraw his or her
      participation without justification at any time and this will not influence the treatment at
      Steno Diabetes Center of the participant.

      Data storage All procedures and facilities for data handling and storage will follow the
      rules and regulations of Datatilsynet. Permission from Datatilsynet for collecting and
      storing the data will be sought prior to the study start.

      All data from will be stored at the Steno Diabetes Center, Niels Steensens Vej 4, in
      Gentofte, Denmark. No person sensitive data will be shared with collaborator outside of Steno
      Diabetes Center. Data on analyses done at the German Diabetes Institute will be handle only
      by use of the patients trail number.

      All data gathered on paper during the clinical examination will be stored in a locked archive
      at Steno Diabetes Center.

      Publication Data is owned by the Steno Diabetes Center A/S. Positive (significant), negative
      (non-significant) and inconclusive results will be published as soon as it is scientifically
      justifiable.

      Significance and perspectives If the project shows an effect of RIC on PAD the next step will
      to test the treatment method in a larger trial where walking distance will be the primary
      outcome. Also it is possible that patients with foot ulcers and patients with critical
      peripheral ischemia could benefit from the treatment.

      RIC treatment could prove to be an attractive non-pharmacological non-surgical treatment
      option for a large population of diabetes patients. The trial will result in 5 publications
      on the efficacy of RIC on neuronal function, on vascular function, on lipidomic profiles, on
      marker of inflammation and oxidative stress (Tentative titles of articles are listed in
      Appendix 3) and patient empowerment and quality of life. The study is recommended by an
      independent Professor of Cardiology (Appendix 4).

      Possible limitations It is debated whether or not diabetes can attenuated the efficacy of RIC
      treatment. Data from randomised clinical trials are conflicting . As the patients in the
      present study population will have some degree of neuropathy this may attenuate the effect of
      RIC on our outcomes. However a recent study has showed an effect of RIC on diabetic foot
      ulcers contradicting the above-mentioned hypothesis, as all diabetes patients with foot
      ulcers have some degree of neuropathy .
    

Intervention name(s): AutoRIC: Remote Ischemic Conditioning; AutoRIC: Sham device treatment
Intervention type(s): Device; Device
Intervention description(s): 4 cycles of 5 minute forearm ischemia/reperfusion (200 mmHG) using the reusable fully automated RIC device "AutoRIC" from CellAegis Devices, Canada; 4 cycles of 5 minute forearm sham treatment (no ischemia/reperfusion, 0 mmHG pressure) with the reusable fully automated RIC device "AutoRIC" from CellAegis Devices, Canada
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Diabetes; Remote Ischemic Conditioning; Neuropathy; Angiopathy