Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial

Näntö‐Salonen, Kirsti; Kupila, Antti; Simell, Satu; Siljander, Heli; Salonsaari, Tiina; Hekkala, Anne; Korhonen, Sari; Erkkola, Risto; Sipilä, Jorma; Haavisto, Lotta; Siltala, Marja; Tuominen, Juhani; Hakalax, Jari; Hyöty, Heikki; Ilonen, Jorma; Veijola, Riitta; Simell, Tuula; Knip, Mikael; Simell, Olli

doi:10.1016/s0140-6736(08)61309-4

Cited by 359 publications

(264 citation statements)

References 31 publications

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“…Injected insulin has failed in prevention trials (21,51). Nasal insulin has failed in prevention trials (52). Oral insulin has failed in new-onset T1D (53-55) and did not meet its primary outcome in a prevention trial (20).…”

Section: Antigen-based Therapies Have Not Worked Yetmentioning

confidence: 99%

Prevention and Reversal of Type 1 Diabetes—Past Challenges and Future Opportunities

Skyler

2015

Diabetes Care

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Over the past three decades there have been a number of clinical trials directed at interdicting the type 1 diabetes (T1D) disease process in an attempt to prevent the development of the disease in those at increased risk or to stabilize—potentially even reverse—the disease in people with T1D, usually of recent onset. Unfortunately, to date there has been no prevention trial that has resulted in delay or prevention of T1D. And, trials in people with T1D have had mixed results with some showing promise with at least transient improvement in β-cell function compared with randomized control groups, while others have failed to slow the decline in β-cell function when compared with placebo. This Perspective will assess the past and present challenges in this effort and provide an outline for potential future opportunities.

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Section: Antigen-based Therapies Have Not Worked Yetmentioning

confidence: 99%

Prevention and Reversal of Type 1 Diabetes—Past Challenges and Future Opportunities

Skyler

2015

Diabetes Care

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“…INIT-II (NCT00336674) is an ongoing randomized; double-blind, placebo-controlled trial using nasal insulin (1.6 or 16 mg) and aims at assessing the effects of nasal insulin on islet autoimmunity. The Prediction and Prevention (DIPP) trial in Finland was a double-blind trial using nasal insulin in children with genetic risk and positive ICA and IAA 36 . In 224 children short acting insulin or placebo was administered intranasally once a day, but no protective effect was seen 36 nor did the nasal insulin modulate the characteristics of the IAA indicating that the insulin autoimmunity was already mature at the beginning of the intervention 37 .…”

Section: Nasal Insulinmentioning

confidence: 99%

“…The Prediction and Prevention (DIPP) trial in Finland was a double-blind trial using nasal insulin in children with genetic risk and positive ICA and IAA 36 . In 224 children short acting insulin or placebo was administered intranasally once a day, but no protective effect was seen 36 nor did the nasal insulin modulate the characteristics of the IAA indicating that the insulin autoimmunity was already mature at the beginning of the intervention 37 . The importance of INIT and DIPP is the demonstration of safety and that ancillary or mechanistic studies demonstrated signs of immune tolerance to insulin.…”

Section: Nasal Insulinmentioning

confidence: 99%

“…Whether a future trial is prevention or intervention safety and long-term effects will have to be a major concern. So far, the safety profile in trials with insulin 22,36 and GAD65 38,40 autoantigen immunomodulation has been high. The different approaches of autoantigen administration have revealed effects on secondary end-point measures such as increased numbers of Treg cells.…”

Section: E Future Directionsmentioning

confidence: 99%

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Immune therapy in type 1 diabetes mellitus

Lernmark

Larsson

2013

Nat Rev Endocrinol

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(200 words) Type 1 diabetes mellitus (T1D) is an autoimmune disorder directed against the pancreatic islet β cells. The genetic risk for the disease is linked to HLA-DQ genotypes and unknown environmental triggers. In most countries, only 10-15% of newly diagnosed T1D children or young adults have a first degree relative with the disease. Autoantibodies against insulin, GAD65, IA-2 or ZnT8 transporter mark islet autoimmunity. These islet autoantibodies may develop already at 1-2 years of age. Immune therapy in T1D is approached at three stages. Primary prevention is treatment of subjects at increased genetic risk. The TRIGR trial is testing if hydrolyzed casein milk formula may reduce T1D in genetically predisposed infants. Secondary prevention is in subjects with persistent islet autoantibodies. On-going trials are either non-autoantigen (BCG, CD3 monoclonal antibodies) or autoantigen (oral and nasal insulin or Alum-formulated GAD65) specific. Intervention at diabetes onset include non-autoantigen (CD3 monoclonal antibodies, IL-2 receptor antibodies, Il-1b receptor inhibitor, Il-1b antibodies, BCG, ATG, DiaPep277) and autoantigen (proinsulin peptides) specific therapy. Although preserved beta-cell function long term has been difficult to achieve in many prior studies, considerable progress is being made through controlled clinical trials and animal investigations to uncover mechanisms of beta-cell destruction. Novel therapies that would prevent islet autoimmunity or halt progressive beta-cell destruction need to be designed.

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“…103 An intranasal approach in HLA-conferred persons at risk, the T1D Prediction and Prevention study (DIPP), did not delay or prevent T1D, although this dose (1 U/kg/d) did induce immunological changes in the insulin Ab profile. 104,118 A similar approach in recent-onset diabetic patients also did not have a beneficial clinical outcome but diminished the level of insulin-specific Abs and IFN-γ secretion by T-cells in response to subcutaneous pancreatic duodenal homeobox-1 protein (Pdx1) and the recently identified secretory granule proteins chromogranin A (ChgA) and islet amyloid polypeptide (IAPP). [74][75][76][77] Interestingly, some studies proposed a model whereby one primary auto-Ag acts as an obligatory trigger for the activation and expansion of self-reactive T-cells, followed by β-cell destruction and more islet-specific Ag release with subsequent further activation of other self-reactive T-cells.…”

Section: Two Ag-based Immunotherapymentioning

confidence: 99%