Nutritional Trial With Probiotic Fortified Milk in Women Affected by Insomnia

Study Overview
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Brief Summary
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The study Nutritional Trial With Probiotic Fortified Milk in Women Affected by Insomnia is a part of a complex and multi-sectoral development research project (PROS.IT) with the participation of University Research Institutes and small/medium Italian enterprises. The general objective of the Project is to promote the collaboration between the best scientific research, both epidemiological and experimental, and the most advanced technologies to develop fortified foods that meeting the specific nutritional requirements of adult consumers. This objective will be achieved by the nutritional improvement of primary production, the development of innovative functional foods at high added value, in addition to traditional products functionalized, which are peculiar of the Italian local districts.

Detailed Description
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Sleep disorders and, in particular, insomnia, are quite common conditions in over 55 population, especially among women. Insomnia becomes a chronic pathology when the difficulty in initiating or maintaining sleep occurs more times a week for several months and is associated to a constant feeling of fatigue, concentration problems, mood disorders and social and family troubles severely impairing the quality of life. In according to the sleep hygiene guidelines, the therapeutic treatments for insomnia include drugs (benzodiazepines, non-benzodiazepines, antidepressants) with often not fully satisfactory results for the patient and entailing a series of side effects, such as daytime sleepiness, lack of attention and energy in addition to mental confusion. Recently, some researches in neurological field have shown that disorders affecting central nervous system, as well as sleep and circadian rhythm disruption, can be associated to specific alteration of the gut microbiota. The enteric nervous system has been referred to as a second brain able to interact with the central nervous system impinging upon higher cognitive functions through a bidirectional communication system known as gut-brain axis. The gut microflora plays a crucial role in gut-brain axis, modulating stress response through the Hypothalamic-Pituitary-Adrenal axis and thus influencing memory, mood, cognition and sleep architecture. Therefore, a non-pharmacological intervention aimed to improve gut microbiota and the inflammatory bowel conditions could be an effective strategy to counteract insomnia. In the framework of Pros.IT project, the Granarolo S.p.A. in collaboration with the University of Bologna has developed a milk enriched with different micronutrients (vitamins, ω-3 fatty acids, prebiotics, curcumin) and infant-type probiotics isolated from human milk and endowed with immunomodulating activity. This supplementation should improve the overall health status, and in particular the plant extracts, prebiotics and probiotics with anti-inflammatory and immunomodulatory activities should ameliorate significantly sleep quality and stress perception through the modulation of gut microbiota and gut-brain axis. The main goal of this study is to evaluate the effect of the administration of a functional milk reinforced with probiotics (250ml/die), vitamins and other micronutrients on sleep of patients suffering from chronic insomnia. An objective assessment it requires a value at least higher than 3% of increase of the sleep efficiency, since the 3% is the percentage of improvement recognized to the common drugs against insomnia. The study is randomized, double-blind, placebo-controlled trial.

Official Title
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Promotion of Consumer's Health: Nutritional Enhancement/Valorization of Agrofood Italian Traditional Products (PROS.IT)

Conditions
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Sleep Disorders

Intervention / Treatment
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* Dietary Supplement: Fortified milk
* Dietary Supplement: Placebo milk


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with an age between 55 and 70 years old, only females, free-living, affected by chronic insomnia defined according to the criteria of the International Classification of Sleep Disorders (2014). Exclusion Criteria: Allergy or intolerance to cow's milk. Use of Benzodiazepines, Z drugs or anti-depressive drugs during the three months preceding the start of the trial. Celiac disease and other intestinal malabsorption or inflammatory bowel diseases (Crohn's disease and ulcerative colitis). Chronic therapy with anticoagulant, corticosteroid, anticancer drugs and immunosuppressants. Diabetes type I and type II, chronic viral hepatitis, neurological disorders or dementia, cancer, poor prognosis disease in the short term. Use of anti-inflammatory drugs or inflammatory-infective events within 7 days before the start of the trial and use of antibiotics or vaccinations within 30 days before.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fortified milk<br>The subjects assumed daily 250 ml of fortified milk for 12 weeks. | Dietary Supplement: Fortified milk<br>* Ultra high temperature UHT, partly-skimmed milk (1% fat), highly digestible (lactose <0.01%), enriched in whey protein (5%) and calcium (0.24%), supplemented with unsaturated fatty acids omega-3 (DHA + EPA), vitamins (D, B12, B6, B9, E, C), prebiotics (FOS) and phyto curcuminoids (sunflower lecithin). Milk had to be associated with a packet of lyophilized and concentrated probiotics (Bifidobacteria infant-type and / or Lactobacilli), at the time of consumption. Milk and probiotics had been produced or supplied by Granarolo s.p.a.<br>* Other names: golden milk;|
| Placebo Comparator: Placebo milk<br>The subjects assumed daily 250 ml of placebo milk for 12 weeks. | Dietary Supplement: Placebo milk<br>* Ultra high temperature UHT, partly-skimmed milk (1% fat), highly digestible (lactose <0.01%) with standard proteins of milk (3.1%) and color additive quantum satis. Milk had to be associated with a packet of maltodextrin Food Grade, at the time of consumption. Milk and maltodextrin had been produced or supplied by Granarolo s.p.a.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Self reported quality of sleep | Sleep quality assessed by questionnaires | Change from baseline Sleep evaluation at 12 weeks milk intake | 
| Measured quality of sleep | assessed by actigraph | Change from baseline Sleep evaluation at 12 weeks milk intake | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of stress | Stress was evaluated by PSS questionnaire and 24-h urinary cortisol levels | 12 weeks | 
| Inflammatory status | Dosage in plasma of the following cytokines: IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, sCD40L, TNF-α, IL-17 A/F by Elisa immunoassay. | 12 weeks | 
| Evalution of glycomics | Plasmatic N-glycans by capillary electrophoresis (DSA-FACE). | 12 weeks | 
| Levels of anxiety | Stress was evaluated by STAI-Y2 | 12 weeks | 
| Levels of depression. | Stress was evaluated by BDI-II questionnaire | 12 weeks | 
| Evalution of epigenetic | Epigenetic analysis of ELOVL2, FHL2, PENK genes by Sequenom | 12 weeks | 
| Gut Microbiota composition | Analysis of gut-microbiota composition by 454 Pyrosequencing of the V4 region of the 16S rRNA gene. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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golden milk, insomnia, gut-brain axis