## Protocol Section
### Identification Module
**NCT ID:** NCT06413069

**Acronym:** AGAMEMNON

**Brief Title:** Effects of Almonds in Glucose-intolerant Adults (AGAMEMNON)

**Official Title:** Effects of Almonds in Glucose-intolerant Adults - a Randomised Controlled Study on Muscle Mass and Obesity, Energy Metabolism and Lipidome, NON-alcoholic Fatty Liver and Inflammation (AGAMEMNON)

#### Organization Study ID Info
**ID:** AGAMEMNON
#### Organization
**Class:** OTHER
**Full Name:** Charite University, Berlin, Germany
### Status Module
#### Completion Date
**Date:** 2026-07-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-24

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-23

**Overall Status:** RECRUITING

#### Primary Completion Date
**Date:** 2026-04-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-05-23

**Type:** ACTUAL

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-14
**Type:** ACTUAL
**Study First Submit Date:** 2024-01-29
**Study First Submit QC Date:** 2024-05-11
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER

**Name:** Almond Board of California

#### Lead Sponsor

**Class:** OTHER

**Name:** Charite University, Berlin, Germany

#### Responsible Party

**Investigator Affiliation:** Charite University, Berlin, Germany

**Investigator Full Name:** Stefan Kabisch

**Investigator Title:** Principal investigator

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** Tree nuts - such as almonds - contribute to beneficial effects of the Mediterranean diet on risk for cardiovascular events, type 2 diabetes, dyslipidemia, hypertension, inflammation and non-alcoholic fatty liver disease. Almonds provide few carbohydrates, but lots of unsaturated fat and dietary fiber. But to which extent and by which mechanisms may almonds improve all aspects of the Metabolic Syndrome? Previous clinical trials showed weaker effects than rodent studies, most possibly due to low statistical power and metabolically insusceptible patients.

The 3-year AGAMEMNON project aims to investigate, if 16 weeks of supplementation with almonds (vs. no treatment) in 150 patients with prediabetes and NAFLD leads to significant improvements in glycemia and liver fat, lipid metabolism, body composition and inflammation. The isocaloric design will outrule effects of weight loss and will allow the analysis of metabolic pathways between fat depots, inflammation, insulin resistance and gut function. Lipidomics are assessed as novel predictor of disease progression and metabolic response.

**Detailed Description:** Background / Significance:

T2D affects 5-10 % of the global population, challenging societies, health systems, economy and quality of life. Dietary treatment may avoid disease burdens, save money and protect general health resources, but is often limited to unspecific weight loss recommendations and advise for physical activity. Despite being the common advice, body weight reduction is faced with inconclusive evidence for its impact on long-term risks (obesity paradox?), lack of long-term compliance and irresponsive or ineligible subgroups of patients. The Mediterranean diet provides the ideal dietary composition and reduces CVD risk, improving every axis of the Metabolic Syndrome, including liver fat. It is unclear, though, to which extent tree nuts contribute to this effect.

In meta-analyses, almonds improve glycemia and lipids. Benefits on body composition and inflammation are also expected, these might extend to NAFLD.

n6-PUFAs (typical components of tree nuts) reduce T2D risk and liver fat in humans. This was shown for sunflower oil, but not yet for nuts. Evidence for NAFLD benefits by almonds in humans is limited to observational studies, post-hoc analyses of mixed interventions, and underpowered RCTs.

Aims / Rationale:

Nuts are safe for NAFLD patients. Previous data indicate, that almonds may elicit benefits on glycemia and liver fat in patients susceptible to this treatment.

Therefore, the investigators' project aims to investigate whole almonds as dietary treatment for glucose intolerance and NAFLD in patients with this typical combined phenotype. NAFLD independently predicts T2D progression and late complications. (Pre)diabetes patients with NAFLD are at higher risk for the entire metabolic syndrome and for early onset of nephropathy and CVD. On the other hand, prediabetes/T2D patients with NAFLD are also especially susceptible to lifestyle treatments. The investigators hypothesize to detect benefits of almonds with respect to glycemia and liver fat, but also lipid metabolism, body composition and inflammation compared to standard diet. Treatment period of 16 weeks is longer than earlier almond studies.

The investigators intend to show, that the metabolic improvement is independent from weight loss and, even in the opposite, supports maintenance of muscle mass. The research group wants to investigate mechanistic links between the metabolic pathways of visceral fat accumulation, inflammation, NAFLD, insulin resistance, dyslipidemia and the gut microbiome. Finally, the investigators aim to assess the lipidome (analysed from the erythrocyte membranes, full blood and plasma samples), which was recently established as a novel biomarker to predict disease progression, metabolic response and treatment-specific improvement.

### Conditions Module

**Conditions:**

- PreDiabetes

- NAFLD

**Keywords:**

- almonds

- dietary treatment

- diabetes prevention

- metabolic syndrome

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

**Intervention Model Description:** parallel, single-blinded, prospective, randomised controlled trial in waiting list design

##### Masking Info

**Masking:** DOUBLE

**Masking Description:** masking not possible; subjects are aware of their allocation after initiation of the intervention

**Who Masked:**

- INVESTIGATOR

- OUTCOMES_ASSESSOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 150

**Type:** ESTIMATED

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Subjects will be supplemented with 60 grams of almonds (treatment) or left untreated (no-nut group) for 16 weeks.

**Intervention Names:**

- Dietary Supplement: Raw whole almonds

**Label:** Almond treatment

**Type:** ACTIVE_COMPARATOR

#### Arm Group 2

**Description:** Patients of the no-nut group will receive 6,7 kgs of almonds after completing 16 weeks of waiting time, supporting their compliance as untreated group.

**Label:** Control condition

**Type:** NO_INTERVENTION

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Almond treatment

**Description:** Subjects will be supplemented with 60 grams of almonds (treatment) or left untreated (no-nut group) for 16 weeks. Patients of the no-nut group will receive 6,7 kgs of almonds after finishing the study, supporting their compliance as untreated group.

**Name:** Raw whole almonds

**Type:** DIETARY_SUPPLEMENT

### Outcomes Module

#### Primary Outcomes

**Description:** change in liver fat content (magnetic resonance spectroscopy)

**Measure:** Liver fat content

**Time Frame:** 16 weeks

**Description:** change in concentration of fasting plasma glucose

**Measure:** concentration of fasting plasma glucose

**Time Frame:** 16 weeks

**Description:** change in concentration of 2-h plasma glucose (75 g oGTT)

**Measure:** concentration of 2-h plasma glucose (75 g oGTT)

**Time Frame:** 16 weeks

#### Secondary Outcomes

**Description:** change in whole body fat content

**Measure:** whole body fat content (%; measured with BIA)

**Time Frame:** 16 weeks

**Description:** change in whole body fat content

**Measure:** whole body fat content (kg; measured with BIA)

**Time Frame:** 16 weeks

**Description:** change in insulin sensitivity (Matsuda)

**Measure:** insulin sensitivity (Matsuda)

**Time Frame:** 16 weeks

**Description:** change in insulin secretion capacity (disposition index-2); metric parameter without defined maxima or minima; higher values indicate better insulin secretion

**Measure:** insulin secretion capacity (disposition index-2); metric parameter without defined maxima or minima; higher values indicate better insulin secretion

**Time Frame:** 16 weeks

**Description:** change in blood pressure (sys/dia)

**Measure:** blood pressure (sys/dia)

**Time Frame:** 16 weeks

**Description:** change in serum concentration of CRP

**Measure:** serum concentration of CRP

**Time Frame:** 16 weeks

**Description:** change in serum concentration of IL-6

**Measure:** serum concentration of IL-6

**Time Frame:** 16 weeks

**Description:** change in serum concentration of IL-10

**Measure:** serum concentration of IL-10

**Time Frame:** 16 weeks

**Description:** change in serum concentration of IL-1ß

**Measure:** serum concentration of IL-1ß

**Time Frame:** 16 weeks

**Description:** change in serum concentration of IL-18

**Measure:** serum concentration of IL-18

**Time Frame:** 16 weeks

**Description:** change in serum concentration of IL-22

**Measure:** serum concentration of IL-22

**Time Frame:** 16 weeks

**Description:** change in fasting triglyceride levels

**Measure:** fasting triglyceride levels

**Time Frame:** 16 weeks

**Description:** change in LDL, HDL, LDL/HDL ratio

**Measure:** LDL, HDL, LDL/HDL ratio

**Time Frame:** 16 weeks

**Description:** change in serum lipidome (hundreds of lipid species)

**Measure:** concentration of serum lipidome parameters (hundreds of lipid species)

**Time Frame:** 16 weeks

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* prediabetes (IFG or IGT or IFG-IGT), measured in plasma samples
* NAFLD (MR-S: \>5,56 %)
* BMI between 25 and 40 kg/m²

Exclusion Criteria:

* Treatment with antidiabetic drugs
* Overt diabetes mellitus of any kind
* Severe cardiovascular or pulmonary disorder
* Renal disorder / Renal insufficiency (eGFR \< 60 ml/min/m²)
* Severe psychiatric disorder (schizophrenia, severe depression; eating disorders)
* Current or recent (\< 5 years) cancer diagnosis
* Liver disease other than NAFLD
* Use of corticosteroid treatments
* Alcohol abuse
* Smoking
* Ongoing or recently finished (3 months before) weight loss
* Current participation in other intervention studies
* Pregnancy
* Metal implants, claustrophobia
* Allergy to almonds

**Maximum Age:** 70 Years

**Minimum Age:** 35 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** stefan.kabisch@charite.de

**Name:** Stefan Kabisch, Dr. med.

**Phone:** 0049-30-450514

**Phone Ext:** 429

**Role:** CONTACT

**Contact 2:**

**Email:** felizitas.kalinowski@charite.de

**Name:** Felizitas Kalinowski

**Phone:** 0049-30450514

**Phone Ext:** 428

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Berlin

**Contacts:**

***Contact 1:***

- **Email:** stefan.kabisch@charite.de

- **Name:** Stefan Kabisch, Dr. med.

- **Phone:** 030 450 514 429

- **Role:** CONTACT

**Country:** Germany

**Facility:** Charite University Hospital Berlin

**Status:** RECRUITING

**Zip:** 12203

### IPD Sharing Statement Module

**IPD Sharing:** UNDECIDED

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000003920

- Term: Diabetes Mellitus

- ID: D000044882

- Term: Glucose Metabolism Disorders

- ID: D000008659

- Term: Metabolic Diseases

- ID: D000004700

- Term: Endocrine System Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC18

- Name: Nutritional and Metabolic Diseases

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC19

- Name: Gland and Hormone Related Diseases

- Abbrev: BC06

- Name: Digestive System Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M12701

- Name: Obesity

- Relevance: LOW

- As Found: Unknown

- ID: M14117

- Name: Prediabetic State

- Relevance: HIGH

- As Found: Prediabetes

- ID: M20295

- Name: Glucose Intolerance

- Relevance: LOW

- As Found: Unknown

- ID: M23005

- Name: Metabolic Syndrome

- Relevance: LOW

- As Found: Unknown

- ID: M16355

- Name: Syndrome

- Relevance: LOW

- As Found: Unknown

- ID: M7115

- Name: Diabetes Mellitus

- Relevance: LOW

- As Found: Unknown

- ID: M10293

- Name: Inflammation

- Relevance: LOW

- As Found: Unknown

- ID: M8375

- Name: Fatty Liver

- Relevance: LOW

- As Found: Unknown

- ID: M30540

- Name: Non-alcoholic Fatty Liver Disease

- Relevance: LOW

- As Found: Unknown

- ID: M11639

- Name: Metabolic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M25403

- Name: Glucose Metabolism Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M7862

- Name: Endocrine System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T5868

- Name: Visceral Steatosis

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000011236

- Term: Prediabetic State

### Intervention Browse Module - Browse Branches

- Abbrev: Hemat

- Name: Hematinics

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M11110

- Name: Liver Extracts

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-31
