The Effect of an Anti-obesity Drug, Semaglutide, as Treatment in New-onset Idiopathic Intracranial Hypertension (IIH) Compared to Standard Weight Management (Dietician) With Regards to Change in Weight and Intracranial Pressure

Study Overview
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Brief Summary
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50 patients with verified new-onset Idiopathic Intracranial Hypertension are randomly allocated to standard weight management (dietician counselling) or trial intervention consisting of subcutaneous injections with Semaglutide for 10 months combined, in the initial 8 weeks following diagnosis, with a Very Low Calorie-Diet (max 800 kcal/day)

Detailed Description
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Idiopathic Intracranial Hypertension is primarily observed in obese female and weight management promotes disease control by yet unsettled mechanisms. Effective, fast and lasting weight loss is crucial, however, hard to achieve. Current weight management strategy in IIH in Denmark is counselling by a dietician. This study investigates whether an initial Very Low Calorie Diet (max 800 kcal/day) for 8 weeks following the diagnosis combined with GLP1-RA treatment throughout 10 months is tolerated and more efficient in achieving substantial weight loss and reduction of intracranial pressure. Furthermore, a number of secondary outcomes are measured including headache burden, quality of life, structure and function of the optic nerve, non-invasive surrogate markers of intracranial pressure, body fat mass, bone health, fatty liver disease and a range of cerebrospinal-, blood- and urine markers of i.a. the hormonal, inflammatory, metabolic, and headache biomarker profile. The intervention may candidate as a future first-line treatment regime.

Official Title
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Glucagon-like Peptide-1 Receptor (GLP-1R) Analogue Assisted Rapid Weight Loss Program as Treatment of Idiopathic Intracranial Hypertension

Conditions
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Idiopathic Intracranial Hypertension, Intracranial Pressure, Obesity, Pseudotumor Cerebri Syndrome, Papilledema, Weight Loss

Intervention / Treatment
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* Drug: Semaglutide
* Dietary Supplement: Very Low Calorie Diet
* Behavioral: Dietician counselling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed new onset definite IIH with papilledema and lumbar opening pressure ≥25 cm cerebrospinal fluid according to Friedmann diagnostic criteria BMI ≥ 27 Use of contraceptive methods with failure rates of less than 1 % throughout the study period for group A and for at least an additional 2 months after cessation of Semaglutide Written, informed consent Exclusion Criteria: Unable to provide written informed consent or participate Malignant IIH with visual threat that requires surgical intervention, i.e., cerebrospinal fluid diversion (shunting), optic nerve sheet fenestration or cerebral venous sinus stenting Pregnancy or breastfeeding Treatment with antidiabetics, blood-thinners or medication that may increase the risk of adverse events Diabetes, congestive heart failure, severe vascular disease, pancreatitis, severe ophthalmological disorders other than IIH (e.g. retinopathy) History or family history of thyroid carcinomas or Multiple Endocrine Neoplasias (MEN1/MEN2) History of bariatric surgery Known hypersensitivity to any contents of Semaglutide® Other severe/uncontrolled mental or physical disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Interventional Model Description: Open label randomized controlled clinical treatment trial Patients are randomly assigned 1:1 to standard-of-care or intervention
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semaglutide<br>Semaglutide up-titration to 2.4 mg for 10 months initially combined with a Very Low Calorie Diet (800 kcal/day) for 8 weeks. Counselling by dietician Standard medical treatment of intracranial hypertension | Drug: Semaglutide<br>* Subcutaneous once-weekly injections of Semaglutide uptitrating to a maximum of 2.4 mg<br>* Other names: Ozempic, Wegovy;Dietary Supplement: Very Low Calorie Diet<br>* Very Low Calorie Diet (max 800 kcal/day) using Nupo Diet meal replacement products<br>Behavioral: Dietician counselling<br>* Counselling by a dietician on weight loss through behavioural changes and life style intervention<br>|
| Active Comparator: Standard care (dietician)<br>Standard weight loss intervention Counselling by dietician Standard medical treatment of intracranial hypertension | Behavioral: Dietician counselling<br>* Counselling by a dietician on weight loss through behavioural changes and life style intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight | Weight change (%) | 8 weeks | 
| Intracranial pressure | Change in lumbar opening pressure in cm cerebrospinal fluid measured by manometry | 8 weeks | 
| Intracranial pressure | Change in lumbar opening pressure (%) | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight | Weight change (%) | 10 months | 
| Intracranial Pressure | Change in lumbar opening pressure in cm cerebrospinal fluid measured by manometry | 10 months | 
| Intracranial Pressure | Change in lumbar opening pressure (%) | 10 months | 
| Quality of Life | Change in total score of Quality of Life (psychological, social, physical, environmental) assessed by the World Health Organization Quality of Life Brief Version Questionnaire (0-100; 0 worst, 100 best) | 8 weeks + 10 months | 
| Headache burden measured by HURT questionnaire | Change in summation of scores in the questionnaire Headache Under Response to Treatment Questionnaire (HURT); 0-24 points were higher numbers are worse outcome | 8 weeks + 10 months | 
| Change in Papilledema | Change in Frisén Grade (0-5, 0 minimal, 5 worst) | 8 weeks + 10 months | 
| Visual fields | Perimetric mean deviation (decibel) by Humphrey automated perimetry | 8 weeks + 10 months | 
| EDI-OCT | Change in Papillary thickness (um) measured by Enhanced Depth Imaging Optical Coherence Tomography (EDI-OCT) | 8 weeks + 10 months | 
| Optic disc elevation | Optic disc elevation (mm) measured by transorbital ultrasonography, (average of 3 scans of each eye with papilledema) | Baseline + 8 weeks + 10 months | 
| Remission | Proportion of patients with abscence of papilledema with or without intracranial pressure <25 cm cerebrospinal fluid | 8 weeks + 10 months | 
| Change in fat mass | Change in body fat percentage measured by Dual Energy X-ray Absorptiometry compared to baseline | 8 weeks + 10 months | 
| Total fat mass | Body fat percentage measured by Dual Energy X-ray Absorptiometry | Baseline + 8 weeks + 10 months | 
| Feasibility | Drop-out rate (proportion of patients withdrawing from participation) | 8 weeks + 10 months | 
| Need of intracranial pressure-lowering medication_1 | Dose (mg) of intracranial pressure-lowering medication needed (Acetazolamide, Topiramate, diuretics) | 8 weeks + 10 months | 
| Fatty liver prevalence | Prevalence of non-alcoholic fatty liver disease evaluated by ultrasonography (subjectively assessed density of liver parenchyma compared to hepatic perivascular density and renal density), assessed by an experienced radiologist with specialization in ultrasonography | Baseline + 8 weeks + 10 months | 
| Monthly headache days | Number of days with headache for the past 30 days preceding visit | Baseline + 8 weeks + 10 months | 
| Headche severity | Number of days with mild, moderate, and severy headache, respectively, in the past 30 days preceding visit | Baseline + 8 weeks + 10 months | 
| Headache medication - Acute analgesic use | Number of days with need of acute analgesic treatment for headache | Baseline + 8 weeks + 10 months | 
| Headache medication - preventive medication | Need of preventive medical treatment for headache | Baseline + 8 weeks + 10 months | 
| Optic nerve sheath diameter | Optic nerve sheath diameter (mm) measured by transorbital ultrasonography (average of 3 scans of each eye with papilledema) | Baseline + 8 weeks + 10 months | 
| Peripapillary capillary density | Change in peripapillary capillary density (ratio of pixels of perpapillary vessels and pixels in the foveal area evaluated by Optic Coherence Tomography Angiography | Baseline + 8 weeks + 10 months | 
| Peripapillary artery-to-venule ratio | Change in peripapillary artery-to-venule diameter ratio measured by confocal Scanning Laser Ophtalmoscopy | Baseline + 8 weeks + 10 months | 
| Truncal fat | Change in percentage of truncal adiposity measured by Dual Energy X-ray Absorptiometry | Baseline + 8 weeks + 10 months | 
| Android-gynoid-ratio | Change in ratio of Android versus gynoid fat percentage using Dual Energy X-ray Absorptiometry | Baseline + 8 weeks and 10 months | 
| Adverse events | Number of adverse events overall, and sub-categorized into adverse events (AE) (any event happening during attachment to the project) and severe adverse events (SAE) in case of the following conditions: Hospitalization or prolongation of hospitalization, death, life-threatening or significant disability/incapacity | 8 weeks + 10 months | 
| Need of intracranial pressure-lowering medication_2 | Number of patients in need of any intracranial pressure-lowering drug (Acetazolamide, Topiramate, diuretics) | Baseline + 8 weeks + 10 months | 
| Insulin like-Growth-Factor-1 | Level of Insulin like-Growth-Factor-1 in serum (ug/L) in women not taking estrogen-containing contraceptives. | Baseline | 
| Insulinlike Growth Factor Binding Protein-3 | Level of Insulinlike Growth Factor Binding Protein-3 in serum (ug/L) in women not taking estrogen-containing contraceptives. | Baseline | 
| Growth hormone | Level of growth hormone in serum ug(L) in women not taking estrogen-containing contraceptives. | Baseline | 
| Lutropin | Level of Lutropin in serum (IU/L) in women not taking estrogen-containing contraceptives. | Baseline | 
| Follitropin | Level of Follitropin in serum (IU/L) in women not taking estrogen-containing contraceptives. | Baseline | 
| Testosteron | Level of testosteron in serum (nmol/L) in women not taking estrogen-containing contraceptives. | Baseline | 
| Estradiol | Level of estradiol in serum (nmol/L) in women not taking estrogen-containing contraceptives. | Baseline | 
| Sex-Hormone Binding Globulin | Level of Sex-Hormone Binding Globulin in serum (nmol/L) in women not taking estrogen-containing contraceptives. | Baseline | 
| Anti-Müllerian Hormone | Level of Anti-Müllerian Hormone (pmol/L) in serum in women not taking estrogen-containing contraceptives. | Baseline | 
| Dehydroepiandrosterone | Level of Dehydroepiandrosterone (DHEAS) in serum (umol/L) in women not taking estrogen-containing contraceptives. | Baseline | 
| Androstenedion | Level of androstenedion (nmol/L) in serum in women not taking estrogen-containing contraceptives. | Baseline | 
| 17-hydroxyprogesterone (mg/d) | Level of 17-hydroxyprogesterone (mg/d) in serum in women not taking estrogen-containing contraceptives. | Baseline | 
| Cortisol 0 min | Level of cortisol (nmol/L) in serum in women not taking estrogen-containing contraceptives. | Baseline | 
| Cortisol 30 min | Level of cortisol (nmol/L) in serum 30 minutes after stimulation with 0,25 mg SynACHTen in women not taking estrogen-containing contraceptives. | Baseline | 
| Pituitary adenylate cyclase-activating peptide (PACAP) Pituitary adenylate cyclase-activating peptide Pituitary adenylate cyclase-activating peptide | Level (picograms per milliliter in plasma and cerebrospinal fluid) of Pituitary adenylate cyclase-activating peptide (PACAP) | Baseline + 8 weeks + 10 months | 
| Calcitonin Gene Related Peptide | Calcitonin Gene Related Peptide (CGRP) level pg/mL (picograms per milliliter in plasma and cerebrospinal fluid) | Baseline + 8 weeks + 10 months | 
| Change in bone marker (CTX) | Change in carboxy-terminal collagen crosslinks (CTX) level (nanograms per liter) | Baseline + 8 weeks + 10 months | 
| Change in bone marker (PiNP) | Change in procollagen type I N-propeptide (PiNP) level (micrograms per liter) compared to baseline | baseline + 8 weeks + 10 months | 
| Regional bone density | Change in regional bone density in grams/square cm (g/cm2) and T- and Z-scores of hip and spine measured by Dual Energy X-ray Absorptiometry compared to baseline | Baseline + 8 weeks + 10 months | 
| Androgen metabolism_1 | Ratio between Etiocholanolone and Androsterone (ng/mg) in 24-hour urine | Baseline + 8 weeks + 10 months | 
| Androgen metabolism_2 | Ratio between 5-alpha-tetrahydrocortisol (5a-THF) and tetrahydrocortisol (THF) in 24-hour urine | Baseline + 8 weeks + 10 months | 
| Androgen metabolism_3 | Level of testosterone in 24-hour urine (ng/L) | Baseline + 8 weeks + 10 months | 
| Androgen metabolism_4 | Level of 3-alpha-androstanediol in 24-hour urine (nmol/L) | Baseline + 8 weeks + 10 months | 
| Androgen metabolism_5 | Level of 11-oxygenated androgens (11-OHA4) (pg/L) in 24-hour urine | Baseline + 8 weeks + 10 months | 
| Intrathecal Semaglutide | Level of semaglutide in cerebrospinal fluid (picomol/L) | 10 months | 
| Ammoniaemia_1 | Levels of plasma ammonium (umol/L) | Baseline + 8 weeks + 10 months | 
| Ammoniaemia_2 | Correlation between plasma ammonium (umol/L) and presence of fatty liver disease as indicated by liver ultrasonography | Baseline + 8 weeks + 10 months | 
| Ketosis | Proportion of patients in ketosis measured by urine stix | 8 weeks + 10 months | 
| Change in metabolic parameters | Change in Homeostatic Model for Insulin Resistance (HOMA2IR) compared to baseline | 8 weeks + 10 months | 
| Change in metabolic parameters | Change in glycated hemoglobin (mmol/mol) compared to baseline | 8 weeks + 10 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Idiopathic Intracranial Hypertension, Papilledema, Weight loss, Obesity, Pseudotumor Cerebri Syndrome, Intracranial Pressure