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 (IIH:DUAL)

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

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)

Study Overview

• Status: Recruiting
• Conditions: Obesity; Weight Loss; Idiopathic Intracranial Hypertension; Papilledema; Intracranial Pressure; Pseudotumor Cerebri Syndrome
• Intervention / Treatment: Drug: Semaglutide; Dietary supplement: Very Low Calorie Diet; Behavioral: Dietician counselling

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Rigmor H Jensen, Professor; Phone Number: 0045-38633059; Email: rigmor.jensen@regionh.dk
• Study Contact Backup: Name: Nadja Skadkær Hansen, MD; Phone Number: 0045-38633553; Email: nadja.skadkaer.hansen@regionh.dk

Study Locations

• Denmark
  • Glostrup, Denmark, 2600
    • Recruiting
    • Danish Headache Center, Department of Neurology, Rigshospitalet
    • Contact: Rigmor H Jensen, Professor; Phone Number: 0045-38633059; Email: rigmor.jensen@regionh.dk
    • Contact: Nadja S Hansen, MD; Phone Number: 0045-38633553; Email: nadja.skadkaer.hansen@regionh.dk
    • Principal Investigator: Nadja S Hansen, MD
  • Odense, Denmark, 5000
    • Not yet recruiting
    • Headache clinic, Department of Neurology, Odense University Hospital
    • Contact: Dagmar Beier, MD; Phone Number: 0045-65415604; Email: dagmar.beier@rsyd.dk
    • Principal Investigator: Dagmar Beier, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Semaglutide; 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; Subcutaneous once-weekly injections of Semaglutide uptitrating to a maximum of 2.4 mg; Other Names: Ozempic, Wegovy; Dietary supplement: Very Low Calorie Diet; Very Low Calorie Diet (max 800 kcal/day) using Nupo Diet meal replacement products; Behavioral: Dietician counselling; Counselling by a dietician on weight loss through behavioural changes and life style intervention
Active Comparator: Standard care (dietician); Standard weight loss intervention Counselling by dietician Standard medical treatment of intracranial hypertension	Behavioral: Dietician counselling; Counselling by a dietician on weight loss through behavioural changes and life style intervention

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight	Weight change (%)	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
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
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
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
Intracranial Pressure	Change in lumbar opening pressure in cm cerebrospinal fluid measured by manometry	10 months
Feasibility	Drop-out rate (proportion of patients withdrawing from participation)	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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Omics	Metabolomic and proteomic profile, exploratory analyses	Baseline + 8 weeks + 10 months

Collaborators and Investigators

• Sponsor: Rigmor Højland Jensen
• Collaborators: Odense University Hospital; Rigshospitalet, Denmark; University of Copenhagen
• Investigators: Study Director: Rigmor H Jensen, Professor, Danish Headache Center

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2022
• Primary Completion (Estimated): March 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: February 23, 2023
• First Submitted That Met QC Criteria: September 6, 2023
• First Posted (Actual): September 7, 2023

Study Record Updates

• Last Update Posted (Actual): September 11, 2023
• Last Update Submitted That Met QC Criteria: September 7, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Obesity; Weight loss; Intracranial Pressure; Papilledema; Idiopathic Intracranial Hypertension; Pseudotumor Cerebri Syndrome
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Eye Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight Changes; Optic Nerve Diseases; Cranial Nerve Diseases; Hypertension; Obesity; Weight Loss; Body Weight; Intracranial Hypertension; Pseudotumor Cerebri; Papilledema
• Other Study ID Numbers: IIH:DUAL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No