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

Obesity Clinical Trial

— IIH:DUAL  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06027567
• Other study ID #: IIH:DUAL
• Status: Recruiting
• Phase: Phase 4
• Start date: September 2, 2022
• Est. completion date: December 31, 2025

Study information

• Verified date: September 2023
• Source: Danish Headache Center
• Contact: Rigmor H Jensen, Professor
• Phone: 0045-38633059
• Email: rigmor.jensen[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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)

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: December 31, 2025
• Est. primary completion date: March 31, 2025
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Body Weight
• Hypertension
• Idiopathic Intracranial Hypertension
• Intracranial Hypertension
• Intracranial Pressure
• Obesity
• Papilledema
• Pseudotumor Cerebri
• Weight Loss

Intervention

Drug:
• Semaglutide
Subcutaneous once-weekly injections of Semaglutide uptitrating to a maximum of 2.4 mg

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

Locations

Country	Name	City	State
Denmark	Danish Headache Center, Department of Neurology, Rigshospitalet	Glostrup
Denmark	Headache clinic, Department of Neurology, Odense University Hospital	Odense

Sponsors (4)

Lead Sponsor	Collaborator
Rigmor Højland Jensen	Odense University Hospital, Rigshospitalet, Denmark, University of Copenhagen

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Omics	Metabolomic and proteomic profile, exploratory analyses	Baseline + 8 weeks + 10 months
Primary	Weight	Weight change (%)	8 weeks
Primary	Intracranial pressure	Change in lumbar opening pressure in cm cerebrospinal fluid measured by manometry	8 weeks
Primary	Intracranial pressure	Change in lumbar opening pressure (%)	8 weeks
Secondary	Weight	Weight change (%)	10 months
Secondary	Intracranial Pressure	Change in lumbar opening pressure in cm cerebrospinal fluid measured by manometry	10 months
Secondary	Intracranial Pressure	Change in lumbar opening pressure (%)	10 months
Secondary	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
Secondary	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
Secondary	Change in Papilledema	Change in Frisén Grade (0-5, 0 minimal, 5 worst)	8 weeks + 10 months
Secondary	Visual fields	Perimetric mean deviation (decibel) by Humphrey automated perimetry	8 weeks + 10 months
Secondary	EDI-OCT	Change in Papillary thickness (um) measured by Enhanced Depth Imaging Optical Coherence Tomography (EDI-OCT)	8 weeks + 10 months
Secondary	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
Secondary	Remission	Proportion of patients with abscence of papilledema with or without intracranial pressure <25 cm cerebrospinal fluid	8 weeks + 10 months
Secondary	Change in fat mass	Change in body fat percentage measured by Dual Energy X-ray Absorptiometry compared to baseline	8 weeks + 10 months
Secondary	Total fat mass	Body fat percentage measured by Dual Energy X-ray Absorptiometry	Baseline + 8 weeks + 10 months
Secondary	Feasibility	Drop-out rate (proportion of patients withdrawing from participation)	8 weeks + 10 months
Secondary	Need of intracranial pressure-lowering medication_1	Dose (mg) of intracranial pressure-lowering medication needed (Acetazolamide, Topiramate, diuretics)	8 weeks + 10 months
Secondary	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
Secondary	Monthly headache days	Number of days with headache for the past 30 days preceding visit	Baseline + 8 weeks + 10 months
Secondary	Headche severity	Number of days with mild, moderate, and severy headache, respectively, in the past 30 days preceding visit	Baseline + 8 weeks + 10 months
Secondary	Headache medication - Acute analgesic use	Number of days with need of acute analgesic treatment for headache	Baseline + 8 weeks + 10 months
Secondary	Headache medication - preventive medication	Need of preventive medical treatment for headache	Baseline + 8 weeks + 10 months
Secondary	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
Secondary	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
Secondary	Peripapillary artery-to-venule ratio	Change in peripapillary artery-to-venule diameter ratio measured by confocal Scanning Laser Ophtalmoscopy	Baseline + 8 weeks + 10 months
Secondary	Truncal fat	Change in percentage of truncal adiposity measured by Dual Energy X-ray Absorptiometry	Baseline + 8 weeks + 10 months
Secondary	Android-gynoid-ratio	Change in ratio of Android versus gynoid fat percentage using Dual Energy X-ray Absorptiometry	Baseline + 8 weeks and 10 months
Secondary	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
Secondary	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
Secondary	Insulin like-Growth-Factor-1	Level of Insulin like-Growth-Factor-1 in serum (ug/L) in women not taking estrogen-containing contraceptives.	Baseline
Secondary	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
Secondary	Growth hormone	Level of growth hormone in serum ug(L) in women not taking estrogen-containing contraceptives.	Baseline
Secondary	Lutropin	Level of Lutropin in serum (IU/L) in women not taking estrogen-containing contraceptives.	Baseline
Secondary	Follitropin	Level of Follitropin in serum (IU/L) in women not taking estrogen-containing contraceptives.	Baseline
Secondary	Testosteron	Level of testosteron in serum (nmol/L) in women not taking estrogen-containing contraceptives.	Baseline
Secondary	Estradiol	Level of estradiol in serum (nmol/L) in women not taking estrogen-containing contraceptives.	Baseline
Secondary	Sex-Hormone Binding Globulin	Level of Sex-Hormone Binding Globulin in serum (nmol/L) in women not taking estrogen-containing contraceptives.	Baseline
Secondary	Anti-Müllerian Hormone	Level of Anti-Müllerian Hormone (pmol/L) in serum in women not taking estrogen-containing contraceptives.	Baseline
Secondary	Dehydroepiandrosterone	Level of Dehydroepiandrosterone (DHEAS) in serum (umol/L) in women not taking estrogen-containing contraceptives.	Baseline
Secondary	Androstenedion	Level of androstenedion (nmol/L) in serum in women not taking estrogen-containing contraceptives.	Baseline
Secondary	17-hydroxyprogesterone (mg/d)	Level of 17-hydroxyprogesterone (mg/d) in serum in women not taking estrogen-containing contraceptives.	Baseline
Secondary	Cortisol 0 min	Level of cortisol (nmol/L) in serum in women not taking estrogen-containing contraceptives.	Baseline
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in bone marker (CTX)	Change in carboxy-terminal collagen crosslinks (CTX) level (nanograms per liter)	Baseline + 8 weeks + 10 months
Secondary	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
Secondary	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
Secondary	Androgen metabolism_1	Ratio between Etiocholanolone and Androsterone (ng/mg) in 24-hour urine	Baseline + 8 weeks + 10 months
Secondary	Androgen metabolism_2	Ratio between 5-alpha-tetrahydrocortisol (5a-THF) and tetrahydrocortisol (THF) in 24-hour urine	Baseline + 8 weeks + 10 months
Secondary	Androgen metabolism_3	Level of testosterone in 24-hour urine (ng/L)	Baseline + 8 weeks + 10 months
Secondary	Androgen metabolism_4	Level of 3-alpha-androstanediol in 24-hour urine (nmol/L)	Baseline + 8 weeks + 10 months
Secondary	Androgen metabolism_5	Level of 11-oxygenated androgens (11-OHA4) (pg/L) in 24-hour urine	Baseline + 8 weeks + 10 months
Secondary	Intrathecal Semaglutide	Level of semaglutide in cerebrospinal fluid (picomol/L)	10 months
Secondary	Ammoniaemia_1	Levels of plasma ammonium (umol/L)	Baseline + 8 weeks + 10 months
Secondary	Ammoniaemia_2	Correlation between plasma ammonium (umol/L) and presence of fatty liver disease as indicated by liver ultrasonography	Baseline + 8 weeks + 10 months
Secondary	Ketosis	Proportion of patients in ketosis measured by urine stix	8 weeks + 10 months
Secondary	Change in metabolic parameters	Change in Homeostatic Model for Insulin Resistance (HOMA2IR) compared to baseline	8 weeks + 10 months
Secondary	Change in metabolic parameters	Change in glycated hemoglobin (mmol/mol) compared to baseline	8 weeks + 10 months