Efficacy, Safety, and Tolerability of Sultiame Combined with Oral Appliance Therapy in Obstructive Sleep Apnea with Incomplete Response
- Trial ID
- 2023-510519-20-00
- Sponsor
- Vaestra Goetalandsregionen
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy**, safety, and tolerability of the carbonic anhydrase inhibitor **sulthiame** in patients with **obstructive sleep apnea** (OSA) who exhibit an incomplete therapeutic response to oral appliance therapy (OAT) alone. This is conducted through a randomized, double-blind, placebo-controlled, cross-over trial comparing sulthiame and placebo in addition to OAT. The clinical relevance of this objective lies in potentially enhancing treatment outcomes for OSA patients who do not fully benefit from OAT, thereby improving their overall health and quality of life.
Secondary objectives include the identification of biomarkers and the assessment of the efficacy of two types of interventions in OSA patients with insufficient therapeutic effects from OAT after treatment with sulthiame versus placebo in a two-week cross-over protocol. Additionally, the study aims to evaluate conventional metrics of OSA using two fundamentally different therapies, both alone and in combination, with respect to endotypic traits and hypoxia-related measures in this disease.
Participants
The clinical trial focuses on individuals diagnosed with **obstructive sleep apnea** who exhibit an incomplete clinical response to oral appliance therapy. The study population comprises both male and female participants, aged between 18 and 75 years. The sponsor has not provided the total number of participants involved in the trial. Participants were selected based on their ability to provide informed consent and their capacity to understand and comply with study procedures. The trial does not specifically target a vulnerable population. Lifestyle factors such as diet, physical activity, or habits are not detailed in the available data. The study aims to evaluate the efficacy, safety, and tolerability of the carbonic anhydrase inhibitor sulthiam in comparison to a placebo, in addition to oral appliance therapy, for patients with an incomplete therapeutic response to the therapy alone.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy**, safety, and tolerability of the carbonic anhydrase inhibitor **sultiame** in patients with **obstructive sleep apnea** who have an incomplete clinical response to oral appliance therapy. This is a randomized, double-blind, placebo-controlled, proof-of-concept trial. The study employs a cross-over design, where participants will receive both the active treatment and placebo in a sequential manner, allowing for direct comparison within the same individual. The trial is expected to commence recruitment on September 1, 2024, and conclude by December 31, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as an apnea/hypopnea index (AHI3a) of 15 or greater, age between 18 and 75 years, and the ability to provide informed consent. Following successful screening, participants will be randomized to receive either sultiame or placebo for a two-week period, after which they will cross over to the alternate treatment for another two weeks. The primary endpoint is the reduction of the AHI3a, while secondary endpoints include changes in other sleep-related variables and objective measures assessed by polysomnography.
Study visits will include baseline assessments, mid-treatment evaluations, and an end-of-study visit to collect final data and ensure participant safety. The expected length of participant involvement is approximately six weeks, including screening, treatment, and follow-up periods. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or non-compliance with study procedures. The trial aims to provide valuable insights into the potential benefits of sultiame in enhancing the therapeutic response in patients with obstructive sleep apnea.
Treatment
The clinical trial involves the administration of **Ospolot 50 mg**, a film-coated tablet containing the active substance **sultiame**. This medication is classified under the ATC code N03AX03 and is produced by DESITIN ARZNEIMITTEL GMBH. The pharmaceutical form is a film-coated tablet, and the route of administration is oral. The dosing regimen involves encapsulating two 50 mg tablets of Ospolot into one capsule, with a maximum daily dose of 200 mg and a total maximum dose of 2800 mg over the treatment period. The maximum treatment period is set at 2 weeks. The trial aims to evaluate the efficacy, safety, and tolerability of sultiame in patients with obstructive sleep apnea.
The study also includes a **placebo** group, which receives a treatment identical in composition to the investigational medicinal product (IMP) except for the absence of the active substance. The placebo is administered in the same pharmaceutical form and via the same oral route as the active treatment. This placebo-controlled design ensures the reliability of the trial outcomes by providing a baseline for comparison against the active treatment group. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the reduction of the **apnea/hypopnea index (AHI3a)** in patients with an insufficient therapeutic effect of an oral appliance therapy (OAT), defined as AHI3a ≥15, after administration of 200 mg of sulthiame (STM) compared to placebo over a 2-week cross-over protocol. Secondary endpoints include changes in other obstructive sleep apnea (OSA)-related variables such as AHI4, mean overnight SpO2, minimum SpO2, oxygen desaturation index 4%, and hypoxic burden. These will be assessed alongside objective measures of sleep, including sleep stages, total sleep time, arousal index, and sleep efficacy, using polysomnography (PSG).
Additional exploratory endpoints will evaluate changes from baseline and cross-over comparisons, focusing on the effect of STM relative to placebo. This includes assessments through questionnaires on daytime functioning, such as the Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ), Clinical Global Impressions (CGI-S, CGI-I), Patient Global Impression (PGI-S, PGI-I), SF-36, and the Columbia-Suicide Severity Rating Scale (C-SSRS). Other PSG variables, potential biomarkers of OSA, and the influence of conventional comorbidities like BMI will also be examined. Changes in vital signs and biochemical markers, including blood pressure, glycemic control, and lipids, will be monitored. These assessments will be conducted under the dosing circumstances outlined in the trial protocol.
Inclusion and Exclusion Criteria
Inclusion Criteria
- AHI3a ≥15
- Provision of informed consent after the scope and nature of the study have been explained prior to any study specific procedures.
- Able to speak, read and understand the local language and possess the ability to respond to questions, follow instructions, complete questionnaires, and comply with the study procedures.
- Male or female gender and aged 18 to 75 years (both inclusive).
Exclusion Criteria
- Patients fulfilling criteria for a dominant central sleep apnea syndrome or dominant episodes with Cheyne Stokes respiration or other clinically significant sleep disorder including periodic limb movement disorder, restless leg syndrome, periodic limb movements arousal index (PLMAI)>15, parasomnia, or narcolepsy.
- Episode of major depression, bipolar disorder, or any other significant psychiatric disorder within the last 12 months prior to screening
- Significant neurological or cognitive disorders including diagnosed dementia, Alzheimer’s disease, Parkinson´s disease, stroke, current epilepsy which, in the opinion of the investigator, might interfere with participation in the study
- Renal or hepatic failure defined as limiting according to the judgement of the investigator
- Type 1 diabetes or insulin treated type 2 diabetes or poorly controlled type 2 diabetes (HbA1c >53 mmol/mL or >7%)
- History of actual suicidal behaviour or suicidal ideation of type 2 to 5 within one year prior to screening, or current suicidal ideation of any type (i.e., 1 to 5) as assessed by the Colombia Suicide Symptom-Rating Scale (C-SSRS) at screening
- Patients actively participating in any active weight loss treatment program including any weight loss medication (prescription or over the counter)
- Patients previously treated by uvulopalatopharyngoplastic surgery (UPPP) or any other type of surgery for OSA
- Any OSA treatment within the last 3 weeks prior to baseline
- Acute porphyria or untreated hyperthyreosis
- An occupation designated as high risk or safety sensitive including handling complex machinery or professional drivers where there may be an increased risk for work or traffic accidents
- Patients currently involved in shiftwork
- Planned surgery during the study period or major surgery within 6 months before first dose
- History of alcohol or drug abuse during the last year
- Any clinical condition that would result in deviation from clinical routine for fitting of an OAT, according to the investigators opinion
- Hypoventilation or hypoxemia due to COPD or other respiratory condition at the discretion of the investigator (pCO2 >6.5kPa)
- Drug-resistant hypertension (>140/90 mmHg in spite of at least ongoing treatment with at least three drugs)
- Patients with insufficiently treated hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg). If treated, patients must have been on the same dose of antihypertensive medication for at least 4 weeks prior to inclusion
- Change of antihypertensive medication within the last 4 weeks prior to the randomization visit (A patient may be re-screened after 4 weeks at the discretion of the investigator providing criteria for blood pressure treatment are fulfilled)
- Myocardial infarction or coronary vessel intervention within the previous 6 months period or unstable angina pectoris
- Previously diagnosed or treated clinically significant cardiac arrhythmia
- A female patient is eligible to participate if she is not pregnant, not breastfeeding, and if at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) (See Appendix C: Guidance for Contraception and Pregnancy testing) OR A WOCBP who agrees to follow the contraceptive guidance provided during the treatment period and for at least 4 weeks after the last dose of study drug.
- A male patient who has not been vasectomized at least 6 months before screening and partners with a WOCBP must be willing to follow the contraceptive guidance provided (See Appendix C) during the treatment period and for at least 4 weeks after the last study drug administration.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 01 Sept 2024 | 15 |
 Sweden | Not Recruiting | 01 Sept 2024 | 35 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo - same composition as IMP except for the active substance | Placebo | N/A | — | — | — | N/A |
Ospolot 50 mg, Filmtabletten | Test | FILMTABLETTEN | ORAL | 200 | 2 | PRD728202 |