Efficacy and Safety of Cannabis Sativa Flower Aerosol via Syqe Inhaler in Diabetic Peripheral Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled Trial
- Trial ID
- 2023-508932-68-00
- Protocol
- Syqe-004
- Sponsor
- Syqe Medical Ltd.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of medical cannabis (MC) aerosol containing 0.25, 0.5, 1.0 mg Δ9-tetrahydrocannabinol (THC) inhaled three times a day (TID) compared to placebo on pain intensity at Week 16 in patients with **Diabetic Peripheral Neuropathic Pain** (DPNP). This is clinically relevant as it aims to determine the potential of MC aerosol as an effective add-on treatment for managing pain associated with DPNP, which is a common and challenging complication of diabetes.
Secondary objectives include:
- Assessing the efficacy of MC aerosol on pain characteristics and severity during maintenance and follow-up periods.
- Evaluating the efficacy on average, worst, and least pain intensity, and 30% and 50% responder rates during the same periods.
- Evaluating the safety and tolerability of MC aerosol administered via the Syqe Fixed-dose Inhaler throughout the study.
- Assessing the pharmacokinetics of multiple-dose MC aerosol.
- Evaluating the use of rescue medication for DPNP pain during various study periods.
- Assessing the effect of MC aerosol on pain-related sleep disturbance during up-titration, maintenance, and follow-up periods.
- Evaluating the effect on quality of life throughout the study.
Participants
The clinical trial involves a total of **55 participants** diagnosed with **Diabetic Peripheral Neuropathic Pain**. The study population includes both male and female subjects, aged between **18 and 75 years**. Participants were selected based on their ability to comprehend and sign the informed consent form, and their willingness to adhere to study restrictions. The trial includes individuals with a stable diagnosis of diabetes mellitus type I or type II, with controlled blood glucose levels through diet, medication, or insulin for at least three months prior to screening. Participants are required to have a body mass index between 18 and 40 kg/m² and must not be current users of cannabis products. The study population is characterized by a lifestyle that excludes the use of any cannabis or cannabis-containing products other than those provided by the study team. Additionally, participants must have been treated with standard care for their condition, such as duloxetine, gabapentin, or pregabalin, with stable dosages for at least 30 days prior to screening. The trial also includes individuals who have not participated in other interventional clinical studies during the study period. The study population is considered vulnerable, and specific measures are in place to ensure their safety and compliance throughout the trial.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, 4-arm parallel-group study to evaluate the efficacy and safety of medical cannabis aerosol delivered via the Syqe Inhaler as an add-on treatment for **Diabetic Peripheral Neuropathic Pain** (DPNP). The trial will involve multiple doses and aims to assess the impact of medical cannabis containing varying doses of Δ9-tetrahydrocannabinol (THC) compared to a placebo on pain intensity over a 16-week period. The study is expected to commence recruitment on October 2, 2024, and conclude by December 7, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, body mass index, and a confirmed diagnosis of DPNP. The screening will also ensure that participants have stable diabetes management and are not current users of cannabis products. Following randomization, participants will attend regular follow-up visits to monitor efficacy and safety outcomes, including changes in pain scores and the occurrence of any adverse events. The primary endpoint is the change from baseline in the weekly-mean 24-hour average pain score at Week 16, measured using the 11-point Numeric Rating Scale (NRS).
The trial will include secondary endpoints such as changes in neuropathic pain symptom inventory, the proportion of patients achieving significant pain reduction, and the assessment of safety and tolerability through various clinical measures. Participants will be involved in the study for the entire 16-week treatment period unless conditions arise that necessitate early termination, such as the occurrence of serious adverse events or non-compliance with study protocols. The study will ensure that all participants adhere to the use of only the provided medical cannabis and abstain from other cannabis products throughout the trial duration.
Treatment
The clinical trial involves the administration of **Cannabis Sativa L. ‘Afina’ inflorescence aerosol** via the Syqe Inhaler, a drug-device combination. The active substance is **Cannabis Sativa flower**, classified as a structurally diverse herbal substance. The pharmaceutical form is inhalation vapour, and the route of administration is inhalation use. The dosing regimen includes inhalation of 0.25, 0.5, or 1.0 mg of **Δ9-tetrahydrocannabinol (THC)** three times daily (TID). The maximum daily dose is 3 mg, with a total maximum dose of 298.5 mg over a treatment period of 16 weeks. The Syqe Fixed-dose Inhaler system, which includes the Syqe Cartridge and Syqe Mouthpiece, is used exclusively for this clinical trial. The device is CE marked, complying with EU 2017/745 MDR standards.
The placebo used in this study, identified as **SQE-001-PB**, is designed to mimic the sensation of inhalation and inhaler operation without emitting any detectable cannabinoid components. The placebo is administered in the same manner as the active treatment, providing a control for evaluating the efficacy and safety of the medical cannabis aerosol. The placebo ensures blinding in this double-blind, randomized, placebo-controlled trial, allowing for an accurate assessment of the treatment's impact on diabetic peripheral neuropathic pain.
Efficacy
The efficacy of the medical cannabis aerosol delivered via the Syqe Inhaler in the treatment of **Diabetic Peripheral Neuropathic Pain** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the weekly-mean 24-hour average pain score, measured using the 11-point Numeric Rating Scale (NRS) at Week 16. This scale is a validated tool for quantifying pain intensity, allowing for a standardized assessment of pain reduction over the course of the trial.
Secondary endpoints include several additional measures of pain and patient outcomes. These include changes from baseline in the Neuropathic Pain Symptom Inventory and the Brief Pain Inventory – Short Form, as well as changes in the weekly-mean 24-hour average, worst, and least pain scores using the NRS. The proportion of patients achieving at least 30% and 50% reduction from baseline in the weekly-mean 24-hour average pain score will also be evaluated. Safety and tolerability assessments will be conducted using the Michigan Neuropathy Screening Instrument Part B, Columbia-Suicide Severity Rating Scale, spirometry, electrocardiogram, and laboratory tests. Pharmacokinetic parameters of Δ9-THC and other cannabinoids will be measured at selected visits. Additionally, the need for and use of rescue medication, changes in sleep scores, and patient-reported outcomes will be analyzed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Able to comprehend and willing to sign the informed consent form (ICF), and willing to abide by the study restrictions.
- Body mass index between 18 and 40 kg/m2, inclusive, at screening.
- During the screening period, have at least 5 out of 7 records of daily average pain intensity recordings in the 7 days prior to randomization.
- Female patients must have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to the administration of study treatment on Day 1; alternatively, female patients of non-child-bearing potential must fulfil 1 of the following criteria at screening: • Post-menopausal defined as aged more than 50 years old and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments. • Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and having luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range as per the central laboratory assessments. • Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.
- Patients of reproductive potential and sexually active must use effective birth control methods, defined as: • For females: hormonal contraceptives, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, abstinence for duration of the trial (if it is patient lifestyle choice). • For males: vasectomy, or abstinence for duration of the trial (if it is patient lifestyle choice). Condom could be used by patients who are not vasectomized or do not agree with abstinence, its use must be in combination with a highly effective contraceptive method by the female partner or woman of childbearing potential.
- Males and females aged ≥18 to ≤75 years at screening.
- Agree to use only MC provided by study team until EOS and not to use any other cannabis or cannabis-containing products including, but not limited to products that are smoked, inhaled, ingested, or topically administered, or over-the-counter CBD products.
- Agree not to participate in other interventional clinical studies during participation in this study.
- Treated with standard of care for DPNP, defined as either duloxetine, gabapentin or pregabalin as monotherapy or a combination of 2, or patients who discontinued the use of standard of care, or amitriptyline used for the management of pain related to DPNP, at least 3 months prior to screening. The standard of care treatment and dosage must have been stable for at least 30 days prior to screening and without intention to change during the study. Patients who receive non-pharmacological, non-invasive pain therapy e.g., behavioral, or cognitive therapy etc., are allowed to enroll, provided there was no change reported to these therapies within 3 months before screening and no changes planned during the study.
- Not current cannabis products users, i.e., patients who were previous cannabis products users for any reason but have not used any cannabis-based products (including CBD only) within 30 days of the screening visit, or patients who have never used cannabis, i.e., cannabis naïve patients.
- A diagnosis of DPNP (at screening), including: • Daily, symmetrical foot pain in diabetic patients, present for at least 3 months, associated with definite or probable peripheral neuropathic pain and classified ≥3 using the Michigan Neuropathy Screening Instrument Part B at screening And • A mean average pain intensity score of ≥4 and ≤9 (Numeric Rating Scale [NRS]; the absolute range of scores [maximum score − minimum score] not exceeding 4) assessed during the last 7 days prior to randomization.
- Confirmed diagnosis of diabetes mellitus type I or type II with stable disease, i.e., patient’s blood glucose to have been controlled by 1 or a combination of the following: diet, glucose control medication, or insulin, all on a stable dose for ≥3 months prior to screening.
- Hemoglobin A1c ≤10% at screening.
Exclusion Criteria
- Evidence of significant uncontrolled concomitant disease that, in the judgment of the investigator, could affect compliance with the protocol at screening or randomization, ability to complete the study, and study assessments.
- History of epilepsy or other seizure disorders (except childhood febrile convulsions).
- Presence of skin conditions in the affected dermatome at screening or randomization that, in the judgment of the investigator, could interfere with the evaluation of the neuropathic pain condition.
- Inadequate hematological function, defined as neutrophil count <1.5 × 109/L and/or platelet count <100 × 109/L at screening.
- History of irreversible neurolytic or neurosurgical therapies, or recent other nonpharmacological treatments that, in the opinion of the investigator, may influence the result of the study assessments.
- Prior use of the Syqe Inhaler for the administration of cannabis sativa L ‘Afina’ aerosol.
- Plans to change current medications or any other intervention intended to treat or relieve DPNP signs or symptoms from screening to EOS.
- Use of prohibited medications as per Section 9.5.2, or participation in an interventional clinical study within 30 days prior to screening.
- Any factor or condition likely to affect compliance, study intervention, visit plan, assessments, scientific integrity, or any clinically significant medical condition which might be worsened by study treatment as judged by the investigator.
- Presence of pain not associated with diabetic peripheral neuropathy or other neuropathies that may interfere with study assessments, as per Investigator’s judgement.
- History of acute coronary syndrome in the last 12 month ; unstable angina; congestive heart failure; cardiogenic syncope; cardiomyopathy or; uncontrolled blood pressure at screening OR UP1 visits, defined as: • Systolic blood pressure ≤90 mm Hg or ≥140 mm Hg, or • Diastolic blood pressure ≤50 mm Hg or ≥95 mm Hg, or • Orthostatic hypotension with a decrease in systolic blood pressure of ≥ 20 mm Hg or a decrease in diastolic blood pressure of ≥10 mm Hg 3 minutes after rising from supine to standing, and • Orthostatic hypotension manifested by symptoms, e.g. lightheadedness, dizziness, syncope, and blurred vision after rising from supine to standing, or • Pulse rate at screening or UP1 visits of ≥120 bpm or ≤50 bpm.
- Known history of significant hypersensitivity, intolerance, adverse reaction or allergy to cannabis products, cannabinoids, or acetaminophen/paracetamol.
- Malignancies in the past 5 years prior to screening, except for cutaneous basal cell or squamous cell carcinoma resolved by excision.
- Liver disease or liver injury as indicated by abnormal liver function tests at screening including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), or total bilirubin exceeding 2 × upper limit of normal.
- History or presence of impaired renal function at screening. • Clinically significant renal insufficiency chronic kidney disease (CKD) <3 or an estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 (Inker 2021) equation of < 30 mL/min ÷ 1.73 m2 at screening (as calculated by the central laboratory). • Evidence of urinary obstruction or difficulty in voiding at screening.
- Pulmonary conditions: a) Abnormal lung function testing indicates forced expiratory volume in the first second (FEV1) <80% predicted value and FEV1/forced vital capacity ratio <70%. b) Presence or history of pulmonary diseases at screening: History of acute or chronic obstructive pulmonary disease (COPD); presence of asthma or • History of diagnosis of any pulmonary disease (interstitial lung disease, pulmonary hypertension, etc) in the judgment of the investigator is likely to be exacerbated by use of the Syqe Fixed-dose Inhaler.
- Ongoing respiratory tract infection.
- Female patients who are breast feeding or pregnant (including a positive serum pregnancy test at screening or a positive urine pregnancy test on Day 1).
- Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, atrial fibrillation, paroxysmal supraventricular arrhythmia, second- or third-degree atrioventricular block without a pacemaker, or any other relevant cardiac disease as judged by the investigator.
- History of clinically significant ECG abnormalities, known familial long QT syndrome or familial ventricular arrythmia, or any clinically significant ECG abnormalities at screening or baseline, including: • QRS complex >120 msec • QTcF >450 msec for men, >470 msec for women • Acute ischemic changes.
- History or presence of mental illness evidenced by • History of recurrent or ongoing major depressive disorders, mania, bipolar disorder, suicidality or a psychotic disorder, or • Family history of schizophrenia or other psychotic illness, or • Current psychiatric condition requiring treatment with a prohibited medication (see prohibited medication list in Section 9.5.2), or • Results from the Columbia-Suicide Severity Rating Scale (C-SSRS) and Mini International Neuropsychiatric Interview (MINI)-Standard (Modules A, C, K, O and diagnostic algorithm at screening, that in the judgment of the investigator indicates history or presence of mental illness, or • Any other current psychiatric condition that might interfere with ability to participate in the study.
- Abnormal neurological condition or abnormal neurological examination other than related to DPN as judged by the investigator at screening that impacts the assessment of study endpoints.
- History of immunodeficiency diseases, including a positive human immunodeficiency virus test result (as per local guidance) at screening.
- A positive hepatitis B surface antigen or hepatitis C test result at screening, unless chronic or acute infection can be ruled out.
- History or presence of drug or alcohol abuse or evidence of such abuse as indicated by the laboratory assays conducted during screening (including Δ9-THC and opiates).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 02 Oct 2024 | 33 |
 Germany | Not Recruiting | 02 Oct 2024 | 38 |
 Poland | Not Recruiting | 02 Oct 2024 | 66 |
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 |
|---|---|---|---|---|---|---|
The placebo (SQE-001-PB) will provide the sensation of an inhalation and inhaler operation without any detectable cannabinoid components emitted. | Placebo | N/A | — | — | — | N/A |
Cannabis Sativa L. ‘Afina’ inflorescence aerosol via the Syqe Inhalerdrug-device combination | Test | INHALATION VAPOUR | INHALATION USE | 3 | 16 | PRD11200190 |