Cannabis sativa flower (Δ9-THC and other cannabinoids) for Diabetic peripheral neuropathic pain

Inclusion criteria

• {"criterion_text":"- 1. Able to comprehend and willing to sign the informed consent form (ICF), and willing to abide by the study restrictions."}
• {"criterion_text":"- 6. 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."}
• {"criterion_text":"- 7. 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."}
• {"criterion_text":"- 8. 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."}
• {"criterion_text":"- 9. Hemoglobin A1c ≤10% at screening."}
• {"criterion_text":"- 10. Body mass index between 18 and 40 kg/m2, inclusive, at screening."}
• {"criterion_text":"- 11. 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."}
• {"criterion_text":"- 12. 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."}
• {"criterion_text":"- 13. 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."}
• {"criterion_text":"- 2. Males and females aged ≥18 to ≤75 years at screening."}
• {"criterion_text":"- 3. 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."}
• {"criterion_text":"- 4. Agree not to participate in other interventional clinical studies during participation in this study."}
• {"criterion_text":"- 5. 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."}

Exclusion criteria

• {"criterion_text":"- 1. 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."}
• {"criterion_text":"- 3. Presence of pain not associated with diabetic peripheral neuropathy or other neuropathies that may interfere with study assessments, as per Investigator’s judgement."}
• {"criterion_text":"- 10. 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: •\tSystolic blood pressure ≤90 mm Hg or ≥140 mm Hg, or •\tDiastolic blood pressure ≤50 mm Hg or ≥95 mm Hg, or •\tOrthostatic 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 •\tOrthostatic hypotension manifested by symptoms, e.g. lightheadedness, dizziness, syncope, and blurred vision after rising from supine to standing, or •\tPulse rate at screening or UP1 visits of ≥120 bpm or ≤50 bpm."}
• {"criterion_text":"- 4. Known history of significant hypersensitivity, intolerance, adverse reaction or allergy to cannabis products, cannabinoids, or acetaminophen/paracetamol."}
• {"criterion_text":"- 5. Malignancies in the past 5 years prior to screening, except for cutaneous basal cell or squamous cell carcinoma resolved by excision."}
• {"criterion_text":"- 6. 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."}
• {"criterion_text":"- 7. 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."}
• {"criterion_text":"- 8. 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."}
• {"criterion_text":"- 9. Ongoing respiratory tract infection."}
• {"criterion_text":"- 25. 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)."}
• {"criterion_text":"- 11. 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."}
• {"criterion_text":"- 18. History of epilepsy or other seizure disorders (except childhood febrile convulsions)."}
• {"criterion_text":"- 12. 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: •\tQRS complex >120 msec •\tQTcF >450 msec for men, >470 msec for women •\tAcute ischemic changes."}
• {"criterion_text":"- 13. History or presence of mental illness evidenced by •\tHistory of recurrent or ongoing major depressive disorders, mania, bipolar disorder, suicidality or a psychotic disorder, or •\tFamily history of schizophrenia or other psychotic illness, or •\tCurrent psychiatric condition requiring treatment with a prohibited medication (see prohibited medication list in Section 9.5.2), or •\tResults 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 •\tAny other current psychiatric condition that might interfere with ability to participate in the study."}
• {"criterion_text":"- 14. 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."}
• {"criterion_text":"- 15. History of immunodeficiency diseases, including a positive human immunodeficiency virus test result (as per local guidance) at screening."}
• {"criterion_text":"- 16. A positive hepatitis B surface antigen or hepatitis C test result at screening, unless chronic or acute infection can be ruled out."}
• {"criterion_text":"- 17. 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)."}
• {"criterion_text":"- 2. 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."}
• {"criterion_text":"- 19. Inadequate hematological function, defined as neutrophil count <1.5 × 109/L and/or platelet count <100 × 109/L at screening."}
• {"criterion_text":"- 20. 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."}
• {"criterion_text":"- 21. Prior use of the Syqe Inhaler for the administration of cannabis sativa L ‘Afina’ aerosol."}
• {"criterion_text":"- 22. Plans to change current medications or any other intervention intended to treat or relieve DPNP signs or symptoms from screening to EOS."}
• {"criterion_text":"- 23. Use of prohibited medications as per Section 9.5.2, or participation in an interventional clinical study within 30 days prior to screening."}
• {"criterion_text":"- 24. 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."}

Primary endpoints

• {"endpoint_text":"- 1. Change from baseline in weekly-mean 24-hour average pain score (using the 11-point Numeric Rating Scale [NRS]) at Week 16.","definition_or_measurement_approach":"Weekly-mean 24-hour average pain score measured using the 11-point Numeric Rating Scale (NRS); change from baseline assessed at Week 16."}

Secondary endpoints

• {"endpoint_text":"- 1. Change from baseline in Neuropathic Pain Symptom Inventory and in Brief Pain Inventory – Short Form.","definition_or_measurement_approach":"Change from baseline in Neuropathic Pain Symptom Inventory and Brief Pain Inventory – Short Form scores."}
• {"endpoint_text":"- 2. Change from baseline in weekly-mean 24-hour average, worst and least pain score (using the 11-point NRS).","definition_or_measurement_approach":"Weekly-mean 24-hour average, worst and least pain scores using 11-point NRS; change from baseline."}
• {"endpoint_text":"- 3. Proportion of patients achieving at least 30% and 50% reduction from baseline in the weekly-mean 24-hour average pain score (using the 11-point NRS).","definition_or_measurement_approach":"Responder rates defined as ≥30% and ≥50% reduction from baseline in weekly-mean 24-hour average pain score (11-point NRS)."}
• {"endpoint_text":"- 4. Proportion of patients with treatment-emergent adverse events (TEAEs) and their severity, AEs leading to study treatment discontinuation, TEAEs of special interest, and serious TEAEs.","definition_or_measurement_approach":"Safety endpoints: incidence and severity of TEAEs, AEs leading to discontinuation, TEAEs of special interest, and serious TEAEs as reported during study."}
• {"endpoint_text":"- 5. Safety and tolerability will also be assessed by Michigan Neuropathy Screening Instrument Part B, Columbia-Suicide Severity Rating Scale, spirometry, electrocardiogram, laboratory blood, and urine tests.","definition_or_measurement_approach":"Safety and tolerability assessed via Michigan Neuropathy Screening Instrument Part B, C-SSRS, spirometry, ECG, laboratory blood and urine tests."}
• {"endpoint_text":"- 6. Pharmacokinetic concentrations and parameters (pre-dose plasma concentration [Ctrough], maximum observed steady state concentration [Cmax ss], time at which maximum observed steady state concentration occurs [Tmax ss], area under the concentration-time curve [AUC]) of Δ9-THC, cannabidiol, cannabinol, 11-OH-THC, and 11-COOH-THC at selected visits.","definition_or_measurement_approach":"PK endpoints: plasma concentrations and PK parameters (Ctrough, Cmax ss, Tmax ss, AUC) for Δ9-THC, cannabidiol, cannabinol, 11-OH-THC, and 11-COOH-THC measured at specified visits."}
• {"endpoint_text":"- 7. Proportion of patients who need rescue medication for the treatment of DPNP.","definition_or_measurement_approach":"Proportion of patients requiring rescue medication during study periods."}
• {"endpoint_text":"- 8. Frequency and amount of rescue medication taken and time to first intake for the treatment of DPNP.","definition_or_measurement_approach":"Frequency, amount, and time-to-first-use metrics for rescue medication use."}
• {"endpoint_text":"- 9. Change from baseline in weekly-mean 24-hour sleep score using the 11-point Daily Sleep Interference Scale and the Pain and Sleep Questionnaire-3.","definition_or_measurement_approach":"Change from baseline in weekly-mean 24-hour sleep interference measured by 11-point Daily Sleep Interference Scale and PSQ-3."}
• {"endpoint_text":"- 10. Change from baseline in Patient-Reported Outcomes Measurement Information System-29 Profile v2.1 total score.","definition_or_measurement_approach":"Change from baseline in PROMIS-29 Profile v2.1 total score."}

Methods

• Print advertisements (country-specific print ads listed in recruitment materials)
• Posters and flyers (site/poster with flyer materials)
• Social media posts (social media recruitment materials listed)
• Site-to-patient letters and doctor-to-patient letters (site and Dr to patient letters)
• Patient brochures and FAQ sheets (patient brochure, patient FAQ)
• E-newsletter content targeted to Patient Advocacy Groups (PAG) and patients
• Phone screening (Phone Screening Script included)
• Landing page advertising and online ad packets (Landing Page Ad, Ad Packet)
• Study mobile app (StudyKIK / App Prototype) for recruitment/screening
• ClinCard/participant payment and related communications (ClinCard materials) and bank transfer guidance
• Site-specific recruitment materials for Czechia, Poland, Germany (localised recruitment packs)

Germany

Earliest CTIS Part Ii Submission Date

04-07-2024

Latest Decision Or Authorization Date

21-11-2025

Processing Time Days

505

Number Of Sites

13

Number Of Participants

38

Czechia

Earliest CTIS Part Ii Submission Date

02-07-2024

Latest Decision Or Authorization Date

24-11-2025

Processing Time Days

510

Number Of Sites

5

Number Of Participants

33

Poland

Earliest CTIS Part Ii Submission Date

02-07-2024

Latest Decision Or Authorization Date

04-12-2025

Processing Time Days

520

Number Of Sites

16

Number Of Participants

66

Primary sponsor

Full Name

Syqe Medical Ltd.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Israel

Contract research organisations

Name

Pharmaceutical Product Development LLC

Responsibilities

Central lab services: Long Chemistry Panel, Hematology Panel, Drug Screen (Standard) and related central lab responsibilities

Name

Syneos Health Inc.

Responsibilities

Study recruitment campaign and multiple study conduct roles

Name

Syneos Health Clinique Inc.

Responsibilities

PK analysis

Name

eResearchTechnology Inc. / eResearchTechnology GmbH

Responsibilities

eCOA and pulmonary/cardiac safety assessments

Name

Medidata Solutions Inc.

Responsibilities

RTSM, RAVE study conduct and associated systems

Name

Fisher Clinical Services UK Limited

Responsibilities

Supply chain / IMP handling

Third parties

• {"country":"Hungary","full_name":"Oximio Hungary Kft.","duties_or_roles":"Equipment distribution (import/export activities)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Welocalize Inc.","duties_or_roles":"Translation services","organisation_type":"Pharmaceutical company"}
• {"country":"Poland","full_name":"Synoptis Industrial Sp. z o.o.","duties_or_roles":"IMP distribution in Poland","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Pharmaceutical Product Development LLC","duties_or_roles":"Central lab: Long Chemistry Panel, Hematology Panel, Drug Screen (Standard); other central lab responsibilities","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"eCOA","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"RTSM, RAVE Study Conduct; study conduct support","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Czechia","full_name":"Alliance Healthcare s.r.o.","duties_or_roles":"IMP distribution in Czechia","organisation_type":"Pharmaceutical company"}
• {"country":"Canada","full_name":"Syneos Health Clinique Inc.","duties_or_roles":"PK Analysis","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Netherlands","full_name":"Emsere B.V.","duties_or_roles":"Site equipment","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Fisher Clinical Services UK Limited","duties_or_roles":"Supply chain / IMP handling (codes indicate distribution roles)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"Patient reimbursement","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Neonstone Limited","duties_or_roles":"Management of investigator portal for rater training and sharing study materials","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Germany","full_name":"eResearchTechnology GmbH","duties_or_roles":"Pulmonary Function Assessments, Cardiac Safety","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"Study recruitment campaign and other study conduct services","organisation_type":"Pharmaceutical company"}