ITX24-01 in Adult Male and Female Patients With Select Types of Severe Chronic Neck- and Lower Back Pain

Purpose: This is a Single Ascending Dose (SAD), Phase 1b, single-center, randomised, double-blind, placebo-controlled study designed to evaluate the safety, tolerability, and preliminary analgesic efficacy of ITX24-01 administered via the medial branch block (MBB) route in patients with severe chronic zygapophysial joint pain (facet joint pain). The study consists of three dose escalation cohorts and one extension cohort.

Study Population: The study population will consist of patients with severe chronic zygapophysial joint pain who meet the specified inclusion and exclusion criteria.

Blinding and Masking: The study employs a double-blind design, where both participants and investigators are blinded to treatment assignments. Masking will be applied to the assessor, investigator, caregiver, and participant to minimize bias.

Randomization and Assignment: Participants will be randomised within each cohort to receive either ITX24-01 or a placebo. In each of the three dose escalation cohorts (Group 1: low dose, Group 2: intermediate dose, Group 3: full dose), 6 participants will receive ITX24-01 and 2 will receive placebo. Group 4 is an extension cohort consisting of 4 participants receiving ITX24-01 and 4 receiving placebo. Randomization occurs after the screening period and before the treatment administration.

Dose-Escalation and Monitoring: Progression from one dose group to the next will only be allowed if the Maximum Tolerated Dose (MTD) has not been reached in the preceding group. A Safety Monitoring Committee (SMC) overseeing safety data will also function as dose-escalation committee reviewing and approving dose increases or -adjustments between groups. If at any dose level an MTD was encountered, doses in subsequent groups will be adjusted.

Extension Cohort: Group 4 serves as an extension cohort, in which additional patients will receive ITX24-01 at the highest dose level at which no MTD was encountered in any of the previous groups. Accordingly, the highest possible dose administered to participants in the extension cohort will be the full dose. If a dose modification (lowering) was instituted at any time in the study, the dose will be lower. The extension cohort will thereby further assess safety and tolerability at the highest dose reached during dose escalation.

Dose Modification: If the MTD is reached in any group, the dose for the subsequent group (or any subsequently enrolled patients in the same group) will be lowered to the dose level of the preceding group, i.e., the preceding lower dose level, at which no MTD had been encountered.

• ITX24-01 (Drug): Fluoroscopy guided local administration by the medial branch block (MBB) route. Dosage form: liquid. Frequency of administration: once (single dose).
• Normal Saline (0.9% NaCl) (Drug): Placebo (negative control). Dosage form: liquid. Frequency of administration: once (single dose).

Primary outcomes

• Safety of ITX24-01 or placebo delivered locally by the medial branch block (MBB) route in adult participants with severe chronic zygapophysial joint pain [During the screening period, on the day of ITX24-01 administration, and up to 6 weeks of follow-up.]: Incidence and severity of adverse events (AEs) and their relatedness to the Investigational Medicinal Product (IMP) determined according to CTCAE (version 5.0).
• Tolerability of ITX24-01 or placebo delivered locally by the medial branch block (MBB) route in adult participants with severe chronic zygapophysial joint pain [At pre-specified time points up to 6 hours after administration of the investigational medicinal product (IMP).]: Pain at the injection site, assessed using a verbal response scale (VRS) from 0 (no pain) to 10 (worst pain).

Secondary outcomes

• Preliminary efficacy of a single dose of ITX24-01 or placebo administered via the medial branch block (MBB) route in patients with severe chronic zygapophysial joint pain [During the screening period and at 6 weeks of follow-up.]: Participant responses collected via the Clinical Outcome Measurement Brief Instrument (COMBI) questionnaire.

Other outcomes

• Healthcare utilization of patients with severe chronic zygapophysial joint pain following a single dose of ITX24-01 or placebo administered via the medial branch block (MBB) route [Within 12 weeks post-treatment.]: Proportion of patients who proceed to medial branch nerve radiofrequency neurotomy (MBN).

Sex: All, ages: 18 Years to any

Inclusion Criteria:

To be eligible to participate in this study, an individual must meet all the following criteria:

1. Male or female. Women of childbearing potential must be willing to use contraceptives, or not be sexually active from the time when, during screening, pregnancy was excluded (by history and/or pregnancy test) until after the day of treatment has been completed (until ≥6 hours after administration of the IMP).
2. Age ≥18 years
3. Diagnosis of chronic zygapophysial joint neck- or lower back pain and elected to undergo medial branch neurotomy (MBN), aka radiofrequency ablation (RFA), as treatment for that pain syndrome. Participants can be patients who have undergone prior MBN (at the same level and side) and who have experienced pain recurrence and have, at the time of enrollment, opted for a repeat MBN procedure (at the same level and side). A positive MBB as determined by the Principal Investigator (PI) is required for all patients that was performed either at the time of the original diagnosis or at the time of pain recurrence. Thereby, for patients with a new diagnosis of chronic zygapophysial joint neck- or lower back pain (not treated with MBN in the past), a positive diagnostic MBB will be required. For patients with pain recurrence, a positive diagnostic MBB that was performed at the time of the original pain diagnosis, i.e., before the first MBN treatment, will be considered sufficient. (If no diagnostic MBB was performed at the time of the original diagnosis, a diagnostic MBB at the time of recurrence will be required.) The diagnosis will be reviewed by the Principal Investigator (PI) during Screening who will consider the timeline and diagnostic rigor of prior medical findings and tests in conjunction with the evaluation performed during screening (history and physical exam). PI agreement with the diagnosis (at their discretion) is required for the participant to meet this criterion.
4. Ambulatory
5. Body weight ≥48 kg
6. Able to understand and comply with the study
7. Willing to provide written informed consent
8. Patients with zygapophysial joint neck- or lower back pain affecting a single joint (who require two injection of the IMP) are allowed in any group of the study (including Group 1). Patients with zygapophysial joint neck- or lower back pain affecting two joints at adjacent levels (who require three injection of the IMP) are allowed in Groups 2, 3 and 4 only.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Pregnant or breastfeeding
2. Diagnosis of thoracic chronic zygapophysial joint pain
3. Allergy or hypersensitivity to lidocaine, bupivacaine or iodinated radiographic contrast media
4. Clinical history of angina, myocardial infarction or stroke experienced within the past year
5. If taking warfarin, an INR ≥ 3.0
6. Suicidal ideation or behavior (SIB)
7. Pathological ECG. Exclude subjects with a marked baseline QTc prolongation defined as QTc >470 ms in males or >480 ms in females; or as QTc >450 ms in males or >470 ms in females with any additional torsades risk factors (heart failure, hypokalaemia, concomitant QT-prolonging drugs).
8. Any other medical condition identified during screening that in the PI's judgement may preclude the safe performance of the study procedure
9. For patients who are enrolled on the basis that they opt for repeat MBN procedure (at the same level and side), the prior MBN procedure must have been performed ≥6 months prior to enrollment.
10. Zygapophysial joint neck- or lower back pain affecting- and requiring MBN of more than two joints or of more than one non-adjacent joint.

• Stojanovic MP, Higgins DM, Popescu A, Bogduk N. COMBI: a convenient tool for clinical outcome assessment in conventional practice. Pain Med. 2015 Mar;16(3):513-9. doi: 10.1111/pme.12581. Epub 2014 Oct 14. No abstract available. PMID 25312899