A Study to Evaluate the Safety and Efficacy of CNTX-6970 in Subjects With Knee Osteoarthritis Pain.

EN20-01: A 24 Week Study to Evaluate the Safety and Efficacy of CNTX-6970 in Subjects With Moderate to Severe Knee Osteoarthritis Pain.

The primary objective of this study is to evaluate the safety and efficacy of CNTX-6970 for the treatment of pain related to OA of the knee compared to placebo. CNTX-6970 is being developed as a new treatment for chronic pain, including painful osteoarthritis of the knee.

The study will employ a randomized, allocation-concealed, multicenter, placebo-controlled, multi-period crossover design (Schmid et al, 2018). This multi-period crossover randomized, controlled trial allows comparability and assessment of efficacy through repeated exposures within each subject to the active treatment and a control (placebo) in randomized sequence. Such multi-period crossover designs are ideal for treatments with rapid onset of action and short half-life such as the asset under study here. We have strived to minimize the complexity of this powerful design by using only 2 blocks with 2 periods each. The modest additional complexity of the proposed multi-period crossover design, compared to a parallel-groups design, is justified by the marked improvement in efficiency. The gains in efficiency afforded by the multi-period crossover design allow a substantial reduction in sample size without sacrificing statistical power. The trial will compare an active treatment vs. placebo. Each block will consist of two treatment periods with each period lasting 6 weeks. Treatment assignments (active drug versus placebo) will be randomized for each patient to the two periods within each block. The period length of 6 weeks was chosen based on several considerations: (i) Most efficacious analgesic drugs demonstrate separation from placebo by 6 weeks; (ii) The decision to move CNTX-6970 forward to Phase 3 will require a clinically meaningful separation from placebo by 6 weeks; (iii) In this Phase 2 study, implementing a treatment block longer than 6 weeks would make the overall design more challenging and burdensome by extending the duration of overall testing beyond 6 months; (iv). In this study, the placebo will consist of inactive tablets identical to the active treatment tablets. Treatment assignments (active drug versus placebo) will be randomized for each patient to the two treatment periods within each block.

The study will employ a randomized, allocation-concealed, multicenter, placebo-controlled, multi-period crossover design.

Blinding of the randomization assignment from trial subjects, staff from the Clinical Sites, CCC, and DCC will be ensured through the use of the IXRS.

The higher dose (i.e., 300mg BID) demonstrated good tolerability and safety, as well as over 90% inhibition of the binding of monocyte chemoattractant protein-1 to its CCR-2 receptor. Moreover, this dose produced nearly 90% binding inhibition at the CCR-5 receptor as well.

CNTX-6970, a novel potent antagonist of CCR2 with lesser effects on CCR5, is being developed as a new treatment for chronic pain, including painful osteoarthritis of the knee.

The primary outcome measure used to assess efficacy will be patient-reported knee pain using the WOMAC Part A (Bellamy, et al., 1988).We will use the numerical rating scale version of the WOMAC, with the subject assessing each of 5 questions using an 11-point (0 to 10) scale; the total score is the sum of the individual item scores (range 0-50). A higher WOMAC score represents worse symptom severity.

The primary safety endpoint is the incidence of treatment emergent adverse events (TEAEs), reported between the administration of study drug on Day 1 and the completion of the study at week 24 or early termination.

Daily Knee Pain Intensity on a 0-10 Numeric Rating Scale (NRS). Pain intensity is reported by patients with chronic pain as one of the most important targets of treatment, and daily pain intensity ratings are a recommended core outcome measure for clinical trials of treatments for chronic pain. Daily ratings are preferable to ratings of recalled pain over longer time periods such as a week, as daily ratings minimize the influence of recall biases (Dworkin et al., 2005). Participants provide one-daily reports (at the end of the day) of their average knee pain intensity on a 0-10 pain intensity NRS over the course of a week, and those daily ratings are averaged to compute a mean knee pain intensity score. Participants will record their Daily Pain Intensity Numeric Rating Scale (NRS) 0-10 each day for one week prior to each clinic visit using NEForm.

WOMAC-C (Function subscale) (Bellamy et al, 1988). The WOMAC-physical function subscale contains 17 items assessing daily functioning, each using an 11-point (0 to 10) numerical rating scale. The total index score (0-170) is the sum of the items. A higher WOMAC function score represents worse functioning and less ability to engage in daily activities.

The HADS is a 14-item self-report questionnaire designed to assess symptoms of anxiety and depression in those with medical illness (Norton et al, 2013). This scale has 14 items, 7 related to anxiety and 7 to depression, rated on 4 points (0 to 3) in domains of intensity or frequency. Scoring is done separately for depression and for anxiety and each domain is interpreted as normal for scores of 0-7, borderline abnormal (borderline case) for scores of 8-10 and abnormal (case) for scores of 11-21. This scale is used to assess depression and anxiety in addition to HEAL/EPPIC-Net core data elements (CDEs) because of its higher sensitivity to change especially in patients with medical illnesses.

PROMIS Sleep Disturbance Scale - 6A (Yu et al, 2011). Sleep disruption has a bi-directional relationship with chronic pain and is an important secondary outcome to measure in pain trials (Edwards et al, 2016). The Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance short form is a convenient 6-item scale that correlates strongly with the longer forms. It shows greater measurement precision for assessing sleep disturbance than other commonly-used (and much longer) questionnaires such as the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale; its brevity and convenience are a major advantage for both research and clinical settings (Yu et al, 2011). The PROMIS Sleep Disturbance Scale is expressed as a T-score, with a population mean of 50 and SD of 10. Possible T scores in this distribution range from 31.7 to 76.1.

The PGIC is a single-item measure of patient-reported improvement that is widely used as a general outcome measure in studies of chronic pain patients, including OA patients (Salaff et al, 2004). It is often used as an index of treatment-associated change, and patient-reported improvements in the form of PGIC scores correlate robustly with significant improvement in pain intensity, pain interference with activities of daily living, mood, and quality of life (Perrot and Lanteri-Minet, 2019).

This procedure consists of stepping fully up and down onto an 8in (20.32cm) high platform with both feet a total of 24 times. The lead leg is alternated between each up/down cycle. Subjects are instructed to use their normal gait for completing this task and are encouraged to complete the task despite increasing pain, without stopping if possible. The procedure is timed, and current knee pain intensity on a 0-10 Numeric Rating Scale (NRS) is assessed immediately before and following the procedure while the subject is in a seated, resting position.

These will be assessed at baseline and at the end of each treatment period (weeks 0, 6, 12, 18 and 24).Serum levels are measured in Picograms per millilitre (pg/mL). Serum analysis will include cytokines and chemokines as a part of establishing biomarker for treatment of OA pain with CNTX-6970.

Monocyte chemoattractant serum protein-1(MCP-1)/CCR-2 receptor binding inhibition by CNTX-6970. This will be assessed at baseline and at the end of each treatment period (weeks 0, 6, 12, 18 and 24). This test provides a single score, expressed as a percentage, 0-100%, with higher scores indicating more binding inhibition.

A subject will be eligible for study participation if they meet all of the following criteria: Individuals between 40 and 90 years of age (inclusive) at the time of the Screening Visit. Willing to use a mobile smart device during the study period. Individuals who do not have access to a mobile device will be provided with one for the duration of the study and trained in its use. Can understand the nature of the study and protocol requirements and is willing to comply with study drug administration requirements and discontinue prohibited concomitant medications. Radiography of both knees with a posterior-anterior, fixed-flexion view taken during the Screening visit. The Index knee must show evidence of chronic OA with a K-L Grading Scale of 1, 2, 3, or 4. Such evidence will be provided by a central reading of the radiography of both knees from an expert radiologist of the CCC of EPPIC-Net. Moderate to severe pain in the Index knee associated with OA and stable for a minimum of 6 months prior to Screening in the opinion of the investigator. Confirmation of OA of the index knee: American College of Rheumatology (ACR) diagnostic criteria. Subjects must have failed 2 or more prior therapies. Failure is deemed to be inadequate relief in the opinion of the investigator. Body mass index (BMI) of ≤ 40 kg/m2. Willing to refrain from illicit drug use during the study, and to have illicit drug testing at screening and at later time points. A subject will be excluded from the study if they meet any of the following criteria: Any form of joint replacement surgery, open surgery, or arthroscopic surgery of the index knee/knee joint with 12 months of Screening. Any painful condition(s) of the index knee due to disease other than OA. For example, periarticular or referred pain involving the index knee, or from joint disease other than OA associated with the index knee. Other chronic pain anywhere in the lower extremities (e.g. hips, legs, feet) that is equal or greater in intensity or impairment than index knee pain or that requires the use of analgesic medications. This includes radicular low back pain with radiation to the knee. Documented history of neuropathic arthropathy in the knee. Significant instability (e.g., cruciate ligament tear or rupture or previous repair) within the past 5 years or current misalignment (>10 degrees varus or valgus) of the index knee. Plans to have surgery, invasive procedures, or intra-articular (IA) injections of the index knee or procedure or surgery otherwise contraindicated for study participation while in the study. a. Concomitant Medications for Pain - i. Continuous use of one of the following medications prescribed for pain: tramadol, gabapentin, duloxetine, pregabalin, milnacipran, or tricyclic antidepressants that is: chronic for at least 12 weeks; and at a stable dose for at least 4 weeks before Screening ii. Intermittent use of opioids that is: ongoing for at least 4 weeks before Screening; at a frequency no more than 4 days/week; and not be taken within 24 hours of a study visit iii. As needed use of acetaminophen iv. Continuous use of medical marijuana (or equivalent) that is chronic for at least 12 weeks and at a stable dose for 4 weeks v. Topical creams (includes CBD topicals) Continuous use allowed if chronic and stable for at least 12 weeks Intermittent use allowed if at a frequency of no more than 4 days/week b. Concomitant Medications for Non-Pain Indications That May Impact Pain - i. Continuous use of medication for non-pain indications that are known to potentially impact pain, e.g. duloxetine for depression, that is at a stable dose for at least 12 weeks prior to Screening. ii. Low-dose aspirin for the purposes of heart disease prophylaxis Corticosteroid injection in the index knee within 30 days of Screening or during study participation (unless the injectable is a long-acting agent such as triamcinolone acetonide extended-release injectable suspension (Zilretta) in which case the injection cannot be within 90 days of screening). Received IA viscosupplementation (e.g., Synvisc®, Hyalgan®) within 90 days of Screening. 10. Use of an investigational medication within 30 days of Screening, or 5 pharmacokinetic or pharmacodynamic half-lives (whichever is longer) or scheduled to receive such an agent while participating in the current study. 11. Current therapy with any immunosuppressive therapy, including corticosteroids (>5 mg/day of prednisone).

The EPPIC-Net DCC's NYU Center for Biospecimen Research and Development (CBRD) will store and manage biological samples (biosamples) collected in this clinical trial. The samples will be used for the present study and also for potential future research as permitted by the study-specific informed consent form. Biosamples stored for this study may include, but are not limited to: whole blood, plasma, stool, synovial fluid, and/or derivatives of these specimens. The samples will be stored only for the period defined in the informed consent form, which may be indefinite. Biospecimens may be shared in accordance with the protocol-defined data and sample sharing plan and the informed consent form. Biosamples will be documented in LabVantage, a secure network linking biospecimens to corresponding clinical and pathological data. LabVantage does not include any identifying personal health information (PHI). The CBRD and LabVantage meet all General Lab Protocol (GLP) and FDA guidelines.

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