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

Knee Osteoarthritis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05025787
• Other study ID #: 2021p002273 (EN20-01)
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 25, 2021
• Est. completion date: July 31, 2024

Study information

• Verified date: February 2024
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 77
• Est. completion date: July 31, 2024
• Est. primary completion date: July 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 90 Years

Eligibility

A subject will be eligible for study participation if they meet all of the following

criteria:

1. Individuals between 40 and 90 years of age (inclusive) at the time of the Screening Visit.

2. 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.

3. 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.

4. 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.

5. 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.

6. Confirmation of OA of the index knee: American College of Rheumatology (ACR) diagnostic criteria.

7. Subjects must have failed 2 or more prior therapies. Failure is deemed to be inadequate relief in the opinion of the investigator.

8. Body mass index (BMI) of = 40 kg/m2.

9. 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:

1. Any form of joint replacement surgery, open surgery, or arthroscopic surgery of the index knee/knee joint with 12 months of Screening.

2. 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.

3. 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.

4. Documented history of neuropathic arthropathy in the knee.

5. 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.

6. 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:

1. chronic for at least 12 weeks; and

2. at a stable dose for at least 4 weeks before Screening ii. Intermittent use of

opioids that is:

1. ongoing for at least 4 weeks before Screening;

2. at a frequency no more than 4 days/week; and

3. 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)

1. Continuous use allowed if chronic and stable for at least 12 weeks

2. 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

7. 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).

8. 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).

Related Conditions & MeSH terms

• Knee Osteoarthritis
• Osteoarthritis
• Osteoarthritis, Knee

Intervention

Drug:
• CNTX-6970
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.
• Placebo
BID

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	UTsouthwestern Medical Center	Dallas	Texas
United States	University of Florida	Gainesville	Florida
United States	Healthcare Research Network	Hazelwood	Missouri
United States	University of California San Diego	La Jolla	California
United States	University of Wisconsin- Madison	Madison	Wisconsin
United States	M&M Clinical Trials	Miami	Florida
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	New York University Langone Health	New York	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	University of Rochester	Rochester	New York
United States	University of California- Davis	Sacramento	California
United States	University of Washington	Seattle	Washington
United States	Center for Clinical Research	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Maurizio Fava, MD

Country where clinical trial is conducted

United States, 

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* Note: There are 63 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC-A)	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.	24 Weeks
Primary	Treatment emergent adverse events (TEAEs)	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.	24 Weeks
Secondary	Numeric Rating Scale (NRS)	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.	24 Weeks
Secondary	Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC-C)	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.	24 Weeks
Secondary	Hospital Anxiety and Depression Scale (HADS)	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.	24 Weeks
Secondary	PROMIS Sleep Disturbance Scale - 6A	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.	24 Weeks
Secondary	Patient Global Impression of Change (PGIC)	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).	24 Weeks
Secondary	Staircase-evoked pain assessment	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.	24 Weeks
Secondary	Serum levels of cytokines and chemokines	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.	24 Weeks
Secondary	MCP-1/CCR-2	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.	24 Weeks