A Study to Evaluate the Safety and Efficacy of CNTX-6970 in Subjects With Knee Osteoarthritis Pain.
The primary objective of this study is to evaluate the safety and efficacy of two doses 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.
- Knee Osteoarthritis
- Eligible Ages
- Between 4 Years and 80 Years
- Eligible Genders
- Accepts Healthy Volunteers
A subject will be eligible for study participation if they meet all of the following
1. Individuals between 40 and 90 years of age (inclusive) at the time of the Screening
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
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)
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
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
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
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.
7. Corticosteroid injection in the index knee within 90 days of Screening or during study
8. Received IA viscosupplementation (e.g., Synvisc®, Hyalgan®) within 90 days of
Screening or any time during study participation.
9. History of clearly documented allergic reaction to celecoxib (Celebrex®), or to sulfa
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).
- Phase 2
- Study Type
- Intervention Model
- Crossover Assignment
- Intervention Model Description
- The study will employ a randomized, allocation-concealed, multicenter, placebo-controlled, multi-period crossover design.
- Primary Purpose
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
- Masking Description
- 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 active comparator in the trial is Celecoxib 100mg BID||
|The lower dose proposed in this Phase 2 trial (100mg BID), which provides 1/3 of the exposure to CNTX-6970 relative to the higher dose, will generate informative data on the dose-related effects of the compound.||
|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.||
- Maurizio Fava, MD
Study ContactAderonke Pederson, MD
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. For example, our simulation experiments (with sample sizes ranging from 30 to 50, carryover effects ranging from 0 to 0.2, and an effect size of 0.4) indicated that the parallel design yields statistical power ranging from 0.20-0.25, whereas our proposed 2-block multi-period crossover design yields power ranging from 0.9-1.0. The trial will compare an active treatment vs. placebo. Each arm of the study will employ a multi-period crossover design with two blocks. 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) Recent meta-analyses suggest that anti-inflammatory treatments such as NSAIDs reach peak effects on pain within a 4-week timeframe in patients with knee osteoarthritis, and multiple RCTs have specifically demonstrated efficacy for celecoxib at 2-6 weeks (Osani et al, 2020). The comparison with celecoxib is used to evaluate "assay sensitivity," i.e., to assess the study protocol's ability to demonstrate superiority of an established efficacious treatment (celecoxib 100mg BID). 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