Dupuytren Contracture, Dupuytren Disease of Finger
Conditions
Keywords
collagenase injection, CCH, CNT201
Brief summary
This trial is a multicenter, Phase 1/2, study to assess the safety, tolerability, efficacy, PK, and immunogenicity of CNT201 in adult participants with DC (Dupuytren's Contracture).
Detailed description
This is an adaptive clinical study design containing 2 steps: * Step 1 (dose escalation) is an open-label, dose escalating design where each participant will be enrolled into 1 of 4 dose levels and receive a single administration of CNT201. A Safety Review Committee (SRC) will decide on the dose escalation steps and which dose(s) will be selected to progress into Step 2 dose expansion stage. * Step 2 (dose expansion) adopts a randomized, double-blind, placebo-controlled study design. Eligible participants will be randomized to receive either CNT201 or a placebo for up to a total of 3 treatment cycles per cord at the discretion of the Investigator.
Interventions
DRUG[Step1] CNT201 First-dose
CNT201: recombinant collagenase • Unit Dose Strength(s)/ Dosage Level(s): First-dose
DRUG[Step1] CNT201 Low-dose
CNT201: recombinant collagenase • Unit Dose Strength(s)/ Dosage Level(s): Low-dose
DRUG[Step1] CNT201 Intermediate-dose
CNT201: recombinant collagenase • Unit Dose Strength(s)/ Dosage Level(s): Intermediate-dose
DRUG[Step1] CNT201 High-dose
CNT201: recombinant collagenase • Unit Dose Strength(s)/ Dosage Level(s): High-dose
DRUG[Step2] CNT201
eligible participants will be randomized to 1 of 2 or more treatment arms, depending on the number of CNT201 doses selected for administration in Step 2
DRUG[Step2] Placebo
• Saline
Sponsors
CONNEXT
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
This is an adaptive clinical study design containing 2 steps: * Step 1 (dose escalation) is an open-label, dose-escalating design. * Step 2 (dose expansion) adopts a randomized, double-blind, placebo-controlled study design.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Men and women, 18 to 75 years of age, inclusive. * Participants with a diagnosis of DC, with a fixed flexion deformity of at least 1 finger, other than the thumb, that have a contracture at least 20°, but not greater than 100°, for MP (not greater than 80° for PIP) joints, caused by a palpable cord. * Participants who have a positive Table Top Test, defined as the inability to simultaneously place the affected finger(s) and palm flat against a tabletop. * Participants who are naive to CNT201 treatment. * Participants who are judged to be in good health, based upon the results of a medical history, physical examination, and safety laboratory profile. * Participants who are willing to voluntarily sign and date the Informed Consent Form (ICF) approved by the Institutional Review Board/Independent Ethics Committee (IRB/IEC).
Exclusion criteria
* Participants previously exposed to collagenase Clostridium histolyticum for treatment of Dupuytren's disease (Xiaflex, Xiapex®). * Participants who have received other treatments for advanced Dupuytren's disease, including surgery (fasciectomy or fasciotomy), needle aponeurotomy/fasciotomy, or injection of verapamil and/or interferon on the selected primary joint within 90 days before the first dose of study treatment. * Participants with a chronic muscular, neurological, or neuromuscular disorder that affects the hands, or other medical condition which in the Investigator's opinion will make the participant unsuitable for enrollment in the study. * Participants who have a known recent history of stroke, bleeding, a disease process that affected the hands, or other medical condition (eg, testing positive for tuberculosis \[TB\] or Coronavirus disease 2019 \[COVID-19\], etc), or history of alcoholism or drug abuse, which in the Investigator's opinion, would make the participant unsuitable for enrollment in the study. * Participants who have a known allergic response to collagenase or any other excipient of CNT201 or Xiaflex. * Participants who have received a doxycycline or tetracycline derivative within 14 days before the beginning of the study (tetracycline derivatives may inhibit the collagenolytic activity of mammalian collagenase homologs). * Participants who have received an anticoagulant (except aspirin ≤150 mg/day) within 7 days before the start of the study. * Female participants who are nursing or pregnant, or plan to become pregnant during the study treatment stage of the study. * Participants who have been treated with any investigational drug within 30 days of first dose of study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| [Step 1] Incidence of adverse events | Day 1 through Day 57 | Adverse events including TEAEs, SAEs, and AESIs assessed by frequency and severity, coded using MedDRA and graded per CTCAE v5.0. All adverse event types will be aggregated and reported as overall incidence of adverse events. |
| [Step 1] Change from baseline in systolic and diastolic blood pressure | Screening, Day 1 (pre-dose and post-dose up to 6 hours), Day 2, 3, 8, 15, 29, and Day 57 | Systolic and diastolic blood pressure will be measured in mmHg, and the change from baseline will be evaluated at each scheduled visit. |
| [Step 1] Change from baseline in pulse rate | Screening, Day 1 (pre-dose and post-dose up to 6 hours), Day 2, 3, 8, 15, 29, and Day 57 | Pulse rate will be measured in beats per minute (bpm), and the change from baseline will be assessed at each scheduled visit. |
| [Step 1] Change from baseline in respiratory rate | Screening, Day 1 (pre-dose and post-dose up to 6 hours), Day 2, 3, 8, 15, 29, and Day 57 | Respiratory rate will be measured in breaths per minute, and the change from baseline will be evaluated at each scheduled visit. |
| [Step 1] Change from baseline in body temperature | Screening, Day 1 (pre-dose and post-dose up to 6 hours), Day 2, 3, 8, 15, 29, and Day 57 | Body temperature will be measured in degrees Celsius (°C), and the change from baseline will be evaluated at each scheduled visit. |
| [Step 1] Change from baseline in 12-lead ECG parameters | Screening and Day 1 (1 hour post-dose) | Electrocardiogram (ECG) parameters including heart rate, PR interval, QRS duration, QT interval, and corrected QT interval using Fridericia's formula (QTcF) will be assessed using automated 12-lead ECG recordings. |
| [Step 1] Number of Participants with Clinically Significant Changes in Clinical Laboratory Test Results | Screening and Day 57 | Clinical laboratory assessments include hematology, clinical chemistry, coagulation, and urinalysis parameters. The number of participants with clinically significant changes from baseline will be summarized. |
| [Step 1] Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Screening, Day 1 (pre-dose), Day29, and Day 57 | Complete physical examinations were performed at scheduled visits. Clinically significant abnormalities, including injection site reactions, were recorded and summarized as the number of participants with abnormalities. |
| [Step 1] Proportion of participants achieving reduction in contracture to within 0-5° of normal extension | Within 29 days of study treatment injection | Finger joint contracture (MP and PIP joints) measured by goniometry. |
| [Step 2] Incidence of TEAEs, SAEs, and AESIs by severity | Screening through Month 12 | Frequency and severity of adverse events coded using MedDRA and graded per CTCAE v5.0. |
| [Step 2] Change from baseline in systolic and diastolic blood pressure | Screening, Day 1 of each injection cycle (pre-dose and post-dose up to 48 hours), Day 3, 8, 29 of each cycle, and Month 12 (each cycle is 28 days) | Systolic and diastolic blood pressure will be measured in mmHg, and the change from baseline will be evaluated at each scheduled visit. |
| [Step 2] Change from baseline in pulse rate | Screening, Day 1 of each injection cycle (pre-dose and post-dose up to 48 hours), Day 3, 8, 29 of each cycle, and Month 12 (each cycle is 28 days) | Pulse rate will be measured in beats per minute (bpm), and the change from baseline will be assessed at each scheduled visit. |
| [Step 2] ] Change from baseline in respiratory rate | Screening, Day 1 of each injection cycle (pre-dose and post-dose up to 48 hours), Day 3, 8, 29 of each cycle, and Month 12 (each cycle is 28 days) | Respiratory rate will be measured in breaths per minute, and the change from baseline will be evaluated at each scheduled visit. |
| [Step 2] Change from baseline in body temperature | Screening, Day 1 of each injection cycle (pre-dose and post-dose up to 48 hours), Day 3, 8, 29 of each cycle, and Month 12 (each cycle is 28 days) | Body temperature will be measured in degrees Celsius (°C), and the change from baseline will be evaluated at each scheduled visit. |
| [Step 2] Change from Baseline in Electrocardiogram Parameters | Screening and Day 1 (1 hour post-dose) of each cycle (each cycle is 28 days) | Electrocardiogram (ECG) parameters including heart rate, PR interval, QRS duration, QT interval, and corrected QT interval using Fridericia's formula (QTcF) will be assessed using automated 12-lead ECG recordings. |
| [Step 2] Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Screening, Day 1 of each injection cycle (pre-dose), Day 29 of each cycle and Month 12 (each cycle is 28 days) | Complete physical examinations were performed at scheduled visits. Clinically significant abnormalities, including injection site reactions, were recorded and summarized as the number of participants with abnormalities. |
| [Step 2] Number of Participants with Clinically Significant Changes in Clinical Laboratory Test Results | Screening through Week 52 | Clinical laboratory assessments include hematology, clinical chemistry, coagulation, and urinalysis parameters. The number of participants with clinically significant changes from baseline will be summarized. |
| [Step 2] Proportion of participants achieving reduction in contracture to within 0-5° of normal extension within 29 days after the first injection | Within 29 days after first injection | Finger joint contracture (MP and PIP joints) measured by goniometry. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| [Step 1] Proportion of participants achieving clinical improvement (≥50% reduction in contracture from Day 1) | Screening, Day 1 (pre-dose and 6 hours post-dose), Day 3, 8, 15, 29, and Day 57 | Assessed by finger goniometry at each scheduled visit. |
| [Step 1] Mean percent change in degree of contracture | Screening, Day 1 (pre-dose and 6 hours post-dose), Day 3, 8, 15, 29, and Day 57 | Assessed by finger goniometry (MP and PIP joints). |
| [Step 1] Time to clinical success (contracture ≤5°) | Screening, Day 1 (pre-dose and 6 hours post-dose), Day 3, 8, 15, 29, and Day 57 | Defined as the first study day on which treated joint contracture is ≤5°. |
| [Step 1] Change in range of motion (full extension, full flexion, and total arc) | Screening, Day 1 (pre-dose and 6 hours post-dose), Day 3, 8, 15, 29, and Day 57 | Assessed by finger goniometry (MP and PIP joints). |
| [Step 1] Participant Global Assessment of Treatment Satisfaction Score | Screening, Day 29, and Day 57 | Treatment satisfaction will be assessed by the investigator using a study-specific 5-point Likert scale (1 = Very satisfied, 2 = Satisfied, 3 = Neither satisfied nor dissatisfied, 4 = Dissatisfied, 5 = Very dissatisfied). Lower scores indicate greater satisfaction. |
| [Step 1] Physician Global Assessment of Disease Severity Score | Screening, Day 29, and Day 57 | Disease/contracture severity will be assessed by the investigator using a study-specific 4-point scale (1 = Normal, 2 = Mild, 3 = Moderate, 4 = Severe). Higher scores indicate greater severity. |
| [Step 1] Physician Global Assessment of Treatment Satisfaction Score | Screening, Day 29, and Day 57 | Treatment satisfaction will be assessed by the investigator using a study-specific 5-point Likert scale (1 = Very satisfied, 2 = Satisfied, 3 = Neither satisfied nor dissatisfied, 4 = Dissatisfied, 5 = Very dissatisfied). Lower scores indicate greater satisfaction. |
| [Step 1] Peak plasma concentration (Cmax) of CNXT1 and CNXT2 | Day 1 (pre-dose through 48 hours post-dose), Day 3, 4, 5, 6, 7 | Assessed from plasma concentrations of CNXT1 and CNXT2 collected at scheduled timepoints. |
| [Step 1] Time to peak plasma concentration (tmax) of CNXT1 and CNXT2 | Day 1 (pre-dose through 48 hours post-dose), Day 3, 4, 5, 6, 7 | Assessed from plasma concentrations of CNXT1 and CNXT2 collected at scheduled timepoints. |
| [Step 1] Area under the plasma concentration-time curve (AUC) of CNXT1 and CNXT2 | Day 1 (pre-dose through 48 hours post-dose), Day 3, 4, 5, 6, 7 | Assessed from plasma concentrations of CNXT1 and CNXT2 collected at scheduled timepoints. |
| [Step 1] Half-life (t½) of CNXT1 and CNXT2 | Day 1 (pre-dose through 48 hours post-dose), Day 3, 4, 5, 6, 7 | Assessed from plasma concentrations of CNXT1 and CNXT2 collected at scheduled timepoints. |
| [Step 1] Clearance (CL) of CNXT1 and CNXT2 | Day 1 (pre-dose through 48 hours post-dose), Day 3, 4, 5, 6, 7 | Assessed from plasma concentrations of CNXT1 and CNXT2 collected at scheduled timepoints. |
| [Step 1] Volume of distribution (Vd/F) of CNXT1 and CNXT2 | Day 1 (pre-dose through 48 hours post-dose), Day 3, 4, 5, 6, 7 | Assessed from plasma concentrations of CNXT1 and CNXT2 collected at scheduled timepoints. |
| [Step 1] Incidence of anti-drug antibodies against CNXT1 and CNXT2 | Day 1 (pre-dose), Day 15, 29, and Day 57 | Antibody incidence, titers, and neutralizing antibodies assessed from blood samples. |
| [Step 2] Proportion of participants achieving contracture ≤5° of normal extension at Day 85 after first injection | Day 85 after first injection | Assessed by finger goniometry. |
| [Step 2] Proportion of participants achieving contracture ≤5° of normal extension within 29 days after the last injection | Within 29 days after last injection | Assessed by finger goniometry. |
| [Step 2] Proportion of participants achieving clinical improvement (≥50% reduction in contracture from Day 1) | Screening, Day 1 of each injection cycle (pre-dose), Day 3, 8, 29 of each cycle, Month 2, 3, 4, 6, 9, and Month 12 (each cycle is 28 days) | Assessed by finger goniometry at each scheduled visit. |
| [Step 2] Mean percent change in degree of contracture | Screening, Day 1 of each injection cycle (pre-dose), Day 3, 8, 29 of each cycle, Month 2, 3, 4, 6, 9, and Month 12 (each cycle is 28 days) | Assessed by finger goniometry (MP and PIP joints). |
| [Step 2] Time to clinical success (contracture ≤5°) | Screening, Day 1 of each injection cycle (pre-dose), Day 3, 8, 29 of each cycle, Month 2, 3, 4, 6, 9, and Month 12 (each cycle is 28 days) | Defined as the first study day on which treated joint contracture is ≤5°. |
| [Step 2] Change in range of motion (full extension, full flexion, and total arc) | Screening, Day 1 of each injection cycle (pre-dose), Day 3, 8, 29 of each cycle, Month 2, 3, 4, 6, 9, and Month 12 (each cycle is 28 days) | Assessed by finger goniometry (MP and PIP joints). |
| [Step 2] Participant Global Assessment of Treatment Satisfaction Score | Screening, Day 29 of each injection cycle, and Month 12 (each cycle is 28 days) | Treatment satisfaction will be assessed by the investigator using a study-specific 5-point Likert scale (1 = Very satisfied, 2 = Satisfied, 3 = Neither satisfied nor dissatisfied, 4 = Dissatisfied, 5 = Very dissatisfied). Lower scores indicate greater satisfaction. |
| [Step 2] Physician Global Assessment of Disease Severity Score | Screening, Day 29 of each injection cycle, and Month 12 (each cycle is 28 days) | Disease/contracture severity will be assessed by the investigator using a study-specific 4-point scale (1 = Normal, 2 = Mild, 3 = Moderate, 4 = Severe). Higher scores indicate greater severity. |
| [Step 2] Physician Global Assessment of Treatment Satisfaction Score | Screening, Day 29 of each injection cycle, and Month 12 (each cycle is 28 days) | Treatment satisfaction will be assessed by the investigator using a study-specific 5-point Likert scale (1 = Very satisfied, 2 = Satisfied, 3 = Neither satisfied nor dissatisfied, 4 = Dissatisfied, 5 = Very dissatisfied). Lower scores indicate greater satisfaction. |
| [Step 2] Time to recurrence | Month 2, 3, 4, 6, 9, and Month 12 | Defined as an increase in joint contracture to ≥20° in the presence of a palpable cord. |
| [Step 2] Proportion of participants with contracture recurrence at Month 12 | Month 12 | Recurrence defined as joint contracture ≥20° in the presence of a palpable cord. |
| [Step 2] Incidence of anti-drug antibodies against CNXT1 and CNXT2 | Screening, Day 1 of Cycle 1, Month 2, 3, 4, 6, 9, and Month 12 (each cycle is 28 days) | Antibody incidence, titers, and neutralizing antibodies assessed from blood samples. |
Countries
Australia
Contacts
CONTACTSuntae Kim
Outcome results
None listed