Calcific Uremic Arteriolopathy, Calciphylaxis
Conditions
Keywords
Calciphylaxis, Calcific Uremic Arteriolopathy, Wound, ESRD
Brief summary
The primary objectives are to assess the efficacy, safety, and tolerability of SNF472 compared to placebo when added to background care for the treatment of calciphylaxis (CUA).
Detailed description
The formation and growth of calcified deposits in arterioles and other small blood vessels appears to be fundamental to the development of CUA especially in end stage renal disease patients. This phase 3 double-blind, randomized, placebo-controlled study is designed to assess the effect of SNF472 when added to background care to improve wound healing, as evaluated using Bates-Jensen Wound Assessment Tool (BWAT) scoring and pain as reported by the subject using a VAS scale. The study consists of a double-blind, randomized, placebo controlled period of 12 weeks followed by an open-label period of 12 weeks.. .
Interventions
DRUGExperimental: SNF472
Administered 3 times weekly by intravenous infusion through the hemodialysis machine in conjunction with the subject's hemodialysis sessions for 12 weeks
Administered 3 times weekly by intravenous infusion through the hemodialysis machine in conjunction with the subject's hemodialysis sessions fo 12 weeks
DRUGExperimatenl SNF472 (Open-label)
Administered 3 times weekly by intravenous infusion through the hemodialysis machine in conjunction with the subject's hemodialysis sessions for 12 weeks
Sponsors
Sanifit Therapeutics S. A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female or male subjects, 18 years of age or older * Receiving maintenance HD in a clinical setting for at least 2 weeks prior to screening * Clinical diagnosis of CUA by the Investigator including ≥1 CUA lesion with ulceration of the epithelial surface * CUA wound-related pain shown by a Pain VAS score ≥50 out of 100 * Primary lesion that can be clearly photographed for the purpose of protocol-specified wound healing assessments. * Willing and able to understand and sign the informed consent form and willing to comply with all aspects of the protocol
Exclusion criteria
* History of treatment with bisphosphonates within 3 months of baseline * Severely ill subjects without a reasonable expectation of survival for at least 6 months * Subjects with a scheduled parathyroidectomy during the study period * Expectation for kidney transplant within the next 6 months based on Investigator assessment or identification of a known living donor * Pregnant or trying to become pregnant, currently breastfeeding, or of childbearing potential (including perimenopausal women who have had a menstrual period within one year) and not willing to comply with protocol required contraception criteria * Significant noncompliance with dialysis * History of active malignancy within the last year with the exception of localized basal cell or squamous cell carcinoma * Clinically significant illness other than CUA within 30 days * Participation in an investigational study and receipt of an investigational drug or investigational use of a licensed drug within 30 days prior to screening. * History or presence of active alcoholism or drug abuse as determined by the Investigator within 6 months * Mental impairment, current significant psychiatric disease, or other conditions or circumstances that would make the subject unlikely to complete the study or comply with the study procedures. * Subjects whose CUA lesions exhibit significant improvement, in the opinion of the Investigator, between the first and second screening visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in the BWAT - CUA Score for the Primary Lesion | from Baseline to Week 12 | The Bates Jensen Wound Assessment Tool (BWAT) CUA score ranges from a minimum score of 8 (best) to a maximum score of 40 (worst). BWAT-CUA= Bates-Jensen Wound Assessment Tool-Calcific Uremic Arteriolopathy |
| Absolute Change in Pain Visual Analog Score | from Baseline to Week 12 | The Pain Visual Analog Scale (VAS) score ranges from a minimum score of 0 (no pain) to 100 (worst possible pain). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in the Wound-Quality of Life Score | from Baseline to Week 12 | The Wound Quality of Life scale is a validated self-assessment tool that has been shown to be feasible for assessing health-related quality of life in patients with chronic wounds. Lower scores are associated with a better quality of life as reported by the patient. The score is computed by averaging the 17 items on impairments assessed on a scale of 0 to 4 for the preceding 7 days. A global score can only be computed if at least 75% of the items have been answered, i.e., at least 13 in 17 items are valid. All the available items' scores were added up and divided by 17. In case of missing assessments for any one of the 17 items, the median of the scores for a particular item within the associated randomized treatment group was used for the imputation purposes. As the absolute change from baseline is reported, a higher negative value is associated with a higher improvement of quality of life. |
| Absolute Change in the BWAT Total Score for the Primary Lesion | from Baseline to Week 12 | The Bates Jensen Wound Assessment Tool (BWAT) score ranges from a minimum score of 9 (best) to a maximum score of 65 (worst) score. |
| Qualitative Wound Image Evaluation for the Primary Lesion | at Week 12 | A qualitative assessment (Worsened, Equal to, or Improved Relative to Baseline) was assigned |
| Rate of Change in Opioid Use as Measured in Morphine Milligram Equivalents (MME) | from Baseline to Week 12 | Change from baseline in opioid use MME = Morphine Milligram Equivalents The calculation of the pre-specified list of opioids was based on the formula: strength per unit × (number of units/days supply) × MME conversion factor = MME/day, as specified in the opioid MME conversion guide (CMS, 2017). The maintenance opioid dose was defined as the average daily opioid dose in MME during the 7-day period prior to Screening Visit 2. To assess the extent to which opioid use may have differed between randomized treatment groups over time, the change from baseline in daily average MME value was analyzed. |
Countries
Belgium, Germany, Poland, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 148 participants were screened in 48 sites in 5 countries; 77 participants were not enrolled because they were screen failures (did not meet eligibility criteria). A total of 71 participants were randomized in the study to receive SNF472 or placebo.
Participants by arm
| Arm | Count |
|---|---|
| SNF472 Part 1 (double-blind period):
Participants received SNF472 for 12 weeks in addition to their background care. Dose: 7 mg/kg SNF472 diluted in 100 mL physiological saline. Administered 3 times weekly by intravenous infusion through the hemodialysis machine in conjunction with the subject's hemodialysis sessions for 12 weeks.
Part 2 (Open-label):
Participants received SNF472 for 12 weeks in addition to their background care. Dose: 7 mg/kg SNF472 diluted in 100 mL physiological saline. Administered 3 times weekly by intravenous infusion through the hemodialysis machine in conjunction with the subject's hemodialysis sessions for 12 weeks. | 37 |
| Placebo Part 1 (double-blind period) Participants received placebo for 12 weeks in addition to their background care.
Dose: Matching placebo (saline) diluted in 100 mL physiological saline. Administered 3 times weekly by intravenous infusion through the hemodialysis machine in conjunction with the subject's hemodialysis sessions fo 12 weeks.
Part 2 (Open-label):
Participants received SNF472 for 12 weeks in addition to their background care. Dose: 7 mg/kg SNF472 diluted in 100 mL physiological saline. Administered 3 times weekly by intravenous infusion through the hemodialysis machine in conjunction with the subject's hemodialysis sessions for 12 weeks. | 34 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part 1 | Adverse Event | 3 | 7 |
| Part 1 | Withdrawal by Subject | 0 | 1 |
| Part 2 | Adverse Event | 1 | 1 |
| Part 2 | Other | 1 | 3 |
| Part 2 | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | SNF472 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 7 Participants | 17 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 27 Participants | 54 Participants |
| Age, Continuous | 57.7 years STANDARD_DEVIATION 12.14 | 57.2 years STANDARD_DEVIATION 11.3 | 57.5 years STANDARD_DEVIATION 11.66 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 31 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 12 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 20 Participants | 18 Participants | 38 Participants |
| Region of Enrollment Europe | 5 participants | 2 participants | 7 participants |
| Region of Enrollment North America | 32 participants | 32 participants | 64 participants |
| Sex: Female, Male Female | 23 Participants | 21 Participants | 44 Participants |
| Sex: Female, Male Male | 14 Participants | 13 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 38 | 6 / 33 | 1 / 60 |
| other Total, other adverse events | 27 / 38 | 21 / 33 | 33 / 60 |
| serious Total, serious adverse events | 13 / 38 | 17 / 33 | 18 / 60 |
Outcome results
Primary
Absolute Change in Pain Visual Analog Score
The Pain Visual Analog Scale (VAS) score ranges from a minimum score of 0 (no pain) to 100 (worst possible pain).
Time frame: from Baseline to Week 12
Population: Modified Intent-to-treat Population (mITT) population: defined as all enrolled subjects who were randomized, received at least one dose of study drug, and had at least one post-randomization efficacy evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SNF472 | Absolute Change in Pain Visual Analog Score | -19.5 score on a scale | Standard Deviation 26.89 |
| Placebo | Absolute Change in Pain Visual Analog Score | -32.2 score on a scale | Standard Deviation 38.53 |
p-value: 0.14696% CI: [-4.8, 27.78]MMRM
Primary
Absolute Change in the BWAT - CUA Score for the Primary Lesion
The Bates Jensen Wound Assessment Tool (BWAT) CUA score ranges from a minimum score of 8 (best) to a maximum score of 40 (worst). BWAT-CUA= Bates-Jensen Wound Assessment Tool-Calcific Uremic Arteriolopathy
Time frame: from Baseline to Week 12
Population: Modified Intent-to-treat Population (mITT) population: defined as all enrolled subjects who were randomized, received at least one dose of study drug, and had at least one post-randomization efficacy evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SNF472 | Absolute Change in the BWAT - CUA Score for the Primary Lesion | -5.3 score on a scale | Standard Deviation 5.18 |
| Placebo | Absolute Change in the BWAT - CUA Score for the Primary Lesion | -6.0 score on a scale | Standard Deviation 6.17 |
p-value: 0.87796% CI: [-2.46, 3]MMRM
Secondary
Absolute Change in the BWAT Total Score for the Primary Lesion
The Bates Jensen Wound Assessment Tool (BWAT) score ranges from a minimum score of 9 (best) to a maximum score of 65 (worst) score.
Time frame: from Baseline to Week 12
Population: Modified Intent-to-treat Population (mITT) population: defined as all enrolled subjects who were randomized, received at least one dose of study drug, and had at least one post-randomization efficacy evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SNF472 | Absolute Change in the BWAT Total Score for the Primary Lesion | -11.0 score on a scale | Standard Deviation 9.85 |
| Placebo | Absolute Change in the BWAT Total Score for the Primary Lesion | -11.7 score on a scale | Standard Deviation 12.23 |
p-value: 0.99596% CI: [-5.27, 5.24]MMRM
Secondary
Absolute Change in the Wound-Quality of Life Score
The Wound Quality of Life scale is a validated self-assessment tool that has been shown to be feasible for assessing health-related quality of life in patients with chronic wounds. Lower scores are associated with a better quality of life as reported by the patient. The score is computed by averaging the 17 items on impairments assessed on a scale of 0 to 4 for the preceding 7 days. A global score can only be computed if at least 75% of the items have been answered, i.e., at least 13 in 17 items are valid. All the available items' scores were added up and divided by 17. In case of missing assessments for any one of the 17 items, the median of the scores for a particular item within the associated randomized treatment group was used for the imputation purposes. As the absolute change from baseline is reported, a higher negative value is associated with a higher improvement of quality of life.
Time frame: from Baseline to Week 12
Population: Modified Intent-to-treat Population (mITT) population: defined as all enrolled subjects who were randomized, received at least one dose of study drug, and had at least one post-randomization efficacy evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SNF472 | Absolute Change in the Wound-Quality of Life Score | -0.67 score on a scale | Standard Deviation 0.798 |
| Placebo | Absolute Change in the Wound-Quality of Life Score | -0.74 score on a scale | Standard Deviation 1.175 |
p-value: 0.70696% CI: [-0.38, 0.56]MMRM
Secondary
Qualitative Wound Image Evaluation for the Primary Lesion
A qualitative assessment (Worsened, Equal to, or Improved Relative to Baseline) was assigned
Time frame: at Week 12
Population: Modified Intent-to-treat Population (mITT) population: defined as all enrolled subjects who were randomized, received at least one dose of study drug, and had at least one post-randomization efficacy evaluation.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SNF472 | Qualitative Wound Image Evaluation for the Primary Lesion | Worsened | 6 Participants |
| SNF472 | Qualitative Wound Image Evaluation for the Primary Lesion | Equal | 0 Participants |
| SNF472 | Qualitative Wound Image Evaluation for the Primary Lesion | Improved | 23 Participants |
| SNF472 | Qualitative Wound Image Evaluation for the Primary Lesion | Missing | 8 Participants |
| Placebo | Qualitative Wound Image Evaluation for the Primary Lesion | Missing | 8 Participants |
| Placebo | Qualitative Wound Image Evaluation for the Primary Lesion | Worsened | 7 Participants |
| Placebo | Qualitative Wound Image Evaluation for the Primary Lesion | Improved | 18 Participants |
| Placebo | Qualitative Wound Image Evaluation for the Primary Lesion | Equal | 1 Participants |
p-value: 0.38495% CI: [0.58, 4.09]Regression, Logistic
Secondary
Rate of Change in Opioid Use as Measured in Morphine Milligram Equivalents (MME)
Change from baseline in opioid use MME = Morphine Milligram Equivalents The calculation of the pre-specified list of opioids was based on the formula: strength per unit × (number of units/days supply) × MME conversion factor = MME/day, as specified in the opioid MME conversion guide (CMS, 2017). The maintenance opioid dose was defined as the average daily opioid dose in MME during the 7-day period prior to Screening Visit 2. To assess the extent to which opioid use may have differed between randomized treatment groups over time, the change from baseline in daily average MME value was analyzed.
Time frame: from Baseline to Week 12
Population: Modified Intent-to-treat Population (mITT) population: defined as all enrolled subjects who were randomized, received at least one dose of study drug, and had at least one post-randomization efficacy evaluation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SNF472 | Rate of Change in Opioid Use as Measured in Morphine Milligram Equivalents (MME) | 0.46 MME/week | Standard Error 0.461 |
| Placebo | Rate of Change in Opioid Use as Measured in Morphine Milligram Equivalents (MME) | -0.11 MME/week | Standard Error 0.499 |
p-value: 0.40695% CI: [-0.79, 1.93]MMRM