Prurigo Nodularis
Conditions
Brief summary
To investigate the anti-pruritic efficacy and safety of Nalbuphine Extended Release (ER) (NAL ER) tablets in Prurigo Nodularis. Participants were randomized to NAL ER (or matching placebo) with the primary endpoint evaluation at Week 14. During the open label extension, participants who received NAL ER were continued on NAL ER and participants who received placebo would then shift to NALER.
Interventions
DRUGNalbuphine ER Tablets
Active Nalbuphine ER Tablets
DRUGPlacebo Tablets
Placebo matching NAL ER with no active substance
Sponsors
Trevi Therapeutics
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
* Individuals diagnosed with generalized nodular PN, covering 2 separate body parts, and 10 or more pruriginous nodules * Severe itch due to PN * Age 18 years and older at the time of consent, and a life expectancy of at least 18 months. * Individuals using antidepressants must be on a stable dose for a minimum of 4 weeks prior to screening. * Participants with a history of acute secondary dermatoses within the preceding 6 months may enroll only if the dermatosis has resolved completely as follows per medical history or participant self-report and current clinical assessment: (a) Localized contact dermatitis, environmental exposures, superficial burns, or viral exanthems must have been resolved for at least 4 weeks prior to screening. (b) Skin or environmental infestations, such as scabies, lice, or bed bugs, must have been resolved for at least 8 weeks prior to screening. * Any identified systemic, non-dermatologic disease that could be a potential cause of concomitant pruritus (e.g., thyroid disease, celiac disease, hepatitis C virus \[HCV\]) must either have resolved, been successfully treated \[i.e., HCV ribonucleic acid (RNA) negative\], or must be successfully managed with stable, optimized treatment (e.g., thyroid replacement, dietary management with resolution of symptoms, respectively) for at least 3 months prior to screening. * Participants who are human immunodeficiency virus (HIV) positive may enroll if they meet the following criteria: (a) currently on a stable (\> 6 months stable use) and well tolerated highly active antiretroviral therapy regimen; (b) cluster of differentiation 4 (CD4) count \> 500 cells/mL; and (c) HIV ribonucleic acid (RNA) \< 50 copies/mL documented for at least 6 months prior to enrollment.
Exclusion criteria
* Pruritus due to localized PN (only one body part affected), or less than 10 nodules * Active, uncontrolled, pruritic dermatoses in need of treatment (such as atopic dermatitis or bullous pemphigoid for example). * History of a major psychiatric disorder such as bipolar disorder or schizophrenia. History of active substance abuse in the last 3 years. * Known intolerance \[gastrointestinal (GI), central nervous system (CNS) symptoms\] or hypersensitivity/drug allergy to opioids. * Use of certain concomitant medications and treatments within a period prior to the study, or requirement for these medications during the study: * Potential participants taking opiates, gabapentin, pregabalin, calcineurin inhibitors, cannabinoid agonists, capsaicin, cryosurgery, topical doxepin, thalidomide or methotrexate, topical antihistamines or topical corticosteroids require a 14-day washout. * Within 4 weeks prior to screening: ultraviolet (UV)-therapy, exposure to any investigational medication, including placebo * Within 3 months prior to screening: Non-insulin biologics (including monoclonal antibodies) that modify the immune system, * Individuals taking monoamine oxidase inhibitors are excluded, as concomitant opiate use may increase the risk for serotonin syndrome. * Myocardial infarction or acute coronary syndrome within the previous 3 months, as reported by the participant. * Individuals with prolonged QT interval corrected for heart rate using Fridericia's formula (QTcF). Note: Other Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ≥ 4- Point Decrease in 7-day Average Worst Itch - Numerical Rating Scale (WI-NRS) up to Week 14 | Baseline up to Week 14 | The NRS is a patient related outcome (PRO) instrument, designed to quantify the intensity of worst itching experienced during a 24-hour period, and can be applied and validated either with reference to the average itch or to the absolute worst itch (WI-NRS) over that 24-hour period. WI-NRS is a set of boxes, one for each number, from 0 (no itching) to 10 (worst possible itching). Higher scores indicate worst itching experience. Responder was defined as a participant with a ≥4-point decrease in the 7-day average WI-NRS from baseline to Week 14. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Prurigo Activity Score (PAS) Assessed by the Percentage of Participants With 1-Category Improvement in the Percentage of Pruriginous Lesions With Excoriations/Crusts (Item 5a) at Week 14 | Baseline, Week 14 | PAS consists of 5 quantitative/qualitative measurements related to examination of skin: Type; number;distribution;quantitative number of lesions in a body part;activity. Prurigo lesion activity is recorded as a stage (0 to 4), based on percentage of overall lesions with relevant characteristic. Three types of PAS responders defined one for each of the following items: Pruriginous lesions with excoriations/crusts (item 5a);Healed lesions (item 5b);Number of lesions (item 2). Pruriginous lesions with excoriations/crusts (item 5a) was recorded from 0 to 4;where 0 = 0-25%1 = 26-50%,2 = 51-75%,3 = 76-90%,4 = 91-100%. Higher score=a greater number of pruriginous lesions with excoriations/crusts. A responder was defined as a participant who has at least 1-category improvement in the relevant item from baseline to Week 14. Baseline is defined as the last non-missing evaluation (including repeated and unscheduled assessments) taken prior to or on the date of first dose of study medication. |
| Change From Baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance Short Form 8a at Week 14 | Baseline, Week 14 | PROMIS Sleep Disturbance Short Form 8a questionnaire is a tool for assessing sleep. It has 8 questions which measures sleep in the past 7 days.There is 1 broad sleep quality question with options:very poor,poor,fair,good,and very good.Remaining 7 questions are answered with:not at all,a little bit,somewhat,quite a bit,and very much.Lowest possible raw score=8; highest possible raw score=40. The T-score rescales raw score into a standardized score with a mean of 50 and an standard deviation of 10 derived from general population.Lowest possible T-score=28.9;highest possible T-score=76.6.Higher T-score shows more of the concept measured,higher the T-Score worse the sleep disturbance.Scores \<55=normal limits, 55-60=mild, 61-70=moderate,and \>70=severe sleep disturbance.Baseline=last non-missing evaluation (including repeated and unscheduled assessments) taken prior to or on the date of first dose of study medication.Negative change from baseline indicated better sleep. |
| Change From Baseline in 7-Day Average WI-NRS to Week 14 | Baseline, Week 14 | The NRS is a PRO instrument, designed to quantify the intensity of worst itching experienced during a 24-hour period, and can be applied and validated either with reference to the average itch or to the absolute worst itch (WI-NRS) over that 24-hour period. WI-NRS is a set of boxes, one for each number, from 0 (no itching) to 10 (worst possible itching). Higher scores indicate worst itching experience. Baseline WI-NRS value was calculated as the arithmetic mean of the WI-NRS values (minimum of 5 required) taken for eligibility review by site at the time of randomization. A negative change from baseline indicates improvement in symptoms. |
| Change From Baseline in PAS Assessed by the Percentage of Participants With 1-Category Improvement in the Percentage of Healed Lesions (Item 5b) at Week 14 | Baseline, Week 14 | PAS consists of 5 quantitative/qualitative measurements related to skin-Type; number; distribution; quantitative number of lesions in body part; activity. Prurigo lesion activity is recorded as stage (0 to 4), based on percentage of overall lesions with relevant characteristic. Three types of PAS responders are defined: Pruriginous lesions with excoriations/crusts (item 5a); Healed lesions (item 5b); Number of lesions (item 2). Prurigo lesions (item 5b), where 0 = 100%,1 = 75-99%,2 = 50-74%,3 = 25-49%,4 = 0-24% healed pruriginous lesions. Lower score=more number of healed pruriginous lesions. A responder was defined as a participant who has at least 1-category improvement in the relevant item from baseline to Week 14. Baseline was defined as the last non-missing evaluation (including repeated and unscheduled assessments) taken prior to or on the date of first dose of treatment. A negative change from baseline would indicate higher number of healed lesions. |
| Change From Baseline in PAS Assessed by the Percentage of Participants With 1-Category Improvement in the Percentage of Lesions (Item 2) at Week 14 | Baseline, Week 14 | PAS consists of 5 quantitative/qualitative measurements of skin- Type; number; distribution; quantitative number of lesions in body part; activity. Prurigo lesion activity is recorded as stage (0 to 4) based on percentage of overall lesions with relevant characteristic. Three types of PAS responders are defined: Pruriginous lesions with excoriations/crusts (item 5a); Healed lesions (item 5b); Number of lesions (item 2). Prurigo lesion activity is recorded as a stage (0 to 4), based on the percentage of overall lesions with the relevant characteristic. A lower score indicates less number of pruriginous lesions. A responder was defined as a participant who has at least 1-category improvement in the relevant item from baseline to Week 14. Baseline was defined as the last non-missing evaluation (including repeated and unscheduled assessments) taken prior to or on the date of first dose of study medication. A negative change from baseline would indicate lower number of lesions. |
| Change From Baseline in Itch-related Quality of Life (ItchyQoL) Total Score at Week 14 | Baseline, Week 14 | The ItchyQoL consists of 22 pruritus-specific items measuring how pruritus affects participant's QoL in the area of symptoms related to the itch condition (6 questions), functional limitations (7 questions), and emotions (9 questions). The participant scored each question never = 1, rarely = 2, sometimes = 3, often = 4, all the time = 5. The ItchyQoL total score were obtained as the sum of the 22 items ranging from 22 to 110, with higher score indicating worsening of pruritus. A negative change from baseline indicated improvement in the pruritus-related difficulties. |
| Change From Baseline in IGA-PN Assessed by the Percentage of Participants With 1-Category Improvement in Stage at Week 14 | Baseline, Week 14 | The IGA-PN collects an investigator global assessment of status of PN skin lesions. The IGA-PN uses a 5-category scale(scoring 0 to 4) to describe 2 aspects of disease. The Activity(amount of excoriation and crusting of prurigo lesions) and the Stage(the quantitative presence and proportion of flattening of lesions),where 0=clear(No nodules),1=Rare, flattened lesions, with no more than single dome-shaped palpable nodules(1-5 nodules), 2=Few,mostly flattened lesions, with small number of dome-shaped palpable nodules(6-19 nodules,3=Many lesions, partially flattened and dome-shaped palpable nodules (20-100 nodules),4=Abundant lesions, majority are dome-shaped palpable nodules (over 100 nodules).Higher number= presence of abundant lesions.Responder as defined as participants who has at a least 1-category improvement from baseline to Week 14.Baseline was defined as the last non-missing evaluation(repeated and unscheduled assessments)taken prior to or on the date of first dose of treatment. |
| Percentage of Participants Having a Patient Benefit Index, Pruritus Version (PBI-P) Score of ≥1 at Week 14 | At Week 14 | PBI-P is an instrument that measures participant-defined treatment objectives and benefits acquired during the course of treatment.During and after therapy, the participant completes a matched on-treatment Treatment Benefits questionnaire and rates the extent to which the treatment objectives have been achieved.It consists of 27 multiple choice questions that can be answered not at all,somewhat,moderately,quite,very.PBI-P global score is computed according to the score obtained for patient needs questionnaire (PNQ) and patient benefit questionnaire (PBQ).Score may only be computed if the participant has provided valid data on importance (PNQ) and benefit (PBQ) for at least 75% of the respective treatment goals,i.e., for at least 21 of the 27 items. Total score ranges from 0-135. Higher scores=more benefit received from the study to the participant.Responses does/did not apply,question answered are considered valid values when counting number of non-missing responses. |
| Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in DB Period | Baseline up to Week 14 | An AE is any untoward medical occurrence in a participant who administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with the study drug. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. DB period TEAEs are defined as AEs that either start or worsen in severity on or after the first DB dose and prior to the first extension titration dose of study medication in the OLE period. TEAEs included both serious & non-serious TEAEs. |
| Number of Participants Who Experienced TEAEs, Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in OLE Period | From Week 14 up to Week 56 | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. OLE period TEAEs are defined as AEs that either start or worsen in severity on or after the first extension titration dose of study medication. TEAEs included both serious & non-serious TEAEs. |
| Change From Baseline in Investigator Global Assessment-Prurigo Nodularis (IGA-PN) Assessed by the Percentage of Participants With 1-Category Improvement in Activity at Week 14 | Baseline, Week 14 | The IGA-PN collects an investigator global assessment of status of PN skin lesions. The IGA-PN uses a 5-category scale (scoring 0 to 4) to describe the status of 2 aspects of disease: The Activity (amount of excoriation and crusting associated with the prurigo lesions), and the Stage (the quantitative presence and proportion of flattening of the lesions). The excoriation/crusting activity on the surface (PN-Activity) where it considers number of PN lesion with excoriations and crusts on the top, 0=clear (No nodules), 1 =small number, 2=minority of nodules, 3=most nodules, 4=severe (vast majority of nodules). A higher number indicates severe status of PN skin lesions. An IGA-PN responder for activity was defined as participants who has at a least 1-category improvement in the respective score from baseline to Week 14. Baseline was defined as the last non-missing evaluation (including repeated and unscheduled assessments) taken prior to or on the date of first dose of study medication. |
Countries
Austria, France, Germany, Poland, United States
Participant flow
Recruitment details
Participants were enrolled at 70 sites in Germany, Poland, Austria, France and the United States from 07 August 2018 to 24 February 2023.
Pre-assignment details
A total of 608 participants were screened, out of which 353 participants were randomized, and 344 participants were treated with NAL ER and/or placebo.
Participants by arm
| Arm | Count |
|---|---|
| NAL ER During the DB period, participants were titrated over 2 weeks to NAL ER 162 mg, orally, BID, followed by 162 mg, orally, BID, for 12 weeks. During the OLE period, participants perceived a titration period of 2 weeks, and continued to receive NAL ER 162 mg, orally, BID, for 38 weeks in total. | 168 |
| Placebo During the DB period, participants perceived a titration period of 2 weeks during which they received placebo to match the active titration period, followed by placebo, orally, BID, for 12 weeks. During the OLE period, participants were titrated over 2 weeks to NAL ER 162 mg, orally, BID, which they received for 38 weeks (including titration). | 176 |
| Total | 344 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Discontinued | 42 | 39 |
| Overall Study | Lost to Follow-up | 7 | 7 |
| Overall Study | Physician Decision | 4 | 5 |
| Overall Study | Reason Not Specified | 15 | 14 |
| Overall Study | Withdrew Consent | 34 | 35 |
Baseline characteristics
| Characteristic | NAL ER | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 59.6 years STANDARD_DEVIATION 13.25 | 57.7 years STANDARD_DEVIATION 13.91 | 55.9 years STANDARD_DEVIATION 14.32 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 13 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 63 Participants | 129 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 99 Participants | 202 Participants | 103 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 13 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 24 Participants | 47 Participants | 23 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 6 Participants | 17 Participants | 11 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 132 Participants | 266 Participants | 134 Participants |
| Sex: Female, Male Female | 100 Participants | 212 Participants | 112 Participants |
| Sex: Female, Male Male | 68 Participants | 132 Participants | 64 Participants |
| Worst Itch - Numerical Rating Scale (WI-NRS) Score | 8.637 score on scale STANDARD_DEVIATION 0.9115 | 8.643 score on scale STANDARD_DEVIATION 0.8993 | 8.650 score on scale STANDARD_DEVIATION 0.8902 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 168 | 0 / 176 | 0 / 107 | 0 / 144 |
| other Total, other adverse events | 112 / 168 | 58 / 176 | 49 / 107 | 95 / 144 |
| serious Total, serious adverse events | 9 / 168 | 8 / 176 | 7 / 107 | 7 / 144 |
Outcome results
Primary
Percentage of Participants With ≥ 4- Point Decrease in 7-day Average Worst Itch - Numerical Rating Scale (WI-NRS) up to Week 14
The NRS is a patient related outcome (PRO) instrument, designed to quantify the intensity of worst itching experienced during a 24-hour period, and can be applied and validated either with reference to the average itch or to the absolute worst itch (WI-NRS) over that 24-hour period. WI-NRS is a set of boxes, one for each number, from 0 (no itching) to 10 (worst possible itching). Higher scores indicate worst itching experience. Responder was defined as a participant with a ≥4-point decrease in the 7-day average WI-NRS from baseline to Week 14.
Time frame: Baseline up to Week 14
Population: The mITT population included all randomized participants who received at least a single dose of IP. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NAL ER | Percentage of Participants With ≥ 4- Point Decrease in 7-day Average Worst Itch - Numerical Rating Scale (WI-NRS) up to Week 14 | 24.24 percentage of participants |
| Placebo | Percentage of Participants With ≥ 4- Point Decrease in 7-day Average Worst Itch - Numerical Rating Scale (WI-NRS) up to Week 14 | 14.50 percentage of participants |
p-value: 0.030995% CI: [1.07, 4.13]Regression, Logistic
Secondary
Change From Baseline in 7-Day Average WI-NRS to Week 14
The NRS is a PRO instrument, designed to quantify the intensity of worst itching experienced during a 24-hour period, and can be applied and validated either with reference to the average itch or to the absolute worst itch (WI-NRS) over that 24-hour period. WI-NRS is a set of boxes, one for each number, from 0 (no itching) to 10 (worst possible itching). Higher scores indicate worst itching experience. Baseline WI-NRS value was calculated as the arithmetic mean of the WI-NRS values (minimum of 5 required) taken for eligibility review by site at the time of randomization. A negative change from baseline indicates improvement in symptoms.
Time frame: Baseline, Week 14
Population: The mITT population included all randomized participants who received at least a single dose of IP. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NAL ER | Change From Baseline in 7-Day Average WI-NRS to Week 14 | -2.5 score on a scale | Standard Deviation 2.36 |
| Placebo | Change From Baseline in 7-Day Average WI-NRS to Week 14 | -1.6 score on a scale | Standard Deviation 2.14 |
Secondary
Change From Baseline in IGA-PN Assessed by the Percentage of Participants With 1-Category Improvement in Stage at Week 14
The IGA-PN collects an investigator global assessment of status of PN skin lesions. The IGA-PN uses a 5-category scale(scoring 0 to 4) to describe 2 aspects of disease. The Activity(amount of excoriation and crusting of prurigo lesions) and the Stage(the quantitative presence and proportion of flattening of lesions),where 0=clear(No nodules),1=Rare, flattened lesions, with no more than single dome-shaped palpable nodules(1-5 nodules), 2=Few,mostly flattened lesions, with small number of dome-shaped palpable nodules(6-19 nodules,3=Many lesions, partially flattened and dome-shaped palpable nodules (20-100 nodules),4=Abundant lesions, majority are dome-shaped palpable nodules (over 100 nodules).Higher number= presence of abundant lesions.Responder as defined as participants who has at a least 1-category improvement from baseline to Week 14.Baseline was defined as the last non-missing evaluation(repeated and unscheduled assessments)taken prior to or on the date of first dose of treatment.
Time frame: Baseline, Week 14
Population: The mITT population included all randomized participants who received at least a single dose of IP. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NAL ER | Change From Baseline in IGA-PN Assessed by the Percentage of Participants With 1-Category Improvement in Stage at Week 14 | 43.8 percentage of participants |
| Placebo | Change From Baseline in IGA-PN Assessed by the Percentage of Participants With 1-Category Improvement in Stage at Week 14 | 32.9 percentage of participants |
Secondary
Change From Baseline in Investigator Global Assessment-Prurigo Nodularis (IGA-PN) Assessed by the Percentage of Participants With 1-Category Improvement in Activity at Week 14
The IGA-PN collects an investigator global assessment of status of PN skin lesions. The IGA-PN uses a 5-category scale (scoring 0 to 4) to describe the status of 2 aspects of disease: The Activity (amount of excoriation and crusting associated with the prurigo lesions), and the Stage (the quantitative presence and proportion of flattening of the lesions). The excoriation/crusting activity on the surface (PN-Activity) where it considers number of PN lesion with excoriations and crusts on the top, 0=clear (No nodules), 1 =small number, 2=minority of nodules, 3=most nodules, 4=severe (vast majority of nodules). A higher number indicates severe status of PN skin lesions. An IGA-PN responder for activity was defined as participants who has at a least 1-category improvement in the respective score from baseline to Week 14. Baseline was defined as the last non-missing evaluation (including repeated and unscheduled assessments) taken prior to or on the date of first dose of study medication.
Time frame: Baseline, Week 14
Population: The mITT population included all randomized participants who received at least a single dose of IP. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NAL ER | Change From Baseline in Investigator Global Assessment-Prurigo Nodularis (IGA-PN) Assessed by the Percentage of Participants With 1-Category Improvement in Activity at Week 14 | 57.1 percentage of participants |
| Placebo | Change From Baseline in Investigator Global Assessment-Prurigo Nodularis (IGA-PN) Assessed by the Percentage of Participants With 1-Category Improvement in Activity at Week 14 | 41.1 percentage of participants |
Secondary
Change From Baseline in Itch-related Quality of Life (ItchyQoL) Total Score at Week 14
The ItchyQoL consists of 22 pruritus-specific items measuring how pruritus affects participant's QoL in the area of symptoms related to the itch condition (6 questions), functional limitations (7 questions), and emotions (9 questions). The participant scored each question never = 1, rarely = 2, sometimes = 3, often = 4, all the time = 5. The ItchyQoL total score were obtained as the sum of the 22 items ranging from 22 to 110, with higher score indicating worsening of pruritus. A negative change from baseline indicated improvement in the pruritus-related difficulties.
Time frame: Baseline, Week 14
Population: The mITT population included all randomized participants who received at least a single dose of IP. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NAL ER | Change From Baseline in Itch-related Quality of Life (ItchyQoL) Total Score at Week 14 | -17.4 score on a scale | Standard Deviation 18.01 |
| Placebo | Change From Baseline in Itch-related Quality of Life (ItchyQoL) Total Score at Week 14 | -8.8 score on a scale | Standard Deviation 17.15 |
p-value: 0.000295% CI: [-10.82, -3.3]Mixed Model for Repeated Measurements
Secondary
Change From Baseline in PAS Assessed by the Percentage of Participants With 1-Category Improvement in the Percentage of Healed Lesions (Item 5b) at Week 14
PAS consists of 5 quantitative/qualitative measurements related to skin-Type; number; distribution; quantitative number of lesions in body part; activity. Prurigo lesion activity is recorded as stage (0 to 4), based on percentage of overall lesions with relevant characteristic. Three types of PAS responders are defined: Pruriginous lesions with excoriations/crusts (item 5a); Healed lesions (item 5b); Number of lesions (item 2). Prurigo lesions (item 5b), where 0 = 100%,1 = 75-99%,2 = 50-74%,3 = 25-49%,4 = 0-24% healed pruriginous lesions. Lower score=more number of healed pruriginous lesions. A responder was defined as a participant who has at least 1-category improvement in the relevant item from baseline to Week 14. Baseline was defined as the last non-missing evaluation (including repeated and unscheduled assessments) taken prior to or on the date of first dose of treatment. A negative change from baseline would indicate higher number of healed lesions.
Time frame: Baseline, Week 14
Population: The mITT population included all randomized participants who received at least a single dose of IP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NAL ER | Change From Baseline in PAS Assessed by the Percentage of Participants With 1-Category Improvement in the Percentage of Healed Lesions (Item 5b) at Week 14 | 39.3 percentage of participants |
| Placebo | Change From Baseline in PAS Assessed by the Percentage of Participants With 1-Category Improvement in the Percentage of Healed Lesions (Item 5b) at Week 14 | 34.7 percentage of participants |
Secondary
Change From Baseline in PAS Assessed by the Percentage of Participants With 1-Category Improvement in the Percentage of Lesions (Item 2) at Week 14
PAS consists of 5 quantitative/qualitative measurements of skin- Type; number; distribution; quantitative number of lesions in body part; activity. Prurigo lesion activity is recorded as stage (0 to 4) based on percentage of overall lesions with relevant characteristic. Three types of PAS responders are defined: Pruriginous lesions with excoriations/crusts (item 5a); Healed lesions (item 5b); Number of lesions (item 2). Prurigo lesion activity is recorded as a stage (0 to 4), based on the percentage of overall lesions with the relevant characteristic. A lower score indicates less number of pruriginous lesions. A responder was defined as a participant who has at least 1-category improvement in the relevant item from baseline to Week 14. Baseline was defined as the last non-missing evaluation (including repeated and unscheduled assessments) taken prior to or on the date of first dose of study medication. A negative change from baseline would indicate lower number of lesions.
Time frame: Baseline, Week 14
Population: The mITT population included all randomized participants who received at least a single dose of IP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NAL ER | Change From Baseline in PAS Assessed by the Percentage of Participants With 1-Category Improvement in the Percentage of Lesions (Item 2) at Week 14 | 25.0 percentage of participants |
| Placebo | Change From Baseline in PAS Assessed by the Percentage of Participants With 1-Category Improvement in the Percentage of Lesions (Item 2) at Week 14 | 18.8 percentage of participants |
Secondary
Change From Baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance Short Form 8a at Week 14
PROMIS Sleep Disturbance Short Form 8a questionnaire is a tool for assessing sleep. It has 8 questions which measures sleep in the past 7 days.There is 1 broad sleep quality question with options:very poor,poor,fair,good,and very good.Remaining 7 questions are answered with:not at all,a little bit,somewhat,quite a bit,and very much.Lowest possible raw score=8; highest possible raw score=40. The T-score rescales raw score into a standardized score with a mean of 50 and an standard deviation of 10 derived from general population.Lowest possible T-score=28.9;highest possible T-score=76.6.Higher T-score shows more of the concept measured,higher the T-Score worse the sleep disturbance.Scores \<55=normal limits, 55-60=mild, 61-70=moderate,and \>70=severe sleep disturbance.Baseline=last non-missing evaluation (including repeated and unscheduled assessments) taken prior to or on the date of first dose of study medication.Negative change from baseline indicated better sleep.
Time frame: Baseline, Week 14
Population: The mITT population included all randomized participants who received at least a single dose of IP. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NAL ER | Change From Baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance Short Form 8a at Week 14 | -9.5 T-score | Standard Deviation 10.01 |
| Placebo | Change From Baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance Short Form 8a at Week 14 | -4.5 T-score | Standard Deviation 8.44 |
p-value: <0.000195% CI: [-6.55, -2.31]Mixed Model for Repeated Measurements
Secondary
Change From Baseline in Prurigo Activity Score (PAS) Assessed by the Percentage of Participants With 1-Category Improvement in the Percentage of Pruriginous Lesions With Excoriations/Crusts (Item 5a) at Week 14
PAS consists of 5 quantitative/qualitative measurements related to examination of skin: Type; number;distribution;quantitative number of lesions in a body part;activity. Prurigo lesion activity is recorded as a stage (0 to 4), based on percentage of overall lesions with relevant characteristic. Three types of PAS responders defined one for each of the following items: Pruriginous lesions with excoriations/crusts (item 5a);Healed lesions (item 5b);Number of lesions (item 2). Pruriginous lesions with excoriations/crusts (item 5a) was recorded from 0 to 4;where 0 = 0-25%1 = 26-50%,2 = 51-75%,3 = 76-90%,4 = 91-100%. Higher score=a greater number of pruriginous lesions with excoriations/crusts. A responder was defined as a participant who has at least 1-category improvement in the relevant item from baseline to Week 14. Baseline is defined as the last non-missing evaluation (including repeated and unscheduled assessments) taken prior to or on the date of first dose of study medication.
Time frame: Baseline, Week 14
Population: The mITT population included all randomized participants who received at least a single dose of IP. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NAL ER | Change From Baseline in Prurigo Activity Score (PAS) Assessed by the Percentage of Participants With 1-Category Improvement in the Percentage of Pruriginous Lesions With Excoriations/Crusts (Item 5a) at Week 14 | 54.5 percentage of participants |
| Placebo | Change From Baseline in Prurigo Activity Score (PAS) Assessed by the Percentage of Participants With 1-Category Improvement in the Percentage of Pruriginous Lesions With Excoriations/Crusts (Item 5a) at Week 14 | 41.1 percentage of participants |
p-value: 0.017995% CI: [1.11, 3.07]Regression, Logistic
Secondary
Number of Participants Who Experienced TEAEs, Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in OLE Period
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the study drug. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. OLE period TEAEs are defined as AEs that either start or worsen in severity on or after the first extension titration dose of study medication. TEAEs included both serious & non-serious TEAEs.
Time frame: From Week 14 up to Week 56
Population: The safety population included all randomized participants who received at least a single dose of IP. Overall number of participants analyzed indicates number of participants who entered OLE period.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NAL ER | Number of Participants Who Experienced TEAEs, Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in OLE Period | Participants with TEAEs | 84 Participants |
| NAL ER | Number of Participants Who Experienced TEAEs, Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in OLE Period | Participants with Serious TEAEs | 7 Participants |
| NAL ER | Number of Participants Who Experienced TEAEs, Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in OLE Period | Participants with Study Drug Discontinuation Due to TEAEs | 8 Participants |
| Placebo | Number of Participants Who Experienced TEAEs, Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in OLE Period | Participants with TEAEs | 116 Participants |
| Placebo | Number of Participants Who Experienced TEAEs, Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in OLE Period | Participants with Serious TEAEs | 7 Participants |
| Placebo | Number of Participants Who Experienced TEAEs, Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in OLE Period | Participants with Study Drug Discontinuation Due to TEAEs | 30 Participants |
Secondary
Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in DB Period
An AE is any untoward medical occurrence in a participant who administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with the study drug. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. DB period TEAEs are defined as AEs that either start or worsen in severity on or after the first DB dose and prior to the first extension titration dose of study medication in the OLE period. TEAEs included both serious & non-serious TEAEs.
Time frame: Baseline up to Week 14
Population: The safety population included all randomized participants who received at least a single dose of IP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NAL ER | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in DB Period | Participants with TEAEs | 136 Participants |
| NAL ER | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in DB Period | Participants with Serious TEAEs | 9 Participants |
| NAL ER | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in DB Period | Participants with Study Drug Discontinuation Due to TEAEs | 53 Participants |
| Placebo | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in DB Period | Participants with TEAEs | 106 Participants |
| Placebo | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in DB Period | Participants with Serious TEAEs | 8 Participants |
| Placebo | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinued From Study Drug Due to TEAEs in DB Period | Participants with Study Drug Discontinuation Due to TEAEs | 13 Participants |
Secondary
Percentage of Participants Having a Patient Benefit Index, Pruritus Version (PBI-P) Score of ≥1 at Week 14
PBI-P is an instrument that measures participant-defined treatment objectives and benefits acquired during the course of treatment.During and after therapy, the participant completes a matched on-treatment Treatment Benefits questionnaire and rates the extent to which the treatment objectives have been achieved.It consists of 27 multiple choice questions that can be answered not at all,somewhat,moderately,quite,very.PBI-P global score is computed according to the score obtained for patient needs questionnaire (PNQ) and patient benefit questionnaire (PBQ).Score may only be computed if the participant has provided valid data on importance (PNQ) and benefit (PBQ) for at least 75% of the respective treatment goals,i.e., for at least 21 of the 27 items. Total score ranges from 0-135. Higher scores=more benefit received from the study to the participant.Responses does/did not apply,question answered are considered valid values when counting number of non-missing responses.
Time frame: At Week 14
Population: The mITT population included all randomized participants who received at least a single dose of IP. Overall number of participants analyzed indicates number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NAL ER | Percentage of Participants Having a Patient Benefit Index, Pruritus Version (PBI-P) Score of ≥1 at Week 14 | 100.0 percentage of participants |
| Placebo | Percentage of Participants Having a Patient Benefit Index, Pruritus Version (PBI-P) Score of ≥1 at Week 14 | 100.0 percentage of participants |