| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| A skin condition characterised by very itchy firm lumps. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037084 |
| E.1.2 | Term | Prurigo nodularis |
| E.1.2 | System Organ Class | 100000004858 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To evaluate the effect of NAL ER on itch as assessed by the percentage of Responders (‘response’ is defined as a ≥ 4-point reduction in the 7-day average Worst Itch Numerical Rating Scale [WI-NRS]) |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objectives are as follows:
• To evaluate the effect of NAL ER on itch-related quality of life as assessed by ItchyQoL total score
• To evaluate the effect of NAL ER on Prurigo Nodularis (PN) skin lesions as assessed by the Prurigo Activity Score (PAS) Question 5a
• To evaluate the effect of NAL ER on sleep using the PROMIS Sleep Disturbance Short Form 8a
Other secondary objectives are as follows:
• To evaluate the effect of NAL ER on itch as assessed by the mean change in WI-NRS
• To evaluate the benefit to subjects of NAL ER using the Patient Benefit Index, pruritus version (PBI-P)
• To characterize the safety and tolerability of NAL ER
• To assess the pharmacokinetics (PK) of nalbuphine and its metabolites |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Individuals diagnosed with generalized PN, defined as the presence of ≥ 10 pruriginous nodules, involving at least 2 distinct anatomical areas: for example, either 2 limbs; or a single limb and some axial portion of the body. Individuals with only axial lesions but involving 2 distinct anatomical areas of involvement, that have no peripheral nervous system overlap, are also eligible: for example, lesions involving a portion of the cranium and a portion of the trunk of the body. For purposes of this study, the axial portion will be defined as any non-appendicular portion of the body.
2. If there is any history of a primary pruritic skin condition other than PN, that condition must have been inactive for at least 6 months prior to screening.
3. Subjects 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 patient 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.
4. Any identified systemic, non-dermatologic disease that could be a potential cause of concomitant pruritus (e.g., thryroid disease, celiac disease, hepatitis C virus [HCV]) must either have resolved, been successfully treated (i.e., HCV 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.
5. WI-NRS score, recorded daily over the 7 contiguous days prior to and including the days of the baseline visit via electronic diary, must have at least 5 measurements recorded and all individual measurements must be ≥ 6. The arithmetic mean value of the measurements must be ≥ 7 as confirmed by the Trialogics Eligibility Check report immediately prior to randomization. The last WI-NRS value used in the calculation should be recorded on the day of the baseline visit and prior to dosing.
6. Subjects using antidepressant must be on a stable dose for a minimum of 4 weeks prior to screening and must be willing to remain on their stable dose for the entire duration of the study.
7. Subjects 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) CD4 count > 500 cells/mL; and (c) HIV ribonucleic acid (RNA) < 50 copies/mL documented for at least 6 months prior to enrollment. If enrolled, these subjects should continue to have their CD4 and HIV RNA monitored by their HIV provider per their standard of care for the duration of the TR11 study, and the data should be reported and documented at the next study visit.
8. Females of childbearing potential must be using an acceptable method of birth control (if sexually active) for 14 days prior to randomization and throughout the study. All females of childbearing potential must have a negative pregnancy test at the screening and baseline visits. For the purpose of this study, all females are considered to be of childbearing potential unless they are postmenopausal (i.e., at least 1 year since last menses and age > 50 years) or surgically sterile (i.e., tubal ligation, hysterectomy, and/or bilateral oophorectomy). Sexually active female subjects of childbearing potential are required to use 1 barrier method (e.g., condom, cervical cap, or diaphragm) of contraception in addition to 1 other method (e.g., intrauterine device in place at least 1 month, stable hormonal contraception for at least 3 months, or Essure procedure, or spermicide).
Female subjects who are abstinent may participate in the study, however; they must be counseled on the requirement to use appropriate
contraception should they become sexually active. This counseling should occur at each study visit and must be documented in source
records.
9. Age 18 years and older at the time of consent, and a life expectancy of at least 18 months.
10. Willing and able to understand and provide written informed consent.
11. Willing and able to comply with study requirements and restrictions.
12. Agree to the confidential use and storage of all data and use of all anonymized data for publication including scientific publication. |
|
| E.4 | Principal exclusion criteria |
1. Pruritus due to localized PN (only 1 body part affected, for example only 1 arm).
2. Active, uncontrolled, pruritic dermatoses in need of treatment (such as atopic dermatitis, or bullous pemphigoid for example).
3. Prurigo Nodularis associated with a history of atopic dermatitis is excluded if acute eczematous lesions are present, as characterized by erythematous, active-predominant lichenified plaques with oozing and crusting.
4. History of a major psychiatric disorder such as bipolar disorder or schizophrenia is excluded. Subjects with a history of isolated major
depression > 3 years previously may be eligible for enrollment if they have access to appropriate psychiatric care. An "isolated major depression" is defined as a single event of depression that includes recurrent thoughts of death, recurrent suicidal ideation with or without a specific plan, or any history of a suicide attempt. Enrollment must be approved by the Medical Monitor.
5. Serum bilirubin > 1.5 × upper limit of normal range at screening unless explained by a clinical diagnosis of Gilbert's Syndrome.
6. Serum hepatic alanine aminotransferase or aspartate aminotransferase enzymes > 100 U/L at screening.
7. Estimated glomerular filtration rate ≤ 44 mL/min/1.73 m^2 at screening.
8. Significant medical condition, occupational restrictions, and/or other factors that in the opinion of the Investigator may interfere with the conduct of the study.
9. Subjects who have an active malignancy (either solid tumor or hematologic) are excluded. Subjects who have a past history of malignancy and who have no evidence of active disease, but who continue on therapy to prevent disease recurrence (i.e., tamoxifen for breast cancer, testosterone blockade for prostate cancer, etc.), may be eligible if approved by the Medical Monitor.
10. History of active substance abuse within the past 3 years.
11. Known intolerance of or hypersensitivity or allergy to nalbuphine or vehicle components.
12. Pregnant or lactating females.
13. Concurrent enrollment in an ongoing clinical trial or anticipated enrollment in a concurrent clinical trial (other than safety follow-up of a COVID-19 vaccination trial, see protocol for further information).
Medication-related Exclusions:
14. Known intolerance (gastrointestinal, central nervous system symptoms) or hypersensitivity/drug allergy to opioids.
15. Potential subjects taking monoamine oxidase inhibitors are excluded, as concomitant opiate use may increase the risk for serotonin syndrome.
16. Potential subjects taking cyclosporin A are excluded unless they undergo a 6-week washout. Subjects are prohibited from using cyclosporin during the study.
17. Potential subjects taking non insulin biologics (including monoclonal antibodies), which modify the immune system, are excluded unless they undergo a 3-month washout.
18. Prior exclusion criterion 18 is not applicable to subjects enrolling in Protocol V6 and later.
19. Exposure to any investigational medication, including placebo requires a 4-week washout (3 months for non insulin biologics[e.g., monoclonal antibodies]).
20. Potential subjects receiving UV-therapy (PUVA, UVA, UVB, Excimer) requires a 4-week washout. Subjects are prohibited from using UV-therapy for the duration of the study.
21. Potential subjects who are taking opiates require a 14 - days washout. Subjects are prohibited from using opioids,
including naltrexone, for the duration of the study.
22. Potential subjects cannot have received gabapentin, pregabalin, calcineurin inhibitors, cannabinoid agonists, capsaicin, cryosurgery, topical doxepin, thalidomide or methotrexate, topical antihistamines and topical corticosteroids require a 14-days washout. These medications are prohibited for the duration of the study. Use of systemic antihistamines are not permitted unless the subject has been on a stable dose for at least 4 weeks prior to screening and there are no plans to change the dose during the study.
23. Potential subjects who have received systemic corticosteroids or local steroid injections of the PN lesions require a 4-week washout. These medications are prohibited for the duration of the study.
24. Potential subjects are excluded if they have had any addition or discontinuation of their regularly used prescription drugs in the 14 days prior to the screening period e-diary WI-NRS collection.
25. Potential subjects taking central nervous system suppressants, such as barbiturates, benzodiazepines (with the exception of short-acting benzodiazepines specifically used on an intermittent and as needed basis), anxiolytics other than benzodiazepines, neuroleptics, and clonidine are excluded. These medications are prohibited for the duration of the study.
Refer to study protocol for cardiac-related exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the difference between the percent “Responders” at Week 14 for the NAL ER treatment arm versus the placebo arm. A “Responder” is defined as a subject with a ≥ 4-point decrease in the 7 day average WI-NRS from baseline to Week 14. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key secondary efficacy Endpoints:
• The mean change in ItchyQoL from baseline to Week 14 for the NAL ER treatment arm versus the placebo arm
• Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the percentage of prurigenous lesions with excoriations/crusts (item 5a) from baseline to Week 14 for the NAL ER treatment arm versus the placebo arm
• The mean change in sleep disturbance (PROMIS Sleep Disturbance Short Form 8a) from baseline to Week 14 for the NAL ER treatment arm
versus the placebo arm
Other secondary efficacy endpoints include the following:
• The mean change in 7-day average WI-NRS from baseline to Week 14 for the NAL ER treatment arm versus the placebo arm
• Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the percentage of healed lesions (item 5b) from
baseline to Week 14 for the NAL ER treatment arm versus the placebo arm
• Change in PAS as assessed by the percentage of subjects having a 1-category improvement in the percentage number of lesions (item 2) from
baseline to Week 14 for the NAL ER treatment arm versus the placebo arm
• Change in Investigator Global Assessment-Prurigo Nodularis (IGA-PN) as assessed by the percentage of subjects having a 1-category improvement
in activity
• Change in IGA-PN as assessed by the percentage of subjects having a 1-category improvement in stage
• The proportion of subjects having a PBI-P score of >=1 at Week 14 for the NAL ER treatment arm versus the placebo arm
Safety:
All on-treatment safety data will be assessed descriptively based on the number and rates of adverse events (AEs), Serious AEs (SAEs), clinical
laboratory measurements, central cardiac core laboratory read-12-lead ECG, vital signs, and physical examinations. Subjects will also complete
the Subjective Opiate Withdrawal Scale (SOWS) on a daily basis for the 2 weeks following the last dose of investigational product, whenever that
occurs and regardless of the reason (unless consent is withdrawn). The totality of these data addresses the secondary objective of
characterizing the overall safety and tolerability of NAL ER in subjects with PN.
An independent Data Safety Monitoring Board will periodically review safety data.
Pharmacokinetics:
Nalbuphine plasma concentration and its metabolites. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Key secondary efficacy endpoints: Week 14 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Crossover: one-way only ie. placebo crosses over to IMP |
| Crossover: one-way only ie. placebo crosses over to IMP |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Austria |
| France |
| Poland |
| Germany |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LVLS
Last Subject completes End of Study Phone Call (at Week 56). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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