| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 19.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10040785 |
| E.1.2 | Term | Skin and subcutaneous tissue disorders |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
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| 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 |
The primary objectives of the study are:
• To evaluate the effects of two doses of nalbuphine HCl ER tablets on the 7-day average daily worst itch (i.e., most severe) intensity during the last 7 days of the Fixed Dose Period (“Evaluation visit”; Visit 5) compared to baseline, as measured by daily electronic patient diary records for the Numerical Rating Scale (NRS) and reported as the proportion of patients with at least a 30% reduction in the baseline 7-day average daily worst itch NRS score
• To evaluate the safety and tolerability of nalbuphine HCl ER in the study population.
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| E.2.2 | Secondary objectives of the trial |
• Average daily itch intensity during the last 7 days of the Fixed Dose Period (“Evaluation visit”; Visit 5) compared to baseline, as measured by daily electronic patient diary records for the Numerical Rating Scale (NRS) and reported as the proportion of patients with at least a 30% reduction in the baseline 7-day average daily NRS score
• Week-by-week changes in 7-day average daily worst itch intensity and average daily itch intensity through the Evaluation visit (Visit 5) compared to baseline, obtained from NRS scores.
• ItchyQoL recorded during each study visit
• Sleep, as measured by Medical Outcomes Study Sleep Scale–Revised (MOS Sleep-R) during each study visit
• Anxiety and depression using the Hospital Anxiety and Depression Scale (HADS) recorded during each study visit
For other secondary endpoints please refer to Section 5.2 of the study protocol. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Individuals suffering from prurigo nodularis (PN) (definition: presence of pruritic nodules and/or papules due to chronic pruritus, i.e. pruritus and PN is actively present for at least 6 weeks prior to randomization).
2.Aged 18 years and older at the time of consent.
3.Generalized PN as defined as PN lesions involving two distinct anatomical areas: for example, either two limbs; or a single limb and some axial portion of the body. The subject is also eligible with only axial lesions with two distinct anatomical areas of involvement that have no peripheral nervous system overlap: 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 is defined as any nonappendicular portion of the body.
4.NRS based worst itch (i.e., most severe) recorded daily over the 7 contiguous days prior to Visit 2 via daily electronic patient diary must have at least five measurements recorded. The mean value of the measurements must be ≥ 5.
Note: The last NRS value used in the calculation may be captured on the day of Visit 2.
5. Males, non-fecund females, or females of childbearing potential using an acceptable method of birth control (if sexually active). 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 post-menopausal (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 patients of childbearing potential are required to use one barrier method (e.g., condom, cervical cap, or diaphragm) of contraception in addition to one other method (e.g., intrauterine device [IUD] in place at least one month, stable hormonal contraception for at least 3 months, or tubal ligation, Essure procedure, or spermicide). For female patients using a barrier method plus spermicide, that method must be used for at least 14 days prior to screening. Female patients 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.
6.Ability and acceptance to provide written informed consent.
7.Willing and able to comply with study requirements and restrictions
8.Agree to the confidential use and storage of all data (including photography) and use of all anonymized data for publication including scientific publication. |
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| E.4 | Principal exclusion criteria |
1. Chronic pruritus due the following conditions:
• Localized PN (only one localization affected, for example only on arms)
• Lichen amyloidosus
• Peripheral segmental neuropathic pruritus (such as notalgia paresthetica, brachioradial pruritus)
2. Active dermatoses in need of treatment (such as atopic dermatitis, bullous pemphigoid) that has not evolved into the diagnosis of prurigo nodularis or other dermatologic conditions that in the opinion of the Investigator could confound the ability to assess the NRS.
3. Major psychiatric disorder in the opinion of the Investigator that could interfere with the assessment of study drug, such as delusional parasitosis
4. Patients receiving treatment for human immunodeficiency virus (HIV) infection
5. Serum bilirubin > 2.5 times upper limit of normal (ULN) range at screening unless explained by a clinical diagnosis of Gilbert’s Syndrome
6. Serum hepatic alanine aminotransferase (AST) or aspartate aminotransferase (ALT) enzymes > 2 times upper limit of normal (ULN) range at screening
7.Estimated glomerular filtration rate (eGFR) ≤ 44 mL/min/1.73 m2 at Screening
8. Use of the following medications only intended for anti-pruritic treatment:
• topical antihistamines (2 weeks prior to e-diary NRS and VRS collection during the Screen. period);
• topical capsaicin (2 weeks prior to e-diary NRS and VRS collection during the Screen. period);
• topical calcineurin inhibitors (2 weeks prior to e-diary NRS and VRS collection during the Screen. period);
• topical antibiotics (2 weeks prior to e-diary NRS and VRS collection during the Screen. period);
• topical steroids (2 weeks prior to e-diary NRS and VRS collection during the Screen. period);
• antiseptic bathes and anti-septic cleansing lotions (2 weeks prior to e-diary NRS and VRS collection during the Screen. period);
• systemic antihistamines (2 weeks prior to e-diary NRS and VRS collection during the Screen. period);
• anti-convulsant class drugs (4 weeks prior to e-diary NRS and VRS collection during the Screen. period);
• systemic steroids (4 weeks prior to e-diary NRS and VRS collection during the Screen. period);
• naltrexone or naloxone (4 weeks prior to e-diary NRS and VRS collection during the Screen. period);
• cyclosporin A and other immunosuppressants (4 weeks prior to e-diary NRS and VRS collection during the Screen. period);
• antidepressant medications (4 weeks prior to e-diary NRS and VRS collection during the Screen. period);
• benzodiazepine class drugs (2 weeks prior to e-diary NRS and VRS collection during the Screen. period);
• neuroleptic class drugs (2 weeks prior to e-diary NRS and VRS collection during the Screen. period);
NOTE: During washout of excluded medications, rescue is permitted with cleansing lotion or pure emollients (emollients without active substances such as menthol, urea, etc.)
9.UV-therapy (PUVA, UVA, UVB, Excimer) (4 weeks prior to e-diary NRS and VRS collection during the Screen. period).
10. Patients who received opiates within 14 days prior to e-diary NRS and VRS collection during the Screen. period
11. Patients with a history of congestive heart failure of Class 2 or higher as graded using the New York Heart Association scale (scale provided in Appendix 5)
12. Patients with a history of angina pectoris grade 2 or higher as graded using the Canadian Cardiovascular Society grading scale (scale provided in Appendix 5)
13. History of ventricular tachycardia, torsade de pointes, family history of sudden death, myocardial infarction or acute coronary syndrome within the previous 3 months, as reported by the patient.
14. Serum potassium below the laboratory lower limit of normality. Potassium supplementation can be prescribed and the serum potassium level repeated
15. QTcF interval >450ms on screening ECG
16. Heart rate <50 BPM on any screening measurement. Subjects with a resting heart rate of <50 bpm will have it repeated once after 5 minutes in the supine position, and if it remains <50 bpm during the repeat, they will be considered a screen failure.
17. Use of a medication known to be associated with risk of torsade de pointes (a list provided in Appendix 5) within 14 days prior to e-diary NRS and VRS collection during the Screen. period
18. Significant medical condition or other factors that in the opinion of the Investigator may interfere with the conduct of the study.
19. Exposure to any investigational medication, including placebo, within 4 weeks of e-diary NRS and VRS collection during the Screen. period.
20. Patients who have a confirmed malignant tumor and are receiving active treatment with a systemic drug (hormonal treatment can be acceptable to study enrollment if approved by the medical monitor).
21. History of substance abuse within the past year as determined by the Investigator.
22. Known hypersensitivity or allergy to nalbuphine or vehicle components.
23. Known drug allergy to opioids.
24. Is a pregnant or lactating female. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PRIMARY EFFICACY ENDPOINT:
The proportion of patients with at least a 30% reduction in the 7-day average daily diary-reported worst itch intensity NRS from Baseline at the Evaluation visit (Visit 5).
PRIMARY SAFETY ENDPOINTS:
The incidence of the following adverse events: nausea, vomiting, constipation, somnolence, sedation, dizziness and vertigo in each nalbuphine treatment group compared to placebo as well as analyzed by gender. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Efficacy endpoints
o The proportion of patients with at least a 30% reduction in the 7-day average daily diary-reported NRS itch intensity from Baseline at the Evaluation visit (Visit 5).
o Mean week-by-week changes in 7-day average daily worst itch intensity and average daily itch intensity through the Evaluation visit (Visit 5) compared to baseline.
o Mean week-by-week changes in the individual 7-day average daily itchy, burning and stinging VRS through the Evaluation visit (Visit 5) compared to baseline.
o ItchyQoL recorded during each study visit compared to baseline.
o Sleep as measured by MOS Sleep-R during each study visit compared to baseline.
o Anxiety and depression using the Hospital Anxiety and Depression Scale (HADS) recorded during each study visit compared to baseline.
o Prurigo Nodularis skin lesions as quantitatively measured by the Prurigo Activity Score (PAS) recorded during the Evaluation visit (Visit 5) compared to baseline.
o Patient Benefit Index, pruritus version (PBI-P) recorded during the Evaluation visit (Visit 5) compared to baseline.
o Dropouts due to lack of anti-pruritic efficacy.
o Use of rescue medications.
Exploratory endpoints:
Histological analysis (H&E) to investigate possible correlation with any clinical response using skin biopsies taken at the Baseline visit and the Evaluation visit, Visit 5 (optional procedures at selected sites only).
Changes in the following during the Washout Period after cessation of treatment of nalbuphine HCl ER tablets or placebo as measured by daily electronic patient diary records:
• 7-day average worst itch intensity (from the NRS)
• 7-day average itch intensity (from the NRS)
• 7-day average itchy, burning and stinging VRS
Changes in the following PROs during the Washout Period after cessation of treatment of nalbuphine HCl ER tablets or placebo as measured at the last study visit (Week 12, Visit 6):
• ItchyQoL
• MOS Sleep-R
• HADS
The potential of nalbuphine HCl ER tablets to impact on the Measurement of nerve fiber density (histology) and MOR/KOR density (histology, Western Blot) in skin biopsies taken at Baseline visit and the Evaluation visit (at selected sites only).
To evaluate the daily changes via diary in the Subjective Opiate Withdrawal Scale (SOWS) during the Washout Period after cessation of treatment of nalbuphine HCl ER tablets or placebo as measured to the last study visit (Visit 6) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | No |
| 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) | No |
| 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 | No |
| E.8.1.7 | Other | No |
| 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 | 3 |
| 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 | 4 |
| 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 |
| Germany |
| Poland |
| United States |
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| 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
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| 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 | 0 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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