| 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 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064848 |
| E.1.2 | Term | Chronic kidney disease |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| 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 |
Efficacy Assessment Phase:
- To evaluate the efficacy of oral difelikefalin at a dose of 1 mg once daily compared to placebo in reducing the intensity of itch after 12 weeks of treatment in advanced Chronic kidney disease (CKD) subjects with moderate-to-severe pruritus
Long-term Extension Phase:
- To evaluate the safety of oral difelikefalin at a dose of 1 mg during up to 52 weeks of Treatment Period 2 in advanced CKD subjects with moderate-to severe pruritus |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy Assessment Phase:
- To evaluate the efficacy of oral difelikefalin at a dose of 1 mg once daily compared to placebo in advanced CKD subjects with moderate-to-severe pruritus in:
• reducing the intensity of itch after 4 and 8 weeks of treatment
• in completely reducing itch intensity after 12 weeks of treatment
• in improving sleep quality
- To evaluate the safety of oral difelikefalin at a dose of 1 mg during 12 weeks of Treatment Period 1 in advanced CKD subjects with moderate-to severe pruritus
Long-term Extension Phase:
- To evaluate the efficacy of oral difelikefalin at a dose of 1 mg once daily compared to placebo in reducing the intensity of itch during up to 64 weeks of the Treatment Periods 1 and 2 in advanced CKD subjects with moderate-to-severe pruritus
Please see Protocol Section 5.3 for the list of secondary objectives during Transition Period. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Willing and able to provide written informed consent prior to participating in this study.
2. Able to communicate clearly with the study investigator and staff and complete the required study procedures and questionnaires.
3. Subjects aged 18 to 85 years, inclusive, at the time of consent.
4. A) Subjects not currently on dialysis with advanced CKD (ie, estimated glomerular filtration rate (eGFR) ≤29 mL/min/1.73 m2 calculated using chronic kidney disease-Epidemiology Collaboration (CKD-EPI) creatinine equation [2021]) based on either a screening laboratory serum creatinine value from this study or at least 2 documented serum creatinine values collected at least 90 days apart within 1 year prior to screening.
B) Subjects receiving hemodialysis 3 times per week for at least 3 months prior to the start of screening;
5. Subject self-reports experiencing at least near-daily (eg, most days of a week) pruritus for at least 6 months prior to screening.
6. Inadequate response to current or prior treatments (including emollients/moisturizers, topical medications, or systemic treatments) for pruritus prior to screening.
7. Female subject is not pregnant or nursing during any period of the study.
8. If female of childbearing potential, must have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to randomization
9. For females, subject must be of nonchildbearing potential defined as:
a. Postmenopausal: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. For women aged 55 years or younger, postmenopausal state should be confirmed by a high follicle-stimulating hormone (FSH) level (> 40 IU/L or > 40 mIU/mL). No FSH confirmation is required in women older than 55 years; or
b. Surgically sterile (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy).
Or, of childbearing potential involved in sexual intercourse that could lead to pregnancy and:
• Agrees to use an adequately effective method of contraception: (eg, hormonal contraceptives from at least 30 days prior to Day 1 until 7 days after the last dose of study drug [oral, intravaginal, transdermal, injectable, or implant], barrier method with spermicide, intrauterine device [IUD], intrauterine hormone releasing system [IUS], bilateral tubal ligation, vasectomized partner provided his vasectomy was performed ≥ 4 months prior to screening, or abstinence) from the time of informed consent until 7 days after the last dose of study drug.
Note: The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal, post ovulation methods) is not acceptable.
10. For male subjects involved in any sexual intercourse that could lead to pregnancy, subject must agree to use one of the effective contraceptive methods listed in Inclusion Criterion #9, from Day 1 (first day of treatment) until at least 7 days after the last study product administration. If the female partner of a male subject uses any of the hormonal contraceptive methods listed above and is the only form of contraception used, this contraceptive method should be used by the female partner from at least 4 weeks before Day 1 until at least 7 days after the last dose of study drug. Male subjects must agree not to donate sperm during the study and for 7 days after receiving the study drug. No restrictions are required for a vasectomized male provided his vasectomy was performed ≥ 4 months prior to screening.
11. Prior to randomization on Day 1 of Treatment Period 1:
a. Has recorded at least 4 WI-NRS scores during the 7-day Run-in Period; and
b. Has a mean baseline WI-NRS score ≥ 5, defined as the average of all non-missing scores reported during the 7-day Run-in Period.
To be eligible for inclusion into the Long-term Extension Phase of the study, each subject will have to fulfill the additional following criteria at the time of entry into the Long-term Extension Phase:
12. Has completed Treatment Period 1.
13. Continues to meet inclusion criteria 1 through 10.
Please see Protocol Section 7.1 for the details. |
|
| E.4 | Principal exclusion criteria |
1. Scheduled to receive renal replacement therapy (dialysis or kidney transplant) during the study.
2. Has a concomitant disease, significant medical condition or physical/laboratory/ECG/vital signs abnormality that, in the opinion of the investigator, puts the subject at undue risk or interferes with interpretation of study results, impedes completion of the study procedures, or compromises the validity of the study measurements.
Examples: unstable or high-risk subjects, such as those with recent myocardial infarction within the last months, New York Heart Association NYHA) Class IV heart failure, uncontrolled hypertension despite being on antihypertensive medication(s), and significant uncontrolled psychiatric disorders.
3. Subject has a known history of clinically significant drug or alcohol abuse in the last year prior to Day 1.
4. Subject had a major surgery within 8 weeks prior to Day 1 or has a major surgery planned during the study.
5. Subjects with a history of hypernatremia within the past 3 months.
6. Subjects unable to sense or respond to thirst appropriately.
7. New or change of treatment received for itch, including antihistamines and corticosteroids (oral, intravenous, or topical), within 14 days prior to the start of Run-in.
8. New or change of prescription for gabapentinoids, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, anticonvulsants/mood stabilizers, tricyclic antidepressants, opioids or benzodiazepines within 14 days prior to the start of Run-in.
9. Serum alanine aminotransferase or aspartate aminotransferase greater than 2.5 times the reference upper limit of normal (ULN) and/or total bilirubin greater than 1.5 times the upper limit of normal (ULN) at screening.
10. Received an investigational drug within 30 days prior to the start of screening or is planning to participate in another clinical study while enrolled in this study.
11. Has pruritus attributed to a cause other than chronic kidney disease (eg, pruritus associated with dermatological, hepatobiliary, neuropathic, and/or hematologic disorders).
12. Has localized itch restricted to the palms of the hands.
13. Receiving an opioid antagonist (eg, naloxone, naltrexone) or opioid-mixed agonist-antagonist (eg, buprenorphine, nalbuphine) within 14 days prior to the start of screening and/or anticipates receiving such medications during the study.
14. Received ultraviolet B treatment within 30 days prior to screening and/or anticipates receiving such treatment during the study.
15. Has a known or suspected allergy to difelikefalin or any component of the investigational product.
16. Subject has a history of cancer or lymphoproliferative disease within 5 years prior to Day 1. Subjects with successfully treated nonmetastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix are not to be excluded.
17. Subject has a current condition resulting in chronic dehydration (eg, ongoing vomiting, chronic diarrhea) or a condition that, in the opinion of the investigator, could predispose to dehydration.
A subject will be excluded from the Long-term Extension Phase of the study if any of the additional following criteria are met at the time of entry into the Long-term Extension Phase.
18. Experienced AEs during the course of Treatment Period 1 that may preclude continued exposure to the study drug.
19. Was noncompliant with protocol procedures during the Efficacy Assessment Phase of this study which is indicative of an inability to follow protocol procedures.
20. Has developed a concomitant disease or any medical condition that, in the opinion of the investigator, could pose undue risk to the subject, impedes completion of the study procedures, or would compromise the validity of the study measurements. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy Assessment Phase:
- Proportion of subjects achieving at least a 4-point improvement from baseline with respect to the weekly mean of the daily 24-hour worst Itching Intensity Numerical Rating Scale (WI-NRS) score at Week 12 of Treatment Period 1.
Long-term Extension Phase:
- Incidence of adverse events (AEs), observed values and changes from baseline in ECG assessments, vital signs, and clinical safety laboratory evaluations |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Refer to Table 2 and Table 3 'Schedule of events' on pages 46-50 of the Protocol |
|
| E.5.2 | Secondary end point(s) |
Efficacy Assessment Phase:
- Proportion of subjects achieving at least a 4-point improvement from baseline with respect to the weekly mean of the WI-NRS at Week 4 and 8 of Treatment Period 1
- Proportion of subjects who are free or almost free of itch defined as subjects with weekly mean WI-NRS of 0-1 at Week 12 of Treatment Period 1
- Change from baseline in Sleep Quality Questionnaire score at the end of Week 12 of Treatment Period 1.
- Incidence of AEs
- Observed values and changes from baseline in ECG assessments, vital signs, and clinical safety laboratory evaluations
Transition Period:
- Observed values and changes from baseline in subjective opiate withdrawal scale (SOWS) total daily score, series of unipolar visual analogue scales (VAS) to assess whether subjects feel sick, feel any bad effect, pain or hallucination, 4 aspects of sleep using the Modified leeds sleep evaluation questionnaire (LSEQ) (getting to sleep, quality of sleep, awakening from sleep and behavior following wakefulness), and daily 24-hour WI-NRS scores during the Transition Period
- Incidence of AEs with onset during the Transition Period
- Incidence of AEs potentially related to withdrawal during the Transition Period
Long-term Extension Phase:
- WI-NRS based endpoints described above for Treatment Period 1, further evaluated daily during the Transition Period and at Weeks 4, 8, 12, 24, 36 and 52 of Treatment Period 2. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Refer to Table 2 and Table 3 'Schedule of events' on pages 46-50 of the Protocol |
|
| 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) | No |
| 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 | 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Korea, Republic of |
| Mexico |
| United States |
| Bulgaria |
| Germany |
| Hungary |
| Italy |
| Poland |
| Romania |
| Spain |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 21 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
Print
