| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10050185 |
| E.1.2 | Term | Palmoplantar pustulosis |
| E.1.2 | System Organ Class | 100000004858 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective is:
• To assess the efficacy of RIST4721 versus placebo in adult subjects with moderate to severe palmoplantar pustulosis (PPP) using a range of efficacy endpoints |
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| E.2.2 | Secondary objectives of the trial |
The secondary objective is:
• To assess the safety of RIST4721 versus placebo in adult subjects with moderate to severe PPP |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a subject must meet all of the following criteria at the screening and Day –1 visits, unless specified otherwise:
1. Male or female subject, aged 18–70 years at the time of consent.
2. Subject has at least a 6-month history of PPP as defined by the presence of pustules on palms and/or soles, but without evidence of infection on palms and soles (information obtained from medical chart or subject’s physician, or directly from the subject).
3. Subject has moderate or severe PPP, as defined by PPPASI ≥8 and PPPGA ≥3 at Day –1, and a minimum of 8 fresh pustules at screening (fresh pustule count on both right/left palms and soles) and 20 fresh pustules at Day –1 (fresh pustule count on both right/left palms and soles).
4. Subject who wants to use an emollient should agree to use the same emollient, at the same frequency of application for 7 days before Day –1 and throughout the study. Note: However, on the day of scheduled visits, subjects cannot apply emollient before their scheduled visit time.
5. For female subject of childbearing potential involved in any sexual intercourse that could lead to pregnancy: the subject must agree to use a highly effective contraceptive method, from at least 4 weeks before Day –1 until at least 4 weeks after the last study drug administration. Highly effective contraceptive methods include hormonal contraceptives (combined oral contraceptive, patch, vaginal ring, injectable, or implant), intrauterine devices or intrauterine systems, male partner(s) vasectomy, tubal ligation, or a double-barrier method of contraception (barrier methods include male condom, female condom, cervical cap, diaphragm, and contraceptive sponge) in conjunction with spermicide. Note: Subjects who are on a hormonal contraceptive must have been on a stable dose for at least 4 weeks before Day –1. Note: The above list of contraceptive methods does not apply to subjects who are abstinent for at least 4 weeks before Day –1 and will continue to be abstinent from penile - vaginal intercourse throughout the study. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant.
Note: For countries where double-barrier methods are not accepted as highly effective contraception, then this option must not be considered. Note: A female of nonchildbearing potential is defined as follows: – Female who has had surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy). – Female who has had a cessation of menses for at least 12 months without an alternative medical cause, and a follicle-stimulating hormone (FSH) test confirming nonchildbearing potential (refer to laboratory reference ranges for confirmatory levels).
6. Female subject of childbearing potential has a negative serum pregnancy test at screening and negative urine pregnancy test at Day –1.
7. Female subject agrees to not have egg retrieval during the study and for 1 month after the last study drug administration.
8. Male subject agrees to use condom and spermicide from Day –1 until at least 3 months after the last study drug administration.
9. Male subject agrees not to donate sperm during the study and for 3 months after the last study drug administration.
10. Subject has negative tuberculosis (TB) infection test. Subject will be evaluated for latent TB infection with a purified protein derivative (PPD) test or a QuantiFERON-TB Gold test, if one has not been performed in the last 6 months. Subjects who demonstrate evidence of latent TB infection (either PPD ≥5 mm of induration or positive QuantiFERON-TB Gold test, irrespective of bacille Calmette-Guérin vaccination status) will not be allowed to participate in the study. Subjects with documented completed treatment for latent TB will be allowed to participate in the study without retesting.
11. Subject must be capable of giving written informed consent, which must be personally signed and dated by the subject and obtained prior to any trial-related activities.
12. Subject must be willing to comply with all study procedures and must be available for the duration of the study. |
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| E.4 | Principal exclusion criteria |
1. Subject is a female who is breastfeeding, pregnant, or who is planning to become pregnant during the study.
2. In the opinion of the investigator performing the initial examination, the subject should not participate in the trial (eg, due to probable noncompliance or inability to understand the nature, meaning, and consequences of the trial, and give adequately informed consent).
3. Subject has evidence of erythrodermic, generalized pustular psoriasis, predominantly guttate psoriasis, or drug induced psoriasis.
4. Subject has a history of skin disease or presence of skin condition (except psoriasis) that, in the opinion of the investigator, would interfere with the study assessments.
5. Subject has moderate to severe psoriasis, as defined by plaque psoriasis covering ≥10% of his/her total BSA at Day –1.
6. Subject is known to have immune deficiency or is immunocompromised.
7. 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 successfully treated localized carcinoma in situ of the cervix are not to be excluded.
8. Subject had a major surgery within 8 weeks prior to Day –1 or has a major surgery planned during the study.
9. Subject has any clinically significant medical condition or ECG/physical/laboratory/vital signs abnormality that would, in the opinion of the investigator, put the subject at undue risk or interfere with interpretation of study results.
10. Subject has positive results for hepatitis B surface antigens (HBsAg), antibodies to hepatitis B core antigens (anti-HBc), hepatitis C virus (HCV), or human immunodeficiency virus (HIV).
11. Any clinically significant history of infection (except for localized herpes simplex) within 4 weeks prior to Day –1.
12. Subject has absolute neutrophil count 1.8 x 109/L at screening.
13. Subject has ALT, AST or total bilirubin values ≥2 times the upper limit of normal (ULN), or other clinical evidence of significant hepatic impairment (eg, ascites, peri-umbilical veins, oesophageal varices) at screening.
14. Subject has a history of clinically significant anemia or Hgb value ≤10 g/dL at screening.
15. Subject has a creatinine clearance ≤60 ml/min at screening (calculated with MDRD formula).
16. Subject has used any topical medication to treat PPP, including corticosteroids, retinoids, vitamin D analogues (such as calcipotriol), or tar, within 2 weeks prior to Day –1.
17. Subject has used topical dapsone within 2 weeks prior to Day –1.
19. Subject has used strong systemic cytochrome P450 3A4/5 inhibitors or inducers within 4 weeks or 5 half-lives, whichever is longer, prior to baseline (Day –1) (topical cytochrome P450 3A4/5 inducers or inhibitors with known limited systemic availability may be permitted). Examples of strong systemic cytochrome P450 3A4/5 inhibitors or inducers are provided in Table 3.
20. Subject has received any UV-B phototherapy (including tanning beds) or excimer laser within 4 weeks prior to Day –1.
21. Subject has had PUVA treatment within 4 weeks prior to Day –1. 22. Subject has received any marketed or investigational biological agent within 12 weeks or 5 half-lives (whichever is longer) prior to Day –1.
23. Subject is currently receiving a nonbiological investigational product or investigational device or has received one within 4 weeks prior to Day –1.
24. Subject had excessive sun exposure or has used tanning booths within 4 weeks prior to Day –1, or subject is planning a trip where excessive sun exposure is expected, or is not willing to minimize natural and artificial sunlight exposure during the study. Use of sunscreen products and protective apparel are recommended when exposure cannot be avoided.
25. Subject has a known or suspected allergy to RIST4721 or any component of the study drug.
26. Subject has a known history of clinically significant drug or alcohol abuse in the last year prior to Day –1.
27. Close affiliation with the investigator (eg, a close relative), including any study staff of the sites or persons working at the CRO or subject is an employee of sponsor.
28. Subject is institutionalized because of legal or regulatory order.
29. For subjects consenting to biopsies only: – Subject has a history of an allergic reaction or significant sensitivity to lidocaine or other local anesthetics. – Subject has a history of hypertrophic scarring or keloid formation in scars or suture sites. – Subject has taken anticoagulant medication, such as heparin, LMW heparin, warfarin, antiplatelets (except low-dose aspirin, which will be allowed), within 2 weeks prior to Day –1, or has a contraindication to skin biopsies. NSAIDs will not be considered antiplatelets and will be allowed. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoints:
• Relative change from baseline in fresh pustule count at Day 28
• Relative change from baseline in total pustule count at Day 28 |
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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) |
Secondary Efficacy Endpoints:
• Absolute change from baseline in fresh pustule count at Day 28
• Absolute change from baseline in total pustule count at Day 28
• Proportion of subjects achieving at least a 50% reduction in fresh pustule count at Day 28
• Proportion of subjects achieving at least a 50% reduction in total pustule count at Day 28
Secondary Safety Endpoints:
• Incidence of TEAEs
• Changes in vital signs, ECG, and laboratory tests
Exploratory Endpoints:
• Absolute change from baseline in fresh pustule count at Day 7, Day 14, and Day 21
• Relative change from baseline in fresh pustule count at Day 7, Day 14, and Day 21
• Absolute change from baseline in total pustule count at Day 7, Day 14, and Day 21
• Relative change from baseline in total pustule count at Day 7, Day 14, and Day 21
• Proportion of subjects achieving a 50% reduction in fresh pustule count at Day 7, Day 14, and Day 21
• Proportion of subjects achieving a 75% reduction in fresh pustule count at Day 7, Day 14, Day 21, and Day 28
• Proportion of subjects achieving a 50% reduction in total pustule count at Day 7, Day 14, and Day 21
• Proportion of subjects achieving a 75% reduction in total pustule count at Day 7, Day 14, Day 21, and Day 28
• Absolute change from baseline in PPPASI at Day 7, Day 14, Day 21, and Day 28
• Relative change from baseline in PPPASI at Day 7, Day 14, Day 21, and Day 28
• Proportion of subjects achieving a PPPASI-50 at Day 7, Day 14, Day 21, and Day 28
• Proportion of subjects achieving a PPPASI-75 at Day 7, Day 14, Day 21, and Day 28
• Absolute change from baseline in PPPGA at Day 7, Day 14, Day 21, and Day 28
• Relative change from baseline in PPPGA at Day 7, Day 14, Day 21, and Day 28
• Proportion of subjects achieving a PPPGA of clear (0) or almost clear (1) with a 2-point decrease at Day 7, Day 14, Day 21, and Day 28
• Proportion of subjects achieving at least a 2-point decrease in PPPGA at Day 7, Day 14, Day 21, and Day 28
• Absolute change from baseline in PPSI at Day 7, Day 14, Day 21, and Day 28
• Proportion of subjects achieving a PPSI-50 at Day 7, Day 14, Day 21, and Day 28
• Proportion of subjects achieving a PPSI-75 at Day 7, Day 14, Day 21, and Day 28
• Relative change from baseline in PPSI at Day 7, Day 14, Day 21, and Day 28
• Absolute change from baseline in pain VAS at Day 7, Day 14, Day 21, and Day 28
• Relative change from baseline in pain VAS at Day 7, Day 14, Day 21, and Day 28
• Absolute change from baseline in DLQI at Day 7, Day 14, Day 21, and Day 28
• Relative change from baseline in DLQI at Day 7, Day 14, Day 21, and Day 28
• Absolute change from baseline in BSA at Day 7, Day 14, Day 21, and Day 28
• Relative change from baseline in BSA at Day 7, Day 14, Day 21, and Day 28
• Absolute change from baseline in PASI at Day 7, Day 14, Day 21, and Day 28
• Relative change from baseline in PASI at Day 7, Day 14, Day 21, and Day 28
• Absolute change from baseline in PGA at Day 7, Day 14, Day 21, and Day 28
• Relative change from baseline in PGA at Day 7, Day 14, Day 21, and Day 28 |
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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 | Yes |
| 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 | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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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| The end of the study is defined as completion of the last visit or procedure shown in the schedule of events for the last enrolled subject in the trial globally for all sites. |
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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 | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| 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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