| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cryopyrin-associated periodic syndrome (CAPS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Autoinflammatory disease of skin, joints, central nervous system, and eyes |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10068850 |
| E.1.2 | Term | Cryopyrin associated periodic syndrome |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| 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 |
•To investigate the safety and tolerability of different dose levels of IZD174 in participants with CAPS
•To explore the efficacy of IZD174 treatment to induce complete remission in participants with CAPS
|
|
| E.2.2 | Secondary objectives of the trial |
•To determine the PK and PD of different dose levels of IZD174 in participants with CAPS
•To explore the efficacy of different dose levels of IZD174 to induce complete remission in participants with CAPS
•To explore the efficacy of different dose levels of IZD174 to induce partial remission in participants with CAPS
•To determine CRP and SAA levels in participants with CAPS following the treatment of IZD174 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participants must be willing and able to provide written informed consent as described in Section 10.1, Appendix 1 (includes compliance with the requirements and restrictions listed in the ICF and in this protocol) after the nature of the study has been explained and prior to the commencement of any study procedures.
2. Male or female adult participants with a confirmed diagnosis of CAPS aged between 18 to 75 years (inclusive at the time of signing the informed consent).
A confirmed diagnosis of CAPS comprises the following:
a. Documented verification of a genetic mutation in NLRP3; and
b. Participant has previously experienced at least 2 typical clinical symptoms of CAPS (may include urticarial skin rash, myalgia, arthralgia, recurrent fever, fatigue/malaise, headache, conjunctivitis, and any other autoinflammatory symptom usual for a given participant); and
c. Participant previously had elevated levels of CRP or SAA (> 2 × ULN).
3. Positive response to IZD174 in ex vivo whole blood lipopolysaccharide (LPS)+Nigericin induced IL-1β release (IC50 < 50 μM).
4. Participants must be willing to discontinue current anti-IL-1 inhibitor treatment prior to dosing if applicable.
5. Participants must demonstrate flaring of CAPS following discontinuation of anti-IL-1 inhibitor treatment or if newly diagnosed. Flaring is defined as IGA score specific at the time of consultation > 5 with an elevation of CRP (> 2 × ULN).
6. Participants must have a body mass index (BMI) between ≥18.0 and ≤38.0 kg/m2 at Screening.
7. Female participants of reproductive age must be non-pregnant and non-lactating, and must use an acceptable, highly effective double contraception as detailed in Section 10.4, Appendix 4 from Screening until 1 month after the last treatment day. Double contraception is defined as a condom and one other form of the following:
- A vaginal ring or an intrauterine device (IUD).
- Documented evidence of surgical sterilization at least 6 months prior to Screening (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy for women or vasectomy for men [with appropriate post-vasectomy documentation of the absence of sperm in semen] provided the male partner is a sole partner).
Women not of childbearing potential must be post menopausal for ≥ 12 months. Post menopausal status will be confirmed through testing of follicle-stimulating hormone (FSH) levels ≥ 40 IU/mL at Screening for amenorrhoeic female participants. Females who are abstinent from heterosexual intercourse will also be eligible.
True abstinence: When this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception].
Participant complete abstinence for the duration of the study and for 1 month after the last study treatment is acceptable.
Female participants who are in same sex relationships are not required to use contraception.
Male participants must be abstinent, or if engaged in sexual relations with a woman of childbearing potential (WOCBP), the participant and his partner must be using an acceptable, highly effective double contraceptive method as detailed in Section 10.4, Appendix 4 from Screening until Follow up Visit.
Participants with same sex partners (abstinence from penile-vaginal intercourse) are eligible when this is their preferred and usual lifestyle.
WOCBP must have a negative pregnancy test at Screening and Baseline and be willing to have additional pregnancy tests as required throughout the study.
8. Male participants must not donate sperm for at least 90 days after the last dose of study drug.
9. Participants must have the ability and willingness to attend the necessary visits to the study centre. |
|
| E.4 | Principal exclusion criteria |
1. Use of any investigational drug or investigational device or investigational medical device or participation in a clinical study within 4 weeks prior to Screening or 5 half lives of the product (whichever is longer).
2. Live vaccinations within 3 months prior to Screening, for the duration of the study and for up to 3 months following the last dose of study drug.
3. Positive QuantiFERON test at the Screening Visit or within 2 months prior to Screening. Participants who have a positive QuantiFERON test with documentation of Bacillus of Calmette and Guerin vaccination, who are at low environmental risk for tuberculosis infection or reactivation and have a negative chest X-ray can be included.
4. Any severe, progressive, or uncontrolled medical condition at Baseline that in the judgment of the Investigator prevents the participant from participating in the study.
5. Prior or ongoing medical history, physical findings, or laboratory abnormality at Screening that, in the Investigator’s (or delegate’s) opinion, may affect full participation or compliance with the protocol, or could adversely affect the safety of the participant.
6. Presence of any underlying physical or psychological medical condition that, in the opinion of the Investigator, would make it unlikely that the participant will complete the study per protocol.
7. Blood donation or significant blood loss within 60 days prior to the first study drug administration.
8. Plasma donation within 7 days prior to the first study drug administration.
9. Active systemic infections (other than common cold) within 2 weeks prior to Baseline.
10. History of severe allergic or anaphylactic reactions.
11. History of (or) is currently immunocompromised.
12. Abnormal laboratory tests at Screening that are considered by the Investigator to be clinically significant.
13. Alkaline phosphatase (ALP), aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >1.5 × ULN at Screening. Repeat testing at Screening is acceptable for out of range values following approval by the Investigator or delegate.
14. Positive test for hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) or human immunodeficiency virus (HIV) antibody at Screening.
15. Participants with a positive toxicology screening panel (urine test including qualitative identification of barbiturates, tetrahydrocannabinol [THC], amphetamines, benzodiazepines, opiates and cocaine.
16. Participants with a history of substance abuse or dependency or history of recreational IV drug use over the last 5 years (by self-declaration).
17. Use of any prescription drugs, over-the-counter (OTC) medication, herbal remedies, supplements or vitamins 1 week prior to dosing. 1 2 therapeutic doses per week of simple analgesia (aspirin, paracetamol, and other nonsteroidal anti-inflammatory drug [NSAID]) may be permitted at the discretion of the Investigator.
18. Inability or unwillingness to undergo repeated visits and venepunctures (e.g., due to poor tolerability or lack of access to veins).
19. Participant is unwilling to refrain from strenuous exercise from 2 days prior to Baseline until the Follow-up Visit.
20. Pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time during the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety and tolerability:
•Vital signs
•12-lead ECG
•Clinical laboratory tests
•Physical examination
•AEs
Efficacy endpoints:
•Number of participants with no disease at Week 12 during individual IZD174 treatment (pooled).
No disease is complete clinical remission, defined as complete clinical response with normal CRP or SAA levels.
Complete clinical response is defined as Investigator global assessment of IGA score specific at the time of consultation of < 3 and IGA general assessment of absent or minimal |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
At different time points throughout the study; refer to schedule of assessments within the protocol
|
|
| E.5.2 | Secondary end point(s) |
•Plasma PK: plasma IZD174 concentrations
•PD: NLRP3 inhibition in ex vivo stimulated whole blood as measured by IL-1β secretion
•CRP (as part of safety assessments)
•SAA
•Efficacy endpoints:
- Number of participants with no disease at Week 12 for participants receiving single daily dose of IZD174 and participants receiving twice daily dose of IZD174
- Number of participants with partially active disease at Week 12 for participants receiving single daily dose of IZD174 and participants receiving twice daily dose of IZD174. Partially active disease is incomplete clinical remission, defined as incomplete clinical response with CRP or SAA levels improved by > 50% over Baseline, but still elevated. Incomplete clinical response is defined as IGA score specific at the time of consultation of 3 and > 50% improvement over Baseline and IGA general assessment improvement by at least one category (e.g., moderate to mild)
- Number of participants with active disease at Week 12 for participants receiving single daily dose of IZD174 and participants receiving twice daily dose of IZD174
Active disease is no clinical remission, defined as no clinical response with CRP or SAA elevated. No clinical response is defined as no improvement or worsening of the clinical symptoms and IGA general assessment unchanged or worsened.
- Duration of clinical remission
Time from onset of remission until loss of complete clinical remission. Loss of Complete clinical remission is defined as: IGA score specific at the time of consultation > 3 and IGA general assessment worse than minimal with CRP or SAA > ULN or IGA score specific at the time of consultation > 3 and IGA general assessment worse than minimal or CRP or SAA > ULN (with no evidence of other cause of CRP/SAA rise such as infection or trauma)
- Time to flare
The time from stopping of study drug until flare. For the purpose of this endpoint, flare is defined as loss of complete clinical remission with CRP or SAA levels to be rising on 2 successive samples at the stopping of study drug. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
At different time points throughout the study; refer to schedule of assessments within 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 | 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| 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 |
| Australia |
| Ireland |
| United Kingdom |
|
| 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
|
| Last visit of the last subject |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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