Phase 1 trial design
Pain, Pruritus, PD, AD, SAD
PRURITUS, SECONDARY, ABSCESSES, DISORDERS
The phase 1 trial of KT-474 consisted of randomized, placebo-controlled SAD and MAD studies in HVs, followed by an open-label study in patients with moderate to severe HS and patients with moderate to severe AD (ClinicalTrials.gov identifier: Key eligibility criteria for HVs included males or females aged 18–55 years without clinically relevant medical histories or presence of clinically relevant medical disorders. Individuals who had used any prescribed medications other than hormonal contraceptives within 30 d or five half-lives (whichever was longer) of KT-474 administration were excluded. Randomization codes for associated treatment were prepared at the contract research organization using a validated computer program for both SAD and MAD portions of the study; a designated site staff member was able to unblind a study participant or cohort through individually sealed documents in case of emergency and was to be reported immediately by the investigator to the unblinded statistician, the Safety Review Committee (SRC) and other designated entities. Within each SAD cohort, eight patients were randomized 6:2 in a double-blind manner to receive a single dose of KT-474 or placebo after having fasted 10 h before and 4 h after the dose. Patients were confined on a phase 1 unit (in Hollywood, Florida, at Research Centers of America or in Fair Lawn, New Jersey, at TKL Research, Inc.) through day 5 and then followed on an outpatient basis through day 14. At each dose level, two sentinel patients were randomized to receive KT-474 or placebo. The remaining patients were dosed after the 24-h post-dose safety data from the sentinel patients had been reviewed by the investigator. Subsequent dose cohorts were initiated after the SRC had determined that all requirements for dose escalation were met based on a blinded review of the safety data through day 14 and PK data through day 5. The following KT-474 doses were assessed in SAD: 25, 75, 150, 300, 600, 1,000 and 1,600 mg. Within each MAD cohort, 12 patients were randomized 9:3 in a double-blind manner to receive KT-474 or placebo once daily (QD) from day 1 to day 14 after having fasted 10 h before and 4 h after the dose. The patients were confined through day 21 and then followed on an outpatient basis through day 28. Subsequent dose cohorts were initiated after the SRC had determined that all requirements for dose escalation were met based on a blinded review of the safety data through day 28, PK data through day 15 and PD data through day 7. The following KT-474 doses (mg daily × 14 d) were assessed in MAD: 25, 50, 100 and 200.Key eligibility criteria for patients with AD or patients with HS included males or females aged 18–75 years with body mass index of 17.5–40.0 kg mThe primary objective of the trial was to determine the safety and tolerability of KT-474 as single and multiple daily doses in HVs and patients with HS and patients with AD, with endpoints including treatment-emergent AEs, treatment-emergent SAEs, concomitant medications, clinical laboratory tests (including hematology, coagulation, chemistry, urinalysis and urine microscopy), vital signs and safety electrocardiogram and Holter monitoring. The secondary objective was to characterize the PK profile of KT-474 in plasma and urine in HVs and patients. The main exploratory objectives were to characterize the PD profile and skin PK of KT-474 in HVs and patients and explore clinical efficacy in HS and AD. The PD endpoints included changes in IRAK4 levels and inflammatory biomarkers in blood and skin as well as changes in ex vivo whole blood cytokine induction. Efficacy endpoints in patients with HS included change from baseline in Total AN count, Pain NRS, Peak Pruritus NRS and HS-PGA. Additional endpoints derived from these included AN 0/1/2 (Total AN count of 0, 1 or 2), HiSCR50 (50% or greater reduction in AN count with no increase in abscesses or fistulas) and Pain NRS30. In patients with AD, efficacy endpoints included change from baseline in EASI, Peak Pruritus NRS and Investigator Global Assessment, with Peak Pruritus response derived from Peak Pruritus NRS (≥4 unit reduction from baseline).