Sickle Cell Disease
Conditions
Keywords
ITU512, Low molecular weight, Small molecule, Sickle cell disease
Brief summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary food effect of ITU512 as well as the fetal hemoglobin (HbF)-inducing capacity of ITU512. This will be the first evaluation of the potential therapeutic effect of ITU512 in healthy participants and patients with sickle cell disease (SCD).
Detailed description
This is a global, randomized, Phase I/II study to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary food effect of single-agent ITU512 in adult healthy participants, and safety, tolerability, PK, PD, and efficacy of ITU512 in adolescent and adult patients with sickle cell disease (SCD). The study consists of a first-in-human Phase I study (Part 1) in healthy participants, and a Phase II study (Part 2) in patients with SCD. Part 1 will comprise of Part 1A, Part 1B, and Part 1C. Part 2 will include Part 2A and 2B and may also include an extension part (Part 2C).
Interventions
DRUGITU512
ITU512 is an investigational, oral, low molecular weight (LMW) compound.
DRUGPlacebo
An inactive substance that looks like and is given the same way as ITU512. The effect(s) of ITU512 will be evaluated against the placebo. Placebos are designed as a control and to have no real effect.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: Part 1 (Healthy participants) * Healthy male participants and female participants of non-childbearing potential between 18-55 years of age * In good health as determined by the investigator's assessment of medical history, physical examination, vital signs, ECG, and laboratory tests * Participants must weigh at least 50 kg at screening and first baseline (admission) and must have a body mass index (BMI) within the range of 18.0-32.0 kg/m2 inclusive. Part 2 (Sickle Cell Disease) \- Male and female participants with a diagnosis of sickle cell disease Key
Exclusion criteria
Part 1 (Healthy participants) * QTcF ≥ 450 msec (as a mean value of triplicates) * History of arrhythmias * History of significant illness which has not resolved within two (2) weeks prior to initial dosing * Women of child-bearing potential (WOCBP) Part 2 (Sickle Cell Disease) * Current use of hydroxyurea/hydroxycarbamide (HU/HC) * QTcF ≥ 450 msec (as a mean value of triplicates) * History of arrhythmias Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1A, Part 1B, Part 1C: Incidence of AEs and SAEs | Up to approximately 60 days | Number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes in vital signs, electrocardiograms (ECGs) and laboratory values qualifying and reported as AEs. |
| Part 1A, Part 1B , Part 1C: Dose discontinued due to AE | Up to 30 days | Number of participants with dose discontinuation due to AEs |
| Part 2A, Part 2B: Incidence of AEs and SAEs | Up to 5 months | Number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes in vital signs, electrocardiograms (ECGs) and laboratory values qualifying and reported as AEs. |
| Part 2A, Part 2B: Dose interruptions and reductions | Up to 4 months | Number of participants with dose interruptions or reductions of ITU512 |
| Part 2A, Part 2B: Dose intensity | Up to 4 months | Dose intensity of ITU512 is computed as the ratio of actual cumulative dose received and actual duration of exposure |
| Part 2B: Fetal hemoglobin (HbF)% | Month 4 | Assessment of fetal hemoglobin expression by measuring fetal hemoglobin (HbF)% by high-performance liquid chromatography (HPLC) assay |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1A, Part 1B: Area under the plasma concentration-time curve (AUC) of ITU512 | From pre-dose up to 144 hours post-dose on Day 1 (Part 1A) and from pre-dose up to 24 hours post-dose on Day 1 and Day 10 (Part 1B) | Pharmacokinetic (PK) parameters calculated based on ITU512 plasma concentrations by non-compartmental methods |
| Part 1A, Part 1B: Maximum plasma concentration (Cmax) of ITU512 | From pre-dose up to 144 hours post-dose on Day 1 (Part 1A) and from pre-dose up to 24 hours post-dose on Day 1 and Day 10 (Part 1B) | PK parameters calculated based on ITU512 plasma concentrations by non-compartmental methods |
| Part 1A, Part 1B: Time to maximum plasma concentration (Tmax) of ITU512 | From pre-dose up to 144 hours post-dose on Day 1 (Part 1A) and from pre-dose up to 24 hours post-dose on Day 1 and Day 10 (Part 1B) | PK parameters calculated based on ITU512 plasma concentrations by non-compartmental methods |
| Part 1A, Part 1B: Renal clearance (CLr) | From pre-dose up to 48 hours post-dose on Day 1 (Part 1A) and from pre-dose up to 24 hours post-dose on Day 1 and Day 10 (Part 1B) | PK parameters calculated based on ITU512 urine concentrations by non-compartmental methods. The renal clearance (CLr) may be determined based on AUC and amount of drug excreted into urine (Ae) available for the same time period. |
| Part 2A, Part 2B: Plasma concentrations of ITU512 | From pre-dose up to 4, 6 or 8 hours post-dose on Day 1 at Month 1 and Month 2 | ITU512 concentration in plasma determined in non-placebo treated participants by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method |
| Part 2A, Part 2B: Urine concentrations of ITU512 | From pre-dose up to 4 or 8 hours post-dose on Day 1 at Month 1 | ITU512 concentration in urine determined in non-placebo treated participants by a LC-MS/MS method |
| Part 2A: Fetal hemoglobin (HbF)% | Up to 4 months | Assessment of fetal hemoglobin expression by measuring fetal hemoglobin (HbF)% by HPLC assay |
| Part 2A, Part 2B: Change from baseline in total hemoglobin (Hb) | Baseline, up to 4 months | Change from baseline in total hemoglobin (Hb) over time measured in blood samples |
| Part 1A, Part 1B, Part 2A, Part 2B: Change from baseline in Fridericia- corrected Holter QT interval (QTcF) | Up to 4 months | Real-time 12-lead safety ECGs will be locally collected and evaluated. Change from baseline in QTcF with respect to PK parameters and/or ITU512 concentrations will be assessed |
| Part 1C: Area under the plasma concentration-time curve from time 0 up to the time of the last quantifiable concentration (AUClast) of ITU512 | From pre-dose up to 144 hours post-dose | PK parameters calculated based on ITU512 plasma concentrations by non-compartmental methods |
| Part 1C: Area under the plasma concentration-time curve from time 0 up to infinity (AUCinf) of ITU512 | From pre-dose up to 144 hours post-dose | PK parameters calculated based on ITU512 plasma concentrations by non-compartmental methods |
| Part 1C: Maximum plasma concentration (Cmax) of ITU512 | From pre-dose up to 144 hours post-dose | PK parameters calculated based on ITU512 plasma concentrations by non-compartmental methods |
| Part 1C: Time to maximum plasma concentration (Tmax) of ITU512 | From pre-dose up to 144 hours post-dose | PK parameters calculated based on ITU512 plasma concentrations by non-compartmental methods |
Countries
Turkey (Türkiye), United States
Contacts
CONTACTNovartis Pharmaceuticals
Outcome results
None listed