Sickle Cell Disease
Conditions
Brief summary
The purpose of this study is to evaluate the pharmacokinetics and safety of etavopivat in paediatric participants with sickle cell disease (SCD). Participants will receive etavopivat and will be enrolled in a staggered manner, starting with the oldest age group and followed sequentially by younger cohorts after review of pharmacokinetic and safety data from the preceding cohort. All participants will undergo a 24-week primary treatment period followed by a 72-week extension treatment period to further evaluate long-term safety and pharmacokinetics of etavopivat. The total duration of the study will be approximately 96 weeks.
Interventions
DRUGEtavopivat
Participants will receive oral tablets or granules of etavopivat once daily.
Sponsors
Forma Therapeutics, Inc.
Novo Nordisk A/S. This study is currently undergoing a sponsor transition from Forma Therapeutics, Inc. to Novo Nordisk A/S.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
* Type of Participant and Disease Characteristics 1. Patient's parent, legal guardian, or legal representative has provided documented informed consent and patients have provided age-appropriate assent 2. Age greater than or equal to (≥) 6 months and lesser than (\<) 18 years of age at time of enrollment, according to the enrolling cohort: * Cohort 1: age 12 to \< 18 years (adolescents) * Cohort 2: age 6 to \< 12 years * Cohort 3: age 2 to \< 6 years * Cohort 4: age 6 months to \< 2 years 3. Patient has confirmed diagnosis of SCD • Documentation of SCD genotype (HbSS, HbSβ0-thalassemia or other sickle cell syndrome variants) based on prior history of laboratory testing. Molecular genotyping is not required. SCD genotype may be determined from the results of Hb electrophoresis, high-performance liquid chromatography (HPLC), or similar testing. Note that Hb electrophoresis is performed by the local laboratory at Screening. 4. Hemoglobin ≥ 5.5 and lesser than or equal to (≤) 10.5 grams per deciliter (g/dL) 5. Pediatric patients with severe SCD, as defined by at least 1 of the following: * 2-15 episodes of documented VOC within the 12 months prior to screening. Documentation must exist in the patient's medical record prior to screening. Events based solely on patient recall without supporting documentation should not be counted towards eligibility. * Hospitalization for any SCD-related complication in the last 12 months prior to starting study treatment * Proteinuria, defined as an albumin:creatinine ratio (ACR) \> 100 mg/g on 2 measures (separated by ≥ 1 month) as an indicator of early renal disease * History of a conditional TCD in the last 12 months prior to starting study treatment, but not currently being treated with chronic transfusion therapy (applicable to participants \> 2 years of age). Conditional TCD is defined as a TAMMV of 170-199 cm/s by TCD or 155-184 cm/s by imaging TCD (TCDi). 6. For participants taking hydroxyurea (HU), the dose of HU (mg/kg) must be stable (no more than a 20% change in dosing) for at least 90 days prior to start of study treatment with no anticipated need for dose adjustments during the study, in the opinion of the Investigator 7. Patients on crizanlizumab or L-glutamine treatment at the time of consent may be eligible if they: * Have been on a stable dose for ≥ 12 months at the time of consent (ie, no changes to the dose except for changes to weight or for safety reasons) * For patients on crizanlizumab, have been ≥ 80% compliant with the planned regimen during the 12 months prior to the time of consent 8. Female patients of childbearing potential who are using acceptable methods of contraception and agree not to donate ova from study start to 90 days after the last dose of study drug, and male patients who are willing to use acceptable methods of contraception and agree not to donate sperm, from study start to 90 days after the last dose of study drug.
Exclusion criteria
* Medical Conditions 1. Female who is breastfeeding or pregnant 2. More than 15 VOCs within the 12 months prior to starting study treatment that required a hospital, emergency room (ER), or clinic visit 3. Hospitalized for sickle cell crisis or other vaso-occlusive event occurring in the 14 days prior to starting study treatment 4. Abnormal TCD in the 12 months prior to starting study treatment Prior/Concomitant Therapy 5. Patients receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) 6. Received any blood products within 30 days of starting study treatment 7. Receiving or use of concomitant medications that are strong inducers of cytochrome P450 (CYP) 3A4/5 within 2 weeks of starting study treatment 8. Use of voxelotor within 28 days prior to starting study treatment or anticipated need for this agent during the study 9. Receipt of erythropoietin or other hematopoietic growth factor treatment within 28 days of starting study treatment or anticipated need for such agents during the study 10. Receipt of prior cellular based therapy (eg, hematopoietic cell transplant, gene modification therapy)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of dose interruptions | During the 24-week primary treatment period |
| Number of dose reductions | During the 24-week primary treatment period |
| Single-dose: maximum plasma concentration (Cmax) | During the 24-week primary treatment period |
| Single-dose: area under the plasma concentration time curve from dosing (time 0) to time t ((AUC)0-t) | During the 24-week primary treatment period |
| Single-dose: area under the plasma concentration time curve from zero to time infinity (AUC0-inf) | During the 24-week primary treatment period |
| Steady-state maximum plasma concentration (Cmax,ss) | During the 24-week primary treatment period |
| Steady-state area under the concentration time curve over the dosing interval (AUCtau,ss) | During the 24-week primary treatment period |
| Steady-state average plasma concentration (Cavg,ss) | During the 24-week primary treatment period |
| Steady-state minimum plasma concentration (Cmin,ss) | During the 24-week primary treatment period |
| Incidence of adverse events (AEs), serious adverse events (SAEs), and AEs related to etavopivat | During the 24-week primary treatment period |
| Number of premature discontinuations | During the 24-week primary treatment period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in Annualized Rate of VOC | Baseline and week 24 | — |
| Change from baseline in time-averaged mean of the maximum velocity (TAMMV) by transcranial Doppler ultrasonography (TCD) | Baseline, week 24, 48, and 96 | — |
| Incidence of AEs, SAEs, and AEs related to etavopivat | During the 72-week treatment extension period | — |
| Number of premature discontinuations | During the 72-week treatment extension period | — |
| Number of dose interruptions | During the 72-week treatment extension period | — |
| Number of dose reductions | During the 72-week treatment extension period | — |
| Hemoglobin (Hb) response rate | Baseline, week 12 and 24 | — |
| Change in Hb from baseline | Baseline, week 12 and 24 | — |
| Change from baseline in number of vaso-occlusive crises (VOCs) | Baseline and week 24 | — |
| Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale | Baseline, week 12 and 24 | PROMIS is a 10-item patient-reported health outcome measurement system used to evaluate quality of life in both children and adults. The assessment is based on the responses - 1. Never, 2. Almost never, 3. Sometimes, 4. Often and 5. Almost always. 'Never' response on the PROMIS fatigue scale indicates better quality of life. |
Countries
Canada, France, Kenya, Lebanon, Nigeria, Turkey (Türkiye), United Kingdom
Contacts
CONTACTNovo Nordisk
STUDY_DIRECTORClinical Transparency (dept. 2834)
Novo Nordisk A/S
Outcome results
None listed