Sickle Cell Disease
Conditions
Keywords
Sickle Cell Disease, SCD
Brief summary
Study participants will undergo up to four periods of voxelotor administered orally at progressively higher dose levels from 1500 mg until either a maximum tolerated dose (MTD) or 3000 mg/day dose is reached, whichever occurs first
Interventions
DRUGVoxelotor
synthetic small molecule supplied as 500 mg tablets
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female with SCD 2. Documentation of SCD genotype HbSS or HbSB0 3. Age 18 to \< 60 years, inclusive 4. Hemoglobin ≥ 5.5 and ≤ 10.5 g/dL during Screening, and considered stable and close to Baseline by the Investigator 5. For participants taking HU, the dose in mg/kg must be stable for at least 90 days prior to signing the informed consent form (ICF) and with no anticipated need for dose adjustments during the study, in the opinion of the Investigator. 6. Participants, who if female and of child-bearing potential, agree to use highly effective methods of contraception or practicing abstinence from study start to 30 days after the last dose of study drug, and who if male, agree to use barrier methods of contraception or practice abstinence from study start to 30 days after the last dose of study drug 7. Participant has provided documented informed consent
Exclusion criteria
1. More than 10 VOCs within 12 months of screening that required a hospital, emergency room, or clinic visit 2. Female participant who is breast feeding or pregnant 3. Receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) or have received an RBC transfusion for any reason within 60 days of signing the ICF or at any time during the Screening Period 4. Hospitalized for sickle cell crisis or other vaso-occlusive event within 30 days prior to dosing (ie, a vaso-occlusive event cannot be within 30 days prior to dosing) 5. Screening laboratory test of alanine aminotransferase (ALT) \> 4 × upper level of normal (ULN) 6. Clinically significant bacterial, fungal, parasitic, or viral infection which requires therapy, including acute bacterial infection requiring antibiotics 7. Known to be COVID-19 positive from within 3 weeks of screening through Day 1 8. Participants with active hepatitis A, B, or C or who are known to be human immunodeficiency virus (HIV) positive 9. Severe renal dysfunction (estimated glomerular filtration rate \< 30 mL/min/1.73 m2 at the Screening visit; calculated by the local laboratory to assess safety) or is on chronic dialysis 10. History of malignancy within the past 2 years prior to treatment Day 1 requiring chemotherapy and/or radiation (with the exception of local therapy for non-melanoma skin malignancy) 11. History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to the following: 1. Unstable angina pectoris or myocardial infarction or elective coronary intervention 2. Congestive heart failure requiring hospitalization 3. Uncontrolled clinically significant arrhythmias 4. Pulmonary hypertension 12. Criteria related to ECG parameters: 1. PR interval \> 220 msec in any participant 2. QRS interval \> 120 msec or QT interval corrected using Fridericia's formula (QTcF) \> 480 msec (both genders) in participants without bundle branch block 3. QRS interval \> 120 msec in participants with newly (within 3 months) emerged bundle branch block 4. A participant with stable bundle branch block with or without stable cardiac disease may be enrolled; QRS interval \> 120 msec and QTcF interval \> 480 msec are acceptable in these participants. 13. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable) 14. Participated in another clinical trial of an investigational agent or medical device within 30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently participating in another trial of an investigational agent or medical device 15. Inadequate venous access as determined by the Investigator/site staff 16. Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may preclude safe participation, confound study interpretation, interfere with compliance, or preclude informed consent 17. Received erythropoietin or other hematopoietic growth factor treatment within 28 days of signing ICF or is anticipated to require such agents during the study 18. Ongoing or recent (within 2 years) substance abuse 19. Known allergy to voxelotor 20. Use of herbal medications (eg, St. John's Wort), sensitive cytochrome P450 (CYP) 3A4 substrates with a narrow therapeutic index, strong CYP3A4 inhibitors, fluconazole, or moderate or strong CYP3A4 inducers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent Adverse Events (AEs) | approximately 300 days | Treatment emergent AEs including SAEs |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Abnormalities in Hb, Unconjugated Bilirubin, % Reticulocyte, Absolute Reticulocyte, and Lactate Dehydrogenase [LDH] | approximately 200 days | — |
| Number of Participants With an Hb Increase > 1 g/dL Compared to Baseline | approximately 200 days | Participants with an Hb increase \> 1 g/dL compared to Baseline. |
| Incidence Rate of VOCs | approximately 200 days | Incidence rate of vaso-occlusive crisis |
Countries
United Kingdom
Participant flow
Recruitment details
Each individual was provided with oral and written information describing the nature, purpose and duration of the study, participation/termination conditions, and risks and benefits. Prior to initiation of any study-related procedures, subjects signed and dated the ICF to participate in the study.
Pre-assignment details
All patients completed the following study procedures prior to a confirmation of eligibility: Signed Informed Consent Form, Review inclusion/exclusion criteria, Medication and Medical History, Height/Weight/ BMI, Vital signs, ECG (12-lead) in triplicate, Physical examination, Serum pregnancy test (females of child-bearing potential only) and so on.
Participants by arm
| Arm | Count |
|---|---|
| Open Label Participants will receive progressively higher doses of voxelotor administration starting from 1500 mg Voxelotor: synthetic small molecule supplied as 500 mg tablets | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Open Label |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age, Continuous | 32 Years |
| Body Mass Index (BMI) | 22 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height | 171 cm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment United Kingdom | 6 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 3 Participants |
| Weight | 66.45 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 4 | 0 / 3 | 0 / 1 |
| other Total, other adverse events | 6 / 6 | 4 / 4 | 2 / 3 | 1 / 1 |
| serious Total, serious adverse events | 4 / 6 | 0 / 4 | 1 / 3 | 0 / 1 |
Outcome results
Primary
Treatment-emergent Adverse Events (AEs)
Treatment emergent AEs including SAEs
Time frame: approximately 300 days
Population: Subjects treated with at least one dose of voxelotor
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Voxelotor 1500 mg | Treatment-emergent Adverse Events (AEs) | Sickle cell disease (SCD) related TEAE | 5 Participants |
| Voxelotor 1500 mg | Treatment-emergent Adverse Events (AEs) | Non-SCD related TEAE | 6 Participants |
| Voxelotor 2000 mg | Treatment-emergent Adverse Events (AEs) | Non-SCD related TEAE | 4 Participants |
| Voxelotor 2000 mg | Treatment-emergent Adverse Events (AEs) | Sickle cell disease (SCD) related TEAE | 1 Participants |
| Voxelotor 2500 mg | Treatment-emergent Adverse Events (AEs) | Sickle cell disease (SCD) related TEAE | 1 Participants |
| Voxelotor 2500 mg | Treatment-emergent Adverse Events (AEs) | Non-SCD related TEAE | 2 Participants |
| Voxelotor 3000 mg | Treatment-emergent Adverse Events (AEs) | Sickle cell disease (SCD) related TEAE | 0 Participants |
| Voxelotor 3000 mg | Treatment-emergent Adverse Events (AEs) | Non-SCD related TEAE | 1 Participants |
Secondary
Incidence Rate of VOCs
Incidence rate of vaso-occlusive crisis
Time frame: approximately 200 days
Population: Subjects treated with at least one dose of Voxelotor
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Voxelotor 1500 mg | Incidence Rate of VOCs | 0 Participants |
Secondary
Number of Participants With an Hb Increase > 1 g/dL Compared to Baseline
Participants with an Hb increase \> 1 g/dL compared to Baseline.
Time frame: approximately 200 days
Population: Subjects treated with at least one dose of Voxelotor
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Voxelotor 1500 mg | Number of Participants With an Hb Increase > 1 g/dL Compared to Baseline | 0 Participants |
Secondary
Number of Participants With Clinically Significant Abnormalities in Hb, Unconjugated Bilirubin, % Reticulocyte, Absolute Reticulocyte, and Lactate Dehydrogenase [LDH]
Time frame: approximately 200 days
Population: Subjects treated with at least one dose of Voxelotor
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Voxelotor 1500 mg | Number of Participants With Clinically Significant Abnormalities in Hb, Unconjugated Bilirubin, % Reticulocyte, Absolute Reticulocyte, and Lactate Dehydrogenase [LDH] | 0 Participants |
| Voxelotor 2000 mg | Number of Participants With Clinically Significant Abnormalities in Hb, Unconjugated Bilirubin, % Reticulocyte, Absolute Reticulocyte, and Lactate Dehydrogenase [LDH] | 0 Participants |
| Voxelotor 2500 mg | Number of Participants With Clinically Significant Abnormalities in Hb, Unconjugated Bilirubin, % Reticulocyte, Absolute Reticulocyte, and Lactate Dehydrogenase [LDH] | 0 Participants |
| Voxelotor 3000 mg | Number of Participants With Clinically Significant Abnormalities in Hb, Unconjugated Bilirubin, % Reticulocyte, Absolute Reticulocyte, and Lactate Dehydrogenase [LDH] | 0 Participants |