Dose Escalation Study to Evaluate the Safety, Tolerability, PK and PD of Voxelotor in Patients With SCD

• ClinicalTrials.gov Identifier: NCT04247594
• Recruitment Status: Terminated
• First Posted: January 30, 2020
• Last Update Posted: September 1, 2022
• Sponsor: Global Blood Therapeutics
• Information provided by (Responsible Party): Global Blood Therapeutics

Tracking Information

• First Submitted Date: January 21, 2020
• First Posted Date: January 30, 2020
• Last Update Posted Date: September 1, 2022
• Actual Study Start Date: January 9, 2020
• Actual Primary Completion Date: June 8, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 29, 2020)

Treatment-emergent AEs [ Time Frame: approximately 200 days ]

Treatment emergent AEs including SAEs

Original Primary Outcome Measures (submitted: January 28, 2020)

Treatment-emergent adverse events [ Time Frame: approximately 200 days ]

Treatment emergent AEs including SAEs

Current Secondary Outcome Measures (submitted: August 29, 2022)

• Change in Hb and clinical measures of hemolysis (unconjugated bilirubin, % reticulocyte, absolute reticulocyte, and lactate dehydrogenase [LDH]) from Baseline [ Time Frame: approximately 200 days ]
  Change in Hb
• Proportion of participants with an Hb increase > 1 g/dL compared to Baseline [ Time Frame: approximately 200 days ]
  participants with an Hb increase > 1 g/dL compared to Baseline
• Incidence rate of VOCs [ Time Frame: approximately 200 days ]

Original Secondary Outcome Measures (submitted: January 28, 2020)

• Change in Hb and clinical measures of hemolysis (unconjugated bilirubin, % reticulocyte, absolute reticulocyte, and lactate dehydrogenase [LDH]) from Baseline [ Time Frame: approximately 200 days ]
  Change in Hb
• Proportion of participants with an Hb increase > 1 g/dL compared to Baseline [ Time Frame: approximately 200 days ]
  participants with an Hb increase > 1 g/dL compared to Baseline

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Dose Escalation Study to Evaluate the Safety, Tolerability, PK and PD of Voxelotor in Patients With SCD
• Official Title: A Phase 2, Open Label, Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Voxelotor in Patients With Sickle Cell Disease
• 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
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Sickle Cell Disease

Intervention

Drug: Voxelotor

synthetic small molecule supplied as 500 mg tablets

Study Arms

Experimental: Cohort A open label

Participants will receive progressively higher doses of voxelotor administration starting from 1500 mg

Intervention: Drug: Voxelotor

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: August 29, 2022): 6
• Original Estimated Enrollment (submitted: January 28, 2020): 45
• Actual Study Completion Date: June 8, 2021
• Actual Primary Completion Date: June 8, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT04247594
• Other Study ID Numbers: GBT440-029
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Global Blood Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Global Blood Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Global Blood Therapeutics
• Verification Date: August 2022