Primary ObjectiveThe primary objective is to assess the effect of vexelotor compared to placebo on improvement in hemoglobinSecondary ObjectivesThe secondary objectives are t o evaluate the effects of voxelotor compared to placebo on : - Clinical…
ID
Source
Brief title
Condition
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy measure is Hb response., defined as increase of Hb
from baseline by > 1 g/dL at 24 weeks. Hb at 24 weeks is determined by
the average value of Hb levels at Week 20 and Week 24.
Secondary outcome
The secondary efficacy endpoints are as follows:
· Change from baseline in hemoglobin at Week 24
· Change and percent change from baseline in hemolysis measures,
including unconjugated bilirubin, absolute reticulocyte, reticulocytes %,
and LDH at Week 24
· Incidence of severe anemic episodes (Hb < 5.5 g/dL)
· Annualized incidence rate of VOC
Background summary
Sickle cell disease (SCD) is an inherited disorder caused by a point mutation
in the
*-globin gene leading to formation of sickle hemoglobin (HbS). SCD
predominantly occurs in
individuals whose ancestors originated from sub-Saharan Africa, Spanish
speaking regions of the
Western Hemisphere (South America, Caribbean, and Central America); Saudi
Arabia; India; and Mediterranean countries including Turkey, Greece, and Italy.
SCD is the most common single gene disorder in African Americans. A primary and
obligatory event in the molecular pathogenesis of SCD is the polymerisation of
deoxygenated HbS and the resultant sickling of red blood cells (RBCs). SCD is
characterized by hemolytic anemia and vaso-occlusion leading to progressive
end-organ damage with a clinical course of life-long pain, disability, and
early death.
Management strategies for SCD have evolved very slowly, and treatment of SCD
remains a serious unmet medical need. Hydroxyurea (HU) is the only approved
therapy for SCD and is indicated to reduce the frequency of painful crisis
requiring visiting a medical facility, although it has a minimal effect on the
severe burden of daily pain. HU is limited by its side effect profile, poor
patient adherence, variable patient responses, and concerns of long-term
toxicity. In addition to HU treatment, blood transfusions are used in this
patient population to alleviate symptomatic anemia and to prevent certain SCD
complications (especially cerebrovascular complications). Attaining
anti-sickling activity by blood transfusions has its own limitations: the
treatments are expensive, not uniformly accessible and accompanied by risks.
The only curative
treatment is bone marrow transplantation from a histocompatible donor, an
option that has been available since the 1990s , but bone marrow
transplantation carries significant risks and is associated with a ~5%
mortality rate. Despite the current standard of care, including HU, blood
transfusion, and palliative therapy for acute attacks, patients with SCD
continue to suffer serious morbidity and premature mortality.
To date, no drugs have been approved that specifically and directly target HbS
polymerization, the underlying mechanism of SCD. There is a significant unmet
need in SCD for new mechanism based, preventive, and potentially
disease-modifying therapies.
Because oxyhemoglobin is a potent inhibitor of HbS, allosteric modification of
Hb to increase the proportion of oxyhemoglobin is a promising strategy to
achieve inhibition of HbS in all RBCs. Prior experimental drugs and approaches
(discontinued due to poor pharmaceutical
properties or off-target toxicity) have provided proof of concept for the Hb
modification approach by demonstrating an increase in oxyhemoglobin, a decrease
in clinical biomarkers of hemolysis, and an improvement in incidence of
vaso-occlusive crisis (VOC). Global Blood Therapeutics (GBT) has developed
GBT440, a small molecule allosteric modulator of Hb oxygen affinity, for the
treatment of SCD. GBT440 is administered orally. Data from the GBT440-001 Phase
1/2 study has confirmed that GBT440 treatment in SCD subjects for up to 90 days
results in increased Hb oxygen affinity, rapid and sustained improvement in
clinical measures of hemolysis consistent with an inhibition of HbS
polymerization, and acceptable safety and tolerability when dosed in the target
range of 20 to 30% Hb modification. Analysis and modeling of the exposure
response relationship from Study GBT440-001 allows for the selection of doses
of GBT440 to be studied in Phase 3, which will maintain approximately 20% to
30% Hb modification (with a higher dose achieving this target in a greater
proportion of subjects).
Study objective
Primary Objective
The primary objective is to assess the effect of vexelotor compared to placebo
on improvement in hemoglobin
Secondary Objectives
The secondary objectives are t o evaluate the effects of voxelotor compared to
placebo on :
- Clinical measures of hemolysis
- Long term VOC incidence
Exploratory objectives
The exploratory objectives are to evaluate the effects of voxelotor compared to
placebo on:
- Sickle Cell Disease Severity Measure (SCDSM)
- EuroQol EQ-5D-5L health questionnaire (EQ-5D-DLTM)
- Clinical Global Impression of Change (CGIC)- Groups 1 and 2 only
- Incidence and time to first RBC transfusion and post baseline onset of VOC
- School and/or work attendance and the use of opiod during the treatment
period as recorded via eDiary
- Measures related to SCD pathophysiology and their utility as pharmacodynamic
markers to evaluate including inflammatory biomarkers (Part1 only), kidney
function and RBC rheology
- Measures predictive of response to voxelotor
Safety Objectives
The safety objectives are to assess the safety of voxelotor compared to placebo
based on AEs, clinical laboratory tests, physical examinations, and other
clinical measures (eg, discontinuations due to AEs, dose reductions).
Pharmacokinetic Objective
The PK objective is to assess the PK of voxelotor as evaluated by population PK
analysis.
Study design
This study is a randomized, placebo-controlled, double blind, parallel group,
multicenter study of participants, age 12 to 65 years, with SCD (HbSS or HbS*0
thal)
conducted in three groups of study participants, Groups 1, 2, and 3. The key
purposes
for each group are:
Group 1:
* Dose selection: different GBT440 doses for further study.
* Final definition of endpoints for patient reported outcomes measure for the
Main Population Analysis
* Electronic patient reported outcomes (ePRO) qualification for the Main
Population Analysis
Group 2:
* To allow for a seamless transition from Group 1 to Group 3 by continuing
enrollment and data collection in the study during the Group 1 treatment
period and data analysis (referred to as Group 1 Analysis).
Group 3:
* Establish efficacy and safety of GBT440 at the selected dose. The final data
analysis set ( referred to as the Main Population) will include
* Group 2 participants
* Assigned to placebo
* Assigned to the selected dose and
* All Group 3 participants.
Intervention
Participants receiving 1500 mg GBT440 will receive five 300 mg capsules or
tablets, administered orally, once daily; participants receiving 900 mg GBT440
will receive three 300 mg capsules or tablets, and 2 placebo capsules or
tablets administered orally, once daily. Participants randomized to placebo
will receive 5 placebo capsules or tablets administered orally, once daily.
Study drug may be taken with or without
food. Participants in Group 1 must take their study drug in the mornings and
must avoid high fat meals for 4 hours before and 4 hours after taking study
drug. Group 2 and Group 3 participants may take study drug in the morning or
evening, preferably at same time each day throughout the study ( Group 2 and
Group 3 participants have no food restrictions/requirements).
Study burden and risks
The emerging clinical experience indicates that GBT440 is safe and well
tolerated over a wide range of doses and is anticipated to have favorable
benefit-to-risk profile in this proposed study in subjects with SCD. This
experience is derived from 11 clinical studies: Phase 1/2 study in healthy
subjects and subjects with SCD (GBT440-001), Phase 2a study in pediatrics
(GBT440-007), the extension study (GBT440-024) and 8 clinical pharmacology
studies (GBT440-002, GBT440-003, GBT440-004, GBT440-005, GBT440-008,
GBT440-017, GBT440-018, and GBT440-019). As of 30 September 2016, a total of
205 healthy subjects 47 adult subjects with SCD and 7 pediatric subjects with
SCD had been treated with single and multiple doses of GBT440 across all 11
studies. In the multiple dose studies, the most common AEs have been headache,
back pain, pain, diarrhea, fatigue, cough, rash, and sickle cell anemia with
crisis, which were mainly Grade 1 or Grade 2 in severity, and most of which
resolved without treatment and are easily monitored. The most common
treatment-related AE (as assessed by the Investigator) that occurred in
subjects with SCD was Grade 1 or 2 headache (28% GBT440 and 36% placebo). In
SCD subjects, all serious and severe (Grade 3) AEs have been deemed not related
to study drug and are consistent with common clinical events in this patient
population. There has been no evidence of mechanism-related toxicity (tissue
hypoxia) as indicated by clinical observations, vital signs, ECGs, hematologic
changes or cardiopulmonary exercise testing. The PK are dose proportional, with
evidence of high GBT440 selectivity for Hb, as evidenced by a high RBC: plasma
drug ratio. GBT440 resulted in a large and sustained reduction in clinical
measures of hemolysis and an improvement in anemia.
The treatment response result from GBT440-001 are consistent with inhibition of
HbS polymerization leading to decreased RBC damage, improved RBC lifespan, and
improvement in inflammation and tissue oxygen delivery.
Overall, the safety and treatment response data to date support further
investigation of GBT440 as a potential disease-modifying therapy for SCD.
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Age
Inclusion criteria
1. Male or female study participants with Sickle Cell Disease:
* Documentation of SCD genotype (HbSS, HbSC, HbS* thalassemia or
other sickle cell syndrome variants) may be based on history of laboratory testing or must be confirmed by laboratory testing during screening
2. Participants have had at least 1 episode of VOC in the past 12 months.
For study eligibility, VOC is defined as a previously documented episode of ACS or acute painful crisis (for which there was no explanation other than VOC) which required prescription or healthcare professionalinstructed use of analgesics for moderate to severe pain (documentation
must exist in the patient medical record prior to Screening)
3. Age 12 to 65 years
4. Hemoglobin (Hb) *6.0 and *10.5 g/dL during screening
5. Absolute reticulocyte count and % reticulocyte count must be >1.5 × ULN during Screening
6. For participants taking hydroxyurea (HU), the dose of HU (mg/kg) must be stable for at least 3 months prior to signing the ICF and with no anticipated need for dose adjustments during the study, in the opinion of the Investigator
7. Participants must demonstrate 75% compliance with ePRO measure completion to be enrolled (participants will be given an ePRO device for at least 28 days during Screening; participants who are 60 to 74% compliant can re-screen once with Investigator approval; re-screening is
not allowed for participants who are <60% compliant) 8. Participants, who if female and of child bearing potential, are using highly effective methods of contraception from study start to 3 months
after the last dose of study drug, and who if male are willing to use barrier methods of contraception, from study start to 3 months after the last dose of study drug
9. Participant has provided documented informed consent or assent (the informed consent form [ICF] must be reviewed and signed by each participant; in the case of pediatric participants, both the consent of the participant's legal representative or legal guardian, and the participant's
assent must be obtained)
Exclusion criteria
1. More than 10 VOCs within the past 12 months that required a hospital,
emergency room or clinic visit
2. Female who is breast feeding or pregnant
3. Patients who are receiving regularly scheduled blood (RBC)
transfusion therapy (also termed chronic, prophylactic, or preventive
transfusion) or have received a RBC transfusion for any reason within 28
days of signing the ICF 4. Hospitalized for sickle cell crisis or other vaso-occlusive event within
14 days of signing the ICF (i.e., a vaso-occlusive event cannot be within 14 days prior to ICF)
5. Hepatic dysfunction characterized by alanine aminotransferase (ALT) >4 × ULN
6. Participants with clinically significant bacterial, fungal, parasitic or viral infection which require therapy:
* Participants with acute bacterial infection requiring antibiotic use
should delay screening/enrollment until the course of antibiotic therapy has been completed.
* Participants with known active hepatitis A, B, or C or who are known to be human immunodeficiency virus (HIV) positive 7. Severe renal dysfunction (estimated glomerular filtration rate at the Screening visit; calculated by the central laboratory) <30mL/min/1.732
or on chronic dialysis
8. 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)
9. History of unstable or deteriorating cardiac or pulmonary disease
within 6 months prior to consent including but not limited to the following:
* Unstable angina pectoris or myocardial infarction or elective coronary intervention
* Congestive heart failure requiring hospitalization
* Uncontrolled clinically significant arrhythmias
10. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable)
11. 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)
12. Inadequate venous access as determined by the Investigator/site staff
13. Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may confound study interpretation, interfere with compliance, or preclude informed consent
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-003370-40-NL |
| ClinicalTrials.gov | NCT03036813 |
| CCMO | NL60453.018.17 |