Immune Thrombocytopenia
Conditions
Brief summary
Study in patients with persistent and chronic Immune Thrombocytopenia (ITP), who have failed to respond or relapsed after prior therapy, with a platelet count \<30,000/µL. Patient will be randomly assigned in 2 groups with two dose levels of SKI-O-703 200mg BID, 400 mg BID, and placebo; administered orally twice a day.
Detailed description
This study will evaluate the efficacy, safety, tolerability,pharmacokinetics (PK), and pharmacodynamics (PD) of select (200 mg BID and 400 mg BID) doses of SKI-O-703 in persistent and chronic ITP patients who have failed to respond or relapsed after prior therapy, with a platelet count \<30,000/µL. on 2 occasions at least 7 days apart with the confirmatory count on the first day of treatment. subjects will participate in 3 treatment groups (24 subjects in each of the active treatment groups and 12 subjects in the placebo group). The total study duration will be 20 weeks per subject, which consists of up to 4 weeks of screening period, 12 weeks of treatment period, and 4 weeks of follow-up period.
Interventions
DRUGSKI-O-703
The SKI-O-703 capsules will contain 100 mg of drug substance.
DRUGPlacebo oral tablet
Placebo capsules are filled with microcrystalline cellulose.
Sponsors
Oscotec Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of primary ITP (persistent or chronic) * Failed to respond or relapsed after at least 1 prior therapy, with a platelet count of \<30,000/µL on 2 occasions at least 7 days apart with the confirmatory count on the first day of treatment * Adequate hematologic, hepatic, and renal function * ECOG performance status of 0, 1, or 2 * Male and female subjects, the subject and their partners of childbearing potential agree to use medically acceptable methods of contraception during the study and for 6 months following discontinuation of study drug (excluding women who are not of childbearing potential and men who have been sterilized. Men who have been sterilized should be confirmed to have negative sperm count on 2 consecutive occasions.) * Male subjects agree not to donate sperm for 90 days after the last dose of study drug * Female subjects have negative pregnancy tests at Screening.
Exclusion criteria
* History of current, active malignancy requiring or likely to require chemotherapeutic or surgical treatment during the study, with the exception of non-melanoma skin cancer, carcinoma in situ of the cervix, and localized prostate cancer managed by active surveillance * Transfusion with blood or blood products or plasmapheresis within 2 weeks before the first administration of study drug * History of known inherited coagulopathy, or recent arterial or deep venous thrombosis within the preceding 6 months * Change in corticosteroid or immunosuppressant dose within 2 weeks prior to Day 1 * Treatment with thrombopoietin receptor agonists within 2 weeks before Day 1 * Treatment with rituximab or splenectomy within the 8 weeks prior to Day 1 * Treatment with intravenous immunoglobulins (IVIGs) within 4 weeks prior to Day 1 * Acute infection requiring oral antibiotics within 2 weeks * Infections requiring intravenous antibiotics or hospitalization within 3 months * Positive test results at Screening for human immunodeficiency virus, hepatitis B surface antigen, or hepatitis C virus antibody or positive result for hepatitis B core antibody with a negative result for hepatitis B surface antigen * Received live vaccine within 28 days prior to Day 1 or plan to receive one during the study * History or presence of any gastrointestinal, hepatic, or renal disease or any other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs * Uncontrolled hypertension * Subject had 12-lead electrocardiogram (ECG) findings of corrected QT interval by Fridericia formula (QTcF) \> 450 msec (males) or \> 470 msec (females), cardiac arrhythmias, or clinically significant cardiac or ECG abnormalities * Subject received any investigational medication within 30 days or 5 half-lives - Concomitant use of any anticoagulants and platelet aggregation inhibiting drugs including aspirin (within 14 days of planned dosing through end of follow-up) * Female subject who is currently pregnant or breastfeeding * Prior treatment with a SYK inhibitor * Planned surgery in the time frame of the dosing period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Response | Up to week 12 | Platelet count \>= 30,000/µL and doubling the baseline (average of 2 previous counts) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With 12-lead Electrocardiogram (ECG) Abnormalities | Up to week 16 | 12-lead electrocardiogram (ECG) abnormalities that were recorded as adverse events |
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | Up to week 16 | The number of participants with Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs leading to Discontinuation each. |
| Number of Participants With Physical Examination Abnormalities | Up to week 16 | Physical examination abnormalities that were recorded as adverse events |
| Number of Participants With Vital Sign Abnormalities | Up to week 16 | Vital sign measurements considered to be clinically significant in the medical and scientific judgement of the investigator are recorded as AEs. |
| Consecutive Increased Platelet Counts (≥2 Consecutive PLT ≥ 30,000/µL) | Up to week 12 | Proportion of participants achieving two or more consecutive platelet counts of ≥ 30,000/μL separated by at least 5 days and without the use of rescue medication |
| Consecutive Increased Platelet Counts (≥2 Consecutive PLT ≥ 50,000/µL) | Up to week 12 | Proportion of participants achieving two or more consecutive platelet counts of ≥ 50,000/μL separated by at least 5 days and without the use of rescue medication |
| Quality of Life Score | Up to week 16 | Qualtiy of Life as measured by the Short Form Questionnaire (SF-36) consists of eight health domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health. Scale scores range 0-100 scores (theoritically), with higher scores indicating better health. Each health domain score contributes to the Physical Component Summary(PCS) and Mental Component Summary(MCS) scores. Both PCS and MCS are summary scores that are calculated using associated factor weights for the respective summary score applied to all eight scales. For overall ranges for PCS and MCS (no theoretical full range available), the SF-36 verion 2 utilizes norm-based scoring involving a linear T-score transformation method so that scores for each of the health domain and component summary measures have a mean of 50 and a standard deviation of 10, based on 2009 U.S. general population. Scores above and below 50 are above and velow the average. |
Countries
Greece, Poland, South Korea, Spain, United States
Participant flow
Recruitment details
A total of 61 subjects were randomly assigned to receive the study drugs, of whom 60 subjects were included in the ITT set and the safety set each. Note: 1 subject was randomly assigned to the 400 mg BID group but did not receive any dose of study drug as the subject was withdrawn due to noncompliance with the protocol.
Participants by arm
| Arm | Count |
|---|---|
| SKI-O-703 200 mg BID 2 capsules of 100 mg SKI-O-703 BID (twice per day) | 26 |
| SKI-O-703 400 mg BID 4 capsules of 100 mg SKI-O-703 BID (twice per day) | 22 |
| Placebo 4 capsules of placebo BID (twice per day) | 12 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | SKI-O-703 200 mg BID | Total | SKI-O-703 400 mg BID |
|---|---|---|---|---|
| Age, Continuous | 61.1 years STANDARD_DEVIATION 22.24 | 56.5 years STANDARD_DEVIATION 14.98 | 56.6 years STANDARD_DEVIATION 16.97 | 54.3 years STANDARD_DEVIATION 16.3 |
| Baseline platelet count | 9.6 cells*10^9/L STANDARD_DEVIATION 7.22 | 10.6 cells*10^9/L STANDARD_DEVIATION 6.69 | 10.7 cells*10^9/L STANDARD_DEVIATION 7.32 | 11.5 cells*10^9/L STANDARD_DEVIATION 8.28 |
| Baseline platelet count category, n (%) <15,000/μL | 8 Participants | 19 Participants | 41 Participants | 14 Participants |
| Baseline platelet count category, n (%) 15,000/μL-30,000/μL | 4 Participants | 7 Participants | 19 Participants | 8 Participants |
| Number of previous lines of therapy category, n (%) 0-2 | 4 Participants | 9 Participants | 19 Participants | 6 Participants |
| Number of previous lines of therapy category, n (%) ≥3 | 8 Participants | 17 Participants | 41 Participants | 16 Participants |
| Previous splenectomy, n (%) No | 12 Participants | 20 Participants | 49 Participants | 17 Participants |
| Previous splenectomy, n (%) Yes | 0 Participants | 6 Participants | 11 Participants | 5 Participants |
| Race/Ethnicity, Customized Ethnicity, n(%) Hispanic or Latino | 1 Participants | 2 Participants | 5 Participants | 2 Participants |
| Race/Ethnicity, Customized Ethnicity, n(%) Not Hispanic or Latino | 11 Participants | 24 Participants | 55 Participants | 20 Participants |
| Race/Ethnicity, Customized Race, n(%) Asian | 1 Participants | 4 Participants | 13 Participants | 8 Participants |
| Race/Ethnicity, Customized Race, n(%) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race, n(%) White | 11 Participants | 22 Participants | 46 Participants | 13 Participants |
| Response to previous treatment, n (%) Non-responder | 9 Participants | 12 Participants | 38 Participants | 17 Participants |
| Response to previous treatment, n (%) Relapsed | 10 Participants | 21 Participants | 49 Participants | 18 Participants |
| Sex: Female, Male Female | 5 Participants | 13 Participants | 34 Participants | 16 Participants |
| Sex: Female, Male Male | 7 Participants | 13 Participants | 26 Participants | 6 Participants |
| TPO-receptor agonist use, n (%) No | 5 Participants | 13 Participants | 25 Participants | 7 Participants |
| TPO-receptor agonist use, n (%) Yes | 7 Participants | 13 Participants | 35 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 22 | 0 / 12 |
| other Total, other adverse events | 15 / 26 | 17 / 22 | 8 / 12 |
| serious Total, serious adverse events | 0 / 26 | 2 / 22 | 3 / 12 |
Outcome results
Primary
Platelet Response
Platelet count \>= 30,000/µL and doubling the baseline (average of 2 previous counts)
Time frame: Up to week 12
Population: ITT Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SKI-O-703 200 mg BID | Platelet Response | 12 Participants |
| SKI-O-703 400 mg BID | Platelet Response | 14 Participants |
| Placebo | Platelet Response | 4 Participants |
Secondary
Consecutive Increased Platelet Counts (≥2 Consecutive PLT ≥ 30,000/µL)
Proportion of participants achieving two or more consecutive platelet counts of ≥ 30,000/μL separated by at least 5 days and without the use of rescue medication
Time frame: Up to week 12
Population: ITT Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SKI-O-703 200 mg BID | Consecutive Increased Platelet Counts (≥2 Consecutive PLT ≥ 30,000/µL) | 10 Participants |
| SKI-O-703 400 mg BID | Consecutive Increased Platelet Counts (≥2 Consecutive PLT ≥ 30,000/µL) | 11 Participants |
| Placebo | Consecutive Increased Platelet Counts (≥2 Consecutive PLT ≥ 30,000/µL) | 1 Participants |
Secondary
Consecutive Increased Platelet Counts (≥2 Consecutive PLT ≥ 50,000/µL)
Proportion of participants achieving two or more consecutive platelet counts of ≥ 50,000/μL separated by at least 5 days and without the use of rescue medication
Time frame: Up to week 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SKI-O-703 200 mg BID | Consecutive Increased Platelet Counts (≥2 Consecutive PLT ≥ 50,000/µL) | 5 Participants |
| SKI-O-703 400 mg BID | Consecutive Increased Platelet Counts (≥2 Consecutive PLT ≥ 50,000/µL) | 9 Participants |
| Placebo | Consecutive Increased Platelet Counts (≥2 Consecutive PLT ≥ 50,000/µL) | 1 Participants |
Secondary
Number of Participants With 12-lead Electrocardiogram (ECG) Abnormalities
12-lead electrocardiogram (ECG) abnormalities that were recorded as adverse events
Time frame: Up to week 16
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SKI-O-703 200 mg BID | Number of Participants With 12-lead Electrocardiogram (ECG) Abnormalities | 0 Participants |
| SKI-O-703 400 mg BID | Number of Participants With 12-lead Electrocardiogram (ECG) Abnormalities | 0 Participants |
| Placebo | Number of Participants With 12-lead Electrocardiogram (ECG) Abnormalities | 0 Participants |
Secondary
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation
The number of participants with Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs leading to Discontinuation each.
Time frame: Up to week 16
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SKI-O-703 200 mg BID | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | Serious Adverse Events (SAEs) | 0 Participants |
| SKI-O-703 200 mg BID | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | Adverse Events (AEs) | 15 Participants |
| SKI-O-703 200 mg BID | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | AEs leading to Discontinuation | 2 Participants |
| SKI-O-703 400 mg BID | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | Serious Adverse Events (SAEs) | 2 Participants |
| SKI-O-703 400 mg BID | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | Adverse Events (AEs) | 17 Participants |
| SKI-O-703 400 mg BID | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | AEs leading to Discontinuation | 0 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | Adverse Events (AEs) | 8 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | AEs leading to Discontinuation | 1 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation | Serious Adverse Events (SAEs) | 3 Participants |
Secondary
Number of Participants With Physical Examination Abnormalities
Physical examination abnormalities that were recorded as adverse events
Time frame: Up to week 16
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SKI-O-703 200 mg BID | Number of Participants With Physical Examination Abnormalities | 4 Participants |
| SKI-O-703 400 mg BID | Number of Participants With Physical Examination Abnormalities | 4 Participants |
| Placebo | Number of Participants With Physical Examination Abnormalities | 3 Participants |
Secondary
Number of Participants With Vital Sign Abnormalities
Vital sign measurements considered to be clinically significant in the medical and scientific judgement of the investigator are recorded as AEs.
Time frame: Up to week 16
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SKI-O-703 200 mg BID | Number of Participants With Vital Sign Abnormalities | 1 Participants |
| SKI-O-703 400 mg BID | Number of Participants With Vital Sign Abnormalities | 2 Participants |
| Placebo | Number of Participants With Vital Sign Abnormalities | 0 Participants |
Secondary
Quality of Life Score
Qualtiy of Life as measured by the Short Form Questionnaire (SF-36) consists of eight health domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health. Scale scores range 0-100 scores (theoritically), with higher scores indicating better health. Each health domain score contributes to the Physical Component Summary(PCS) and Mental Component Summary(MCS) scores. Both PCS and MCS are summary scores that are calculated using associated factor weights for the respective summary score applied to all eight scales. For overall ranges for PCS and MCS (no theoretical full range available), the SF-36 verion 2 utilizes norm-based scoring involving a linear T-score transformation method so that scores for each of the health domain and component summary measures have a mean of 50 and a standard deviation of 10, based on 2009 U.S. general population. Scores above and below 50 are above and velow the average.
Time frame: Up to week 16
Population: Safety set defined as all subjects who received at least 1 dose of study drug (SKI-O-703 or placebo).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SKI-O-703 200 mg BID | Quality of Life Score | Physical component summary(Change from baseline) | 0.772 score on a scale | Standard Deviation 5.764 |
| SKI-O-703 200 mg BID | Quality of Life Score | Mental component summary(Change from baseline) | 4.913 score on a scale | Standard Deviation 11.1022 |
| SKI-O-703 400 mg BID | Quality of Life Score | Physical component summary(Change from baseline) | 0.556 score on a scale | Standard Deviation 6.4798 |
| SKI-O-703 400 mg BID | Quality of Life Score | Mental component summary(Change from baseline) | -0.930 score on a scale | Standard Deviation 8.9426 |
| Placebo | Quality of Life Score | Physical component summary(Change from baseline) | 1.338 score on a scale | Standard Deviation 5.4218 |
| Placebo | Quality of Life Score | Mental component summary(Change from baseline) | 1.643 score on a scale | Standard Deviation 10.4183 |
Post Hoc
Bleeding Score
The ITP Bleeding Scale(IBLS) is an immune thrombocytopenic purpura(ITP)-specific bleeding score. The IBLS comprises of 11 site-specific grades, assessed at 9 anatomical sites by history(Hx). In addition, two of these sites, skin and oral, were also assessed by physical examination(PE). These 11 grades include: skin (PE), skin(Hx), oral(PE), oral(Hx), epistaxis, gastrointestinal, urinary, gynecological, pulmonary, intracranial hemorrhage, and subconjunctival hemorrhage, and ranged from Grade 0 (none) to Grade 2 (marked bleeding). The grade of IBLS was transformed from categorical type to numerical type (Grade 0 to 0, Grade 1 to 1, Grade 2 to 2, and 0 being better and 2 being worst). Each subject sumed up the transformed scores across all 11 sites per visit assessment. The total overall score ranges from 0-22 with the higher score indicating worst outcome.
Time frame: Up to week 16
Population: The overall number analyzed is different each visit as patients were dropped.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SKI-O-703 200 mg BID | Bleeding Score | Week 5 | 0.84 score on a scale | Standard Deviation 2.249 |
| SKI-O-703 200 mg BID | Bleeding Score | Week 12 | 1.21 score on a scale | Standard Deviation 4.283 |
| SKI-O-703 200 mg BID | Bleeding Score | Week 1 Day 1 | 2.15 score on a scale | Standard Deviation 2.908 |
| SKI-O-703 200 mg BID | Bleeding Score | End of Study(week 16) | 0.42 score on a scale | Standard Deviation 0.974 |
| SKI-O-703 200 mg BID | Bleeding Score | Week 9 | 1.16 score on a scale | Standard Deviation 3.986 |
| SKI-O-703 400 mg BID | Bleeding Score | Week 1 Day 1 | 1.29 score on a scale | Standard Deviation 2.411 |
| SKI-O-703 400 mg BID | Bleeding Score | Week 5 | 1.33 score on a scale | Standard Deviation 3.276 |
| SKI-O-703 400 mg BID | Bleeding Score | Week 9 | 0.45 score on a scale | Standard Deviation 0.759 |
| SKI-O-703 400 mg BID | Bleeding Score | Week 12 | 0.45 score on a scale | Standard Deviation 0.759 |
| SKI-O-703 400 mg BID | Bleeding Score | End of Study(week 16) | 0.80 score on a scale | Standard Deviation 1.005 |
| Placebo | Bleeding Score | Week 9 | 0.91 score on a scale | Standard Deviation 1.64 |
| Placebo | Bleeding Score | End of Study(week 16) | 0.70 score on a scale | Standard Deviation 1.16 |
| Placebo | Bleeding Score | Week 5 | 0.64 score on a scale | Standard Deviation 1.12 |
| Placebo | Bleeding Score | Week 1 Day 1 | 1.75 score on a scale | Standard Deviation 2.137 |
| Placebo | Bleeding Score | Week 12 | 0.55 score on a scale | Standard Deviation 1.036 |