Immune Thrombocytopenia Purpura
Conditions
Brief summary
The primary objectives of this study are to assess the safety and tolerability of single rising doses of MK-8723 in healthy adult participants and adult participants with chronic immune thrombocytopenia purpura (ITP) and to assess pharmacodynamics of MK-8723 in participants with ITP. The primary hypothesis is that the true placebo-adjusted platelet response rate to MK-8723 in adult patients with chronic ITP is \>50%.
Detailed description
In Part 1 of the trial, safety and pharmacokinetics of MK-8723 will be evaluated in healthy participants. In Part 2 of the trial, safety, pharmacokinetics, and pharmacodynamics will be evaluated among participants with ITP. In Part 1, dose escalation will occur in up to 5 serial panels of participants; each participant will receive a single intravenous (IV) dose of MK-8723 (or placebo). In Part 2, dose escalation will occur in up to 3 serial panels of participants with ITP; each participant will receive a single IV dose of MK-8723 (or placebo), once safety and tolerability of the corresponding dose is shown in Part 1. Amendment 3 specified a re-enrollment procedure for eligible participants in Part 2 to participate in more than one dosing panel.
Interventions
DRUGMK-8723
MK-8723 administered as a single IV infusion over approximately 4 hours on Day 1.
DRUGMatching Placebo
Matching placebo to MK-8723 administered as a single IV infusion over approximately 4 hours on Day 1.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
(Part 1): * Female participants must be non-pregnant, non-breast feeding, and of non-childbearing potential * Has a Body Mass Index (BMI) \<=32 kg/m\^2 * Has a body weight \>= 50 kg and \<= 100 kg * Has been judged to be in good health based on medical history, physical examination, vital sign measurements, electrocardiogram (ECG), and laboratory safety tests * Non-smoker or has not used nicotine or nicotine-containing products for at least 3 months Inclusion Criteria (Part 2): * Has been diagnosed with ITP at least 3 months prior * Female ITP participants must be non-pregnant, non-breast feeding, and either of 1) non-childbearing potential or 2) must have serum beta human chorionic gonadotropin (HCG) level consistent with a non-pregnant state, and agree to use acceptable contraception from pretrial period until 84 days postdose * Has a BMI \<=36 kg/m\^2 * Has been judged to be in good health, other than ITP diagnosis, based on medical history, physical examination, vital sign measurements, ECG, and laboratory safety tests
Exclusion criteria
(Part 1): * Has a history or clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological abnormalities or diseases * Has a history of cancer (malignancy) * Has a history of significant multiple and/or severe allergies or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food * Is positive for hepatitis B surface antigen, hepatitis C antibodies, or human immunodeficiency virus (HIV) * Has had major surgery or donated or lost 1 unit of blood in the 4 weeks prior * Has participated in another investigational trial within 4 weeks (12 weeks for biologics) * Has received a live virus vaccination within 42 days or plans to receive such while participating in the trial * Is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs and herbal remedies from 2 weeks prior and for the duration of the trial * Consumes greater than 3 glasses of alcoholic beverages per day * Consumes greater than 6 servings of caffeine-containing beverages per day * Is currently a regular user of any illicit drugs or has a history of drug and/or alcohol abuse within 3 months * Has a history of ITP or other autoimmune disease * Has an active infection that is clinically significant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing an Adverse Event | Up to 84 days | An AE is defined as any unfavorable and unintended medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
| Number of Participants Discontinuing Study Due to an Adverse Event (AE) | Up to 84 Days | An AE is defined as any unfavorable and unintended medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
| Number of Participants With a Positive Platelet Response to MK-8723 | Up to Day 14 | In participants with ITP, platelet response is a rapid, sensitive, and highly qualitative measure of response to anti-inflammatory therapy. A positive platelet response was defined as: 1) A doubling of platelet counts at the time point of maximum response (through Day 14) as compared to Day 0 AND an increase to an absolute level of ≥50,000/μL in participants with a baseline platelet count of \<50,000/μL, OR 2) A 50% increase in the platelet count at the time point of maximum response (through Day 14) as compared to Day 0 in participants with a baseline platelet count of ≥50,000/μL. The analysis was specified only for participants with ITP (Part 2) that received treatment with MK-8723 or matching placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of MK-8723 From Time 0 to Infinity (AUC0-∞) Among Healthy Participants and Participants With ITP | All dose groups: Predose and 4 (end of infusion), 6, 12, 24 hrs postdose and Days 3, 4, 5, 7, 10, 14, 21, 28; 30 mg/kg and 100 mg/kg dose groups: Days 43, 56, 71, 84 | AUC0-∞ is a measure of total body exposure to drug. Serum samples for determination of AUC0-∞ were collected at pre-specified time-points. |
| Maximum Concentration (Cmax) of MK-8723 Among Healthy Participants and Participants With ITP | All dose groups: Predose and 4 (end of infusion), 6, 12, 24 hrs postdose and Days 3, 4, 5, 7, 10, 14, 21, 28; 30 mg/kg and 100 mg/kg dose groups: Days 43, 56, 71, 84 | Serum samples for determination of Cmax were collected at pre-specified time-points. |
Participant flow
Recruitment details
Amendment 3 specified a re-enrollment procedure for eligible participants in Part 2 to participate in more than one dosing panel.
Pre-assignment details
2 participants that completed Part 2 10 mg/kg were re-enrolled in Part 2 100 mg/kg & dosed. Both participants completed Part 2 100 mg/kg. 1 participant originally assigned to Part 2 30 mg/kg received placebo in error & is included in Part 2 Placebo.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: MK-8723 1 mg/kg in Healthy Participants MK-8723 1 mg/kg administered as a single IV infusion to healthy participants in Part 1. | 6 |
| Part 1: MK-8723 3 mg/kg in Healthy Participants MK-8723 3 mg/kg administered as a single IV infusion to healthy participants in Part 1. | 6 |
| Part 1: MK-8723 10 mg/kg in Healthy Participants MK-8723 10 mg/kg administered as a single IV infusion to healthy participants in Part 1. | 6 |
| Part 1: MK-8723 30 mg/kg in Healthy Participants MK-8723 30 mg/kg administered as a single IV infusion to healthy participants in Part 1. | 6 |
| Part 1: MK-8723 100 mg/kg in Healthy Participants MK-8723 100 mg/kg administered as a single IV infusion to healthy participants in Part 1. | 6 |
| Part 1: Matching Placebo to MK-8723 Matching placebo to MK-8723 administered as a single IV infusion to healthy participants in Part 1. | 10 |
| Part 2: MK-8723 10 mg/kg in ITP Participants MK-8723 10 mg/kg administered as a single IV infusion to participants with ITP in Part 2. 2 participants subsequently enrolled in Part 2 MK-8723 100 mg/kg. | 3 |
| Part 2: MK-8723 30 mg/kg in ITP Participants MK-8723 30 mg/kg administered as a single IV infusion to participants with ITP in Part 2. | 2 |
| Part 2: MK-8723 100 mg/kg in ITP Participants MK-8723 100 mg/kg administered as a single IV infusion to participants with ITP in Part 2. This group includes 2 participants that re-enrolled from Part 2 MK-8723 10 mg/kg. | 3 |
| Part 2: Matching Placebo to MK-8723 Matching placebo to MK-8723 administered as a single IV infusion to participants with ITP in Part 2. | 4 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1: MK-8723 1 mg/kg in Healthy Participants | Part 1: MK-8723 3 mg/kg in Healthy Participants | Part 1: MK-8723 10 mg/kg in Healthy Participants | Part 1: MK-8723 30 mg/kg in Healthy Participants | Part 1: MK-8723 100 mg/kg in Healthy Participants | Part 1: Matching Placebo to MK-8723 | Part 2: MK-8723 10 mg/kg in ITP Participants | Part 2: MK-8723 30 mg/kg in ITP Participants | Part 2: MK-8723 100 mg/kg in ITP Participants | Part 2: Matching Placebo to MK-8723 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 25.7 Years STANDARD_DEVIATION 2.7 | 32.7 Years STANDARD_DEVIATION 13 | 31.0 Years STANDARD_DEVIATION 12.2 | 25.7 Years STANDARD_DEVIATION 4.2 | 32.7 Years STANDARD_DEVIATION 10.5 | 30.1 Years STANDARD_DEVIATION 9.5 | 38.7 Years STANDARD_DEVIATION 22.3 | 53.0 Years STANDARD_DEVIATION 4.2 | 38.3 Years STANDARD_DEVIATION 22.7 | 50.3 Years STANDARD_DEVIATION 13.5 | 33.2 Years STANDARD_DEVIATION 13 |
| Age, Customized >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Age, Customized Between 18 and 65 years | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 10 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 51 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 5 Participants | 6 Participants | 6 Participants | 9 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 6 | 2 / 6 | 4 / 6 | 1 / 6 | 4 / 6 | 6 / 10 | 1 / 3 | 2 / 2 | 2 / 3 | 2 / 4 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 10 | 0 / 3 | 0 / 2 | 0 / 3 | 0 / 4 |
Outcome results
Primary
Number of Participants Discontinuing Study Due to an Adverse Event (AE)
An AE is defined as any unfavorable and unintended medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 84 Days
Population: The APaT population consisting of all participants who received at least one dose of study drug was used for the safety analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: MK-8723 1 mg/kg in Healthy Participants | Number of Participants Discontinuing Study Due to an Adverse Event (AE) | 0 Participants |
| Part 1: MK-8723 3 mg/kg in Healthy Participants | Number of Participants Discontinuing Study Due to an Adverse Event (AE) | 0 Participants |
| Part 1: MK-8723 10 mg/kg in Healthy Participants | Number of Participants Discontinuing Study Due to an Adverse Event (AE) | 0 Participants |
| Part 1: MK-8723 30 mg/kg in Healthy Participants | Number of Participants Discontinuing Study Due to an Adverse Event (AE) | 0 Participants |
| Part 1: MK-8723 100 mg/kg in Healthy Participants | Number of Participants Discontinuing Study Due to an Adverse Event (AE) | 0 Participants |
| Part 1: Matching Placebo to MK-8723 | Number of Participants Discontinuing Study Due to an Adverse Event (AE) | 0 Participants |
| Part 2: MK-8723 10 mg/kg in ITP Participants | Number of Participants Discontinuing Study Due to an Adverse Event (AE) | 0 Participants |
| Part 2: MK-8723 30 mg/kg in ITP Participants | Number of Participants Discontinuing Study Due to an Adverse Event (AE) | 0 Participants |
| Part 2: MK-8723 100 mg/kg in ITP Participants | Number of Participants Discontinuing Study Due to an Adverse Event (AE) | 0 Participants |
| Part 2: Matching Placebo to MK-8723 | Number of Participants Discontinuing Study Due to an Adverse Event (AE) | 0 Participants |
Primary
Number of Participants Experiencing an Adverse Event
An AE is defined as any unfavorable and unintended medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 84 days
Population: The All Participants as Treated (APaT) population consisting of all participants who received at least one dose of study drug was used for the safety analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: MK-8723 1 mg/kg in Healthy Participants | Number of Participants Experiencing an Adverse Event | 2 Participants |
| Part 1: MK-8723 3 mg/kg in Healthy Participants | Number of Participants Experiencing an Adverse Event | 2 Participants |
| Part 1: MK-8723 10 mg/kg in Healthy Participants | Number of Participants Experiencing an Adverse Event | 4 Participants |
| Part 1: MK-8723 30 mg/kg in Healthy Participants | Number of Participants Experiencing an Adverse Event | 1 Participants |
| Part 1: MK-8723 100 mg/kg in Healthy Participants | Number of Participants Experiencing an Adverse Event | 4 Participants |
| Part 1: Matching Placebo to MK-8723 | Number of Participants Experiencing an Adverse Event | 6 Participants |
| Part 2: MK-8723 10 mg/kg in ITP Participants | Number of Participants Experiencing an Adverse Event | 1 Participants |
| Part 2: MK-8723 30 mg/kg in ITP Participants | Number of Participants Experiencing an Adverse Event | 2 Participants |
| Part 2: MK-8723 100 mg/kg in ITP Participants | Number of Participants Experiencing an Adverse Event | 2 Participants |
| Part 2: Matching Placebo to MK-8723 | Number of Participants Experiencing an Adverse Event | 2 Participants |
Primary
Number of Participants With a Positive Platelet Response to MK-8723
In participants with ITP, platelet response is a rapid, sensitive, and highly qualitative measure of response to anti-inflammatory therapy. A positive platelet response was defined as: 1) A doubling of platelet counts at the time point of maximum response (through Day 14) as compared to Day 0 AND an increase to an absolute level of ≥50,000/μL in participants with a baseline platelet count of \<50,000/μL, OR 2) A 50% increase in the platelet count at the time point of maximum response (through Day 14) as compared to Day 0 in participants with a baseline platelet count of ≥50,000/μL. The analysis was specified only for participants with ITP (Part 2) that received treatment with MK-8723 or matching placebo.
Time frame: Up to Day 14
Population: The per protocol population consisting of all participants in compliance with the protocol (e.g., availability of measurements, absence of major protocol violations) was used for the pharmacodynamic (platelet response) analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: MK-8723 1 mg/kg in Healthy Participants | Number of Participants With a Positive Platelet Response to MK-8723 | 0 Participants |
| Part 1: MK-8723 3 mg/kg in Healthy Participants | Number of Participants With a Positive Platelet Response to MK-8723 | 0 Participants |
| Part 1: MK-8723 10 mg/kg in Healthy Participants | Number of Participants With a Positive Platelet Response to MK-8723 | 0 Participants |
| Part 1: MK-8723 30 mg/kg in Healthy Participants | Number of Participants With a Positive Platelet Response to MK-8723 | 0 Participants |
Secondary
Area Under the Concentration-time Curve of MK-8723 From Time 0 to Infinity (AUC0-∞) Among Healthy Participants and Participants With ITP
AUC0-∞ is a measure of total body exposure to drug. Serum samples for determination of AUC0-∞ were collected at pre-specified time-points.
Time frame: All dose groups: Predose and 4 (end of infusion), 6, 12, 24 hrs postdose and Days 3, 4, 5, 7, 10, 14, 21, 28; 30 mg/kg and 100 mg/kg dose groups: Days 43, 56, 71, 84
Population: The per protocol population consisting of all participants in compliance with the protocol (e.g., availability of measurements, absence of major protocol violations) was used for the pharmacokinetic (AUC0-∞) analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: MK-8723 1 mg/kg in Healthy Participants | Area Under the Concentration-time Curve of MK-8723 From Time 0 to Infinity (AUC0-∞) Among Healthy Participants and Participants With ITP | 4830 hr*μg/mL | Geometric Coefficient of Variation 22.1 |
| Part 1: MK-8723 3 mg/kg in Healthy Participants | Area Under the Concentration-time Curve of MK-8723 From Time 0 to Infinity (AUC0-∞) Among Healthy Participants and Participants With ITP | 22300 hr*μg/mL | Geometric Coefficient of Variation 21.9 |
| Part 1: MK-8723 10 mg/kg in Healthy Participants | Area Under the Concentration-time Curve of MK-8723 From Time 0 to Infinity (AUC0-∞) Among Healthy Participants and Participants With ITP | 65800 hr*μg/mL | Geometric Coefficient of Variation 13.4 |
| Part 1: MK-8723 30 mg/kg in Healthy Participants | Area Under the Concentration-time Curve of MK-8723 From Time 0 to Infinity (AUC0-∞) Among Healthy Participants and Participants With ITP | 186000 hr*μg/mL | Geometric Coefficient of Variation 7.28 |
| Part 1: MK-8723 100 mg/kg in Healthy Participants | Area Under the Concentration-time Curve of MK-8723 From Time 0 to Infinity (AUC0-∞) Among Healthy Participants and Participants With ITP | 711000 hr*μg/mL | Geometric Coefficient of Variation 50.5 |
| Part 1: Matching Placebo to MK-8723 | Area Under the Concentration-time Curve of MK-8723 From Time 0 to Infinity (AUC0-∞) Among Healthy Participants and Participants With ITP | 66200 hr*μg/mL | Geometric Coefficient of Variation 57.9 |
| Part 2: MK-8723 10 mg/kg in ITP Participants | Area Under the Concentration-time Curve of MK-8723 From Time 0 to Infinity (AUC0-∞) Among Healthy Participants and Participants With ITP | 203000 hr*μg/mL | Geometric Coefficient of Variation 22.6 |
| Part 2: MK-8723 30 mg/kg in ITP Participants | Area Under the Concentration-time Curve of MK-8723 From Time 0 to Infinity (AUC0-∞) Among Healthy Participants and Participants With ITP | 668000 hr*μg/mL | Geometric Coefficient of Variation 19.4 |
Secondary
Maximum Concentration (Cmax) of MK-8723 Among Healthy Participants and Participants With ITP
Serum samples for determination of Cmax were collected at pre-specified time-points.
Time frame: All dose groups: Predose and 4 (end of infusion), 6, 12, 24 hrs postdose and Days 3, 4, 5, 7, 10, 14, 21, 28; 30 mg/kg and 100 mg/kg dose groups: Days 43, 56, 71, 84
Population: The per protocol population consisting of all participants in compliance with the protocol (e.g., availability of measurements, absence of major protocol violations) was used for this pharmacokinetic (Cmax) analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: MK-8723 1 mg/kg in Healthy Participants | Maximum Concentration (Cmax) of MK-8723 Among Healthy Participants and Participants With ITP | 18.7 μg/mL | Geometric Coefficient of Variation 11.4 |
| Part 1: MK-8723 3 mg/kg in Healthy Participants | Maximum Concentration (Cmax) of MK-8723 Among Healthy Participants and Participants With ITP | 72.3 μg/mL | Geometric Coefficient of Variation 8.53 |
| Part 1: MK-8723 10 mg/kg in Healthy Participants | Maximum Concentration (Cmax) of MK-8723 Among Healthy Participants and Participants With ITP | 225 μg/mL | Geometric Coefficient of Variation 15.5 |
| Part 1: MK-8723 30 mg/kg in Healthy Participants | Maximum Concentration (Cmax) of MK-8723 Among Healthy Participants and Participants With ITP | 844 μg/mL | Geometric Coefficient of Variation 12.2 |
| Part 1: MK-8723 100 mg/kg in Healthy Participants | Maximum Concentration (Cmax) of MK-8723 Among Healthy Participants and Participants With ITP | 2160 μg/mL | Geometric Coefficient of Variation 23.9 |
| Part 1: Matching Placebo to MK-8723 | Maximum Concentration (Cmax) of MK-8723 Among Healthy Participants and Participants With ITP | 195 μg/mL | Geometric Coefficient of Variation 11.7 |
| Part 2: MK-8723 10 mg/kg in ITP Participants | Maximum Concentration (Cmax) of MK-8723 Among Healthy Participants and Participants With ITP | 741 μg/mL | Geometric Coefficient of Variation 24.8 |
| Part 2: MK-8723 30 mg/kg in ITP Participants | Maximum Concentration (Cmax) of MK-8723 Among Healthy Participants and Participants With ITP | 2450 μg/mL | Geometric Coefficient of Variation 8.63 |