Cerebral Palsy, Dystonia, Hereditary Spastic Paraplegia, Hypertonia, Muscle, Multiple Sclerosis, Muscle Spasticity, Spinal Cord Injuries, Stroke
Conditions
Keywords
Fast twitch type 2 myosin ATPase
Brief summary
To assess the safety and tolerability of single and multiple doses of MTR-601 in normal healthy volunteers under fed and fasted conditions. To evaluate the plasma and urine pharmacokinetics (PK) of MTR-601. To evaluate the pharmacodynamic (PD) effects of MTR-601 on muscle strength and muscle accumulation of MTR-601 by muscle biopsy and other potential mechanistic, predictive and PD markers of MTR-601.
Detailed description
This randomized, placebo-controlled, first-in-human (FIH) study of MTR-601 in normal healthy volunteers will consist of 3 single ascending dose (SAD) level cohorts, 1 SAD Level 2, Two-Dose cohort, 3 multiple ascending dose (MAD) level cohorts, and 1 optional MAD level cohort, each comprised of 8 subjects (6 MTR-601; 2 placebo). The total sample size will be up to 80 subjects to accommodate withdrawal of consent or replacement for other non-treatment-emergent adverse events (non-TEAE) reasons. SAD Levels 1-4 dosing: * Each of the SAD dose level cohorts will have 2 sentinel subjects followed at least 72 hours later by the remaining 6 subjects in 1 or more groups in a staggered fashion. Both sentinel subjects will be evaluated for 72 hours by the Investigator for safety prior to dosing the cohort's remaining 6 subjects. * Dosing will begin at dose Level 1 (10 mg). * Subjects in SAD Levels 1,3 and 4 will be dosed in a fed state (standard non-high-fat breakfast). * Subjects in the SAD Level 2, Two-Dose (20 mg) will be dosed in a fasting state on Day 1 with a subsequent 4-day washout period, followed by dosing in a fed state (standard not- high fat breakfast) on Day 6. * SAD Level 4 (80 mg) dosing is optional and may be adjusted based upon PK and safety results from earlier cohorts. MAD Levels 1-2 dosing: * The MAD portion of the study will commence at MAD Level 1 (10 mg) after the safe completion of the subjects in at least the SAD Level 2 Two-Dose cohort. * Subjects in MAD Levels 1-2 (no more than 20mg) will be dosed in a fed state (standard non-high-fat breakfast) over 14 continuous days of dosing. * MAD cohorts may be enrolled in small groups to accommodate clinic scheduling, with subjects dosed in a staggered fashion.
Interventions
DRUGMTR-601
Safety and tolerability of oral MTR-601, a highly selective fast twitch myosin 2 ATPase inhibitor in normal healthy volunteers
Sponsors
Motric Bio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind - placebo-controlled.
Intervention model description
This randomized, placebo-controlled, first-in-human (FIH) study of MTR-601 in normal healthy volunteers will consist of 3 single ascending dose (SAD) level cohorts, 1 SAD Level 2, Two-Dose cohort, 3 multiple ascending dose (MAD) level cohorts, and 1 optional MAD level cohort, each comprised of 8 subjects (6 MTR-601; 2 placebo).
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Willing to adhere to study procedures and provide written informed consent prior to the start of any study procedures. 2. 18-45 years of age at the time of consent and in good physical health based on medical history, physical examination including vital signs, as well as laboratory, electrocardiogram (ECG), Echocardiography (LVEF in the normal range of 50-70%), normal muscle strength upon physical examination, and spirometry test values in the normal range. 3. Weight ≥50 kg and body mass index (BMI) \<33 kg/m2. 4. Females or males with female partners must use a medically accepted contraceptive regimen (i.e., condoms with spermicide, abstinence, nonhormonal intrauterine device (IUD), Essure procedure, or diaphragm with spermicide) from at least 30 days prior to first dose through 90 days after the last dose OR females must be of non-childbearing potential, defined as: 1. Have been surgically sterilized (bilateral oophorectomy) or hysterectomized at least 6 months prior to screening. Surgical sterilization procedures or hysterectomy must be supported with clinical documentation/medical records and noted in the Relevant Medical History/Current Medical Condition section of the electronic case report form (eCRF). 2. Be postmenopausal (i.e., must have no regular menstrual bleeding for at least 2 years prior to inclusion). Menopause will be confirmed by a plasma follicle-stimulating hormone (FSH) level of \>40 IU/L. 5. Non-smoker and must not have used any tobacco products within 3 months prior to screening. 6. In good physical and mental health as determined by past medical history, physical examination, psychiatric examination, 12-lead ECG, Echocardiography, spirometry, urinary system ultrasound, vital sign measurements, and clinical laboratory evaluations and calculations(e.g., eGFR greater than 90 ml/1.73 m2) at screening or check-in to the clinical research unit (CRU) on Day -1, as assessed by the Investigator (or designee). Congenital nonhemolytic hyperbilirubinemia; or suspicion of Gilbert's syndrome based on total and direct bilirubin is not acceptable. 7. Has clinical laboratory test results within the reference ranges of the testing laboratory, except for results outside reference ranges that are deemed not clinically significant by the Investigator (or designee) at screening and check-in to the CRU on Day -1. 8. Vital signs are within normal limits and FVC (after 3 minutes resting in supine position, will be measured in the seated position) is greater than 90% of the predicted value for gender, age and height with good expiratory effort.
Exclusion criteria
Subjects who meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence, Severity and Relatedness of Treatment-emergent Adverse Events (TEAEs). TEAE Severity Will be Measured as Mild, Moderate or Severe, and Relatedness Will be Either Related or Not Related. | From baseline to last follow-up visit (Day 7 for SAD Dose Levels 1, 3, and 4, Day 12 for SAD Dose Level 2, Day 20 MAD Dose Levels 1-6) | To assess the safety and tolerability of single and multiple doses of MTR-601 in normal healthy volunteers under fed and fasted conditions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of MTR-601 In Single Ascending Doses | Day 1 | To evaluate the plasma and urine pharmacokinetics (PK) of MTR-601 |
| Maximum Plasma Concentration (Cmax) of MTR-601 in Multiple Ascending Doses | Day 1 | To evaluate the plasma pharmacokinetics (PK) of MTR-601 in Multiple Ascending Doses on Day 1 |
| Maximum Plasma Concentration at Steady State (Cmax, ss) of MTR-601 in Multiple Ascending Doses | Day 14 | To evaluate the plasma pharmacokinetics (PK) of MTR-601 in Multiple Ascending Doses on Day 14 |
| Time to Maximum Plasma Concentration (Tmax) of MTR-601 in Single Ascending Doses | Day 1 | To evaluate the plasma and urine pharmacokinetics (PK) of MTR-601 |
| Time to Maximum Plasma Concentration (Tmax) of MTR-601 in Multiple Ascending Doses | Day 1 | To evaluate the plasma pharmacokinetics (PK) of MTR-601 in Multiple Ascending Doses on Day 1 |
| Time to Maximum Plasma Concentration at Steady State (Tmax, ss) of MTR-601 in Multiple Ascending Doses | Day 14 | To Evaluate the Time to Maximum Plasma Concentration at Steady State (Tmax, ss) of MTR-601 in Multiple Ascending Doses on Day 14 |
| Plasma Area Under the Curve Through 24 Hours (AUC0-24) of MTR-601 in Single Ascending Doses | 0-24 Hours | To evaluate the Plasma area under the curve (AUC0-24) of MTR-601 in Single Ascending Doses to 24 Hours |
| Plasma Area Under the Curve to Infinity (AUCinf) of MTR-601 in Single Ascending Dose | 0-96 hours | To extraplolate the plasma Area Under the Curve to infinite time of MTR-601 in Single Ascending Doses |
| Plasma Half-life (T1/2) of MTR-601 in Single Ascending Doses | 0-96 Hours | To evaluate the plasma pharmacokinetics (PK) of MTR-601 in Single Ascending Doses |
| Plasma Concentration Corresponding to the Time of Last Measurable Observation (Clast) | 0-96 Hours | To evaluate the plasma concentration corresponding to the time of last measurable observation of MTR-601 in Single Ascending Doses |
| Plasma Clearance of Drug After Extravascular Administration (CL/F) in Single Ascending Doses | 0-96 Hours | To evaluate the plasma pharmacokinetics (PK) of MTR-601 in Single Ascending Doses |
| Volume of Distribution After Extravascular Administration (Vz/F) of MTR-901 in Single Ascending Doses | 0-96 Hours | To evaluate the volume of distribution after extravascular administration (Vz/F) of MTR-901 in Single Ascending Doses |
| Maximum Plasma Concentration at 24 Hours (C24) of MTR-601 in Multiple Ascending Doses | Day 1 | To evaluate the plasma pharmacokinetics (PK) of MTR-601 in Multiple Ascending Doses on Day 1 |
| Area Under the Curve Over the Dosing Interval (AUCtau) of MTR-601 in Multiple Ascending Doses | Day 1 | To evaluate the Area Under the Curve over the Dosing Interval (AUCtau) of MTR-601 in Multiple Ascending Doses on Day 1 |
| Area Under the Curve at Steady State Over the Dosing Interval (AUCtau) of MTR-601 in Multiple Ascending Doses | Day 14 | To evaluate the Area Under the Curve at Steady State over the Dosing Interval (AUCtau) of MTR-601 in Multiple Ascending Doses on Day 14 |
| Average Plasma Drug Concentration of MTR-601 in Multiple Ascending Doses | Day 14 | To evaluate the Average plasma drug concentration of MTR-601 in Multiple Ascending Doses on Day 14 |
| Volume of Distribution After Extravascular Administration (Vz/F) of MTR-901 in Multiple Ascending Doses | Day 14 | To evaluate the Volume of Distribution After Extravascular Administration (Vz/F) of MTR-901 in Multiple Ascending Doses on Day 14 |
| Accumulation Ratio of Maximum Plasma Concentration (AR_Cmax) of MTR-901 in Multiple Ascending Doses | Day 14 | To evaluate the Accumulation Ratio of Maximum Plasma Concentration (AR\_Cmax) of MTR-901 in Multiple Ascending Doses on Day 14 |
| Maximum Accumulation Concentration of Area Under the Curve (AR_AUC0-24, qd) of MTR-901 in Multiple Ascending Doses | Day 14 | To evaluate the Maximum Accumulation Concentration of Area Under the Curve (AR\_AUC0-24, qd) of MTR-901 in Multiple Ascending Doses on Day 14 |
| Plasma Clearance of Drug After Extravascular Administration (CL/F) of MTR-601 in Multiple Ascending Doses | Day 14 | To evaluate the Plasma Clearance of Drug After Extravascular Administration (CL/F) of MTR-601 in Multiple Ascending Doses on Day 14 |
| Cumulative Amount of MTR-601 Excreted Unchanged in Urine (Ae) in Single Ascending Doses | Up to 96 Hours | To evaluate the Cumulative amount of MTR-601 Excreted Unchanged in Urine in Single Ascending Doses |
| Fraction of Dose of MTR-601 Excreted Unchanged in Urine (Fe) in Single Ascending Doses | Up to 96 Hours | To evaluate theFraction of Dose of MTR-601 Excreted Unchanged in Urine in Single Ascending Doses |
| Renal Clearance (Clr) of MTR-601 in Single Ascending Doses | Up to 96 Hours | To evaluate the Renal Clearance (Clr) of MTR-601 in Single Ascending Doses in Single Ascending Doses |
| Cumulative Amount of MTR-601 Excreted Unchanged in Urine (Ae) In Multiple Ascending Doses | Day 1 | To evaluate the Cumulative amount of MTR-601 Excreted Unchanged in Urine in Multiple Ascending Doses |
| Fraction of Dose of MTR-601 Excreted Unchanged in Urine (Fe) in Multiple Ascending Doses | Day 1 | To evaluate theFraction of Dose of MTR-601 Excreted Unchanged in Urine in Multiple Ascending Doses |
| Renal Clearance (Clr) of MTR-601 in Multiple Ascending Doses | Day 14 | To evaluate the Renal Clearance (Clr) of MTR-601 in Multiple Ascending Doses |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAlan Hand, MD
Worldwide Clinical Trials
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 30.7 years STANDARD_DEVIATION 7.47 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 48 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 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 | 54 Participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 4 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 | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 10 | 0 / 12 |
| other Total, other adverse events | 1 / 6 | 0 / 6 | 1 / 6 | 3 / 6 | 2 / 6 | 3 / 6 | 5 / 6 | 5 / 6 | 5 / 6 | 7 / 7 | 4 / 6 | 5 / 6 | 4 / 10 | 9 / 12 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 10 | 0 / 12 |
Outcome results
None listed