Facioscapulohumeral Muscular Dystrophy, Limb Girdle Muscular Dystrophy
Conditions
Keywords
FSHD, LGMD
Brief summary
ATYR1940-C-006 is a multi-national, multicenter study being conducted at centers in the United States (US) and Europe who participated in Study ATYR1940-C-003 (Stage 1 only) or Study ATYR1940-C-004 (that is, the parent studies).
Detailed description
Study ATYR1940-C-006 is a multi-national, multi-center, open-label extension study designed to evaluate the long-term safety, effects on muscle, and pharmacodynamics of ATYR1940 in participants with Limb-girdle muscular dystrophy (LGMD) or FSHD previously treated in the Study ATYR1940-C-003 (Stage 1 only) or Study ATYR1940-C-004 that is, the parent studies). This study will be conducted at the same study centers at which participants were enrolled in the parent studies. Participants who completed the treatment period in the parent study and, in the Investigator's opinion, demonstrated acceptable tolerability of ATYR1940, are considered by the Investigator to be compliant with ATYR1940 and the study procedures, and do not meet any criterion for ATYR1940 discontinuation are eligible for participation in the current study, contingent upon Investigator and participant agreement to continue ATYR1940 treatment. For the first 12 weeks in this extension study, participants will receive ATYR1940 at the highest tolerated dose received in the parent study; no dose adjustments are allowed during this 12-week period. After 12 weeks, if the participant is demonstrating good tolerability, the ATYR1940 dose may be increased on a participant-specific basis at the Investigator's discretion, in consultation with the Sponsor and Medical Monitor. ATYR1940 dose increases to \>3.0 mg/kg are not permissible. All participants will receive ATYR1940 on a weekly basis in this study, regardless of the frequency of dosing in the parent study. ATYR1940 will be administered via intravenous (IV) infusion over 90 minutes. If medically indicated, the infusion duration and volume may be adjusted at the Investigator's discretion in consultation with the Medical Monitor and Sponsor.
Interventions
DRUGATYR1940
Concentrate for solution for infusion
Sponsors
aTyr Pharma, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
1. Enrolled in and completed the treatment period in the parent study. 2. Demonstrated, in the Sponsor's and Investigator's opinions, acceptable tolerability of ATYR1940. 3. In the Investigator's opinion, participant has shown acceptable compliance with ATYR1940 and the study procedures in the parent study and is willing and able to comply with all procedures in the current study. 4. Is, in the opinion of the Investigator and Sponsor, a suitable candidate for continued ATYR1940 treatment. 5. Provide written informed consent or assent after the nature of the study has been explained and prior to the performance of any research-related procedures.
Exclusion criteria
1. Is expected to require treatment with curcumin or systemic albuterol (intermittent inhaled albuterol is permissible) during study participation; or use of a product that putatively enhances muscle growth (for example, insulin-like growth factor, growth hormone) or activity (for example, Coenzyme Q, Coenzyme A, creatine, L-carnitine) on a chronic basis; or statin treatment initiation or significant adjustment to statin regimen (stable, chronic statin use is permissible). 2. Planned to receive any vaccination during study participation. 3. Abnormal baseline findings, medical condition(s), or laboratory findings that, in the Investigator's opinion, might jeopardize the participant's safety or decrease the chance of obtaining satisfactory data needed to achieve the objectives of the study. 4. Evidence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematological, metabolic, dermatological, or gastrointestinal disease, or has a condition that requires immediate surgical intervention, other treatment, or may not allow safe participation. 5. If female and of childbearing potential (premenopausal and not surgically sterile), has a positive pregnancy test at entry or is unwilling to use contraception from the time of entry through the 3-month Follow-up visit. Acceptable methods of birth control include abstinence, barrier methods, hormones, or intra-uterine device. 6. If male, is unwilling to use a condom plus spermicide during sexual intercourse from the time of entry through the 1 month Follow-up visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Manual Muscle Testing (MMT) Score at Week 12 | Baseline, Week 12 | MMT (muscle strength) will be graded using a modified Medical Research Council scale. Scores were converted to 13-point scale (range from 0 \[on contraction palpable\] to 12 \[normal strength\]). An overall total score was calculated by summing all scores for a total possible score of 336. Decreased muscle strength was indicated by a decreased score. An overall total score was calculated as long as 24 of the 28 individual scores were non-missing. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Up to End of Study (up to approximately Week 39) | TEAEs were defined as adverse events (AEs) with an onset following administration of the first dose of study drug. AEs were defined as any untoward medical occurrence in a participant administered study drug and that does not necessarily have a causal relationship with the study drug. Worsening of a pre-existing medical condition should have been considered an AE if there was either an increase in severity, frequency, or duration of the condition or an association with significantly worse outcomes. SAEs were defined as any AE that, in the view of either the Investigator or Sponsor, resulted in any of the following outcomes as fatal, life-threatening, required in-participant hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, an important medical event. A summary of all SAEs and Other AEs (nonserious) regardless of causality is located in 'Reported Adverse Events' Section. |
| Number of Participants With Positive Anti-Drug Antibodies (ADA) | Up to End of Study (up to approximately Week 39) | Summarized titers are reported below. |
| Number of Participants With a Jo-1 Antibody (Ab) Test Result ≥1.5 Units/Milliliter (U/mL) | Up to End of Study (up to approximately Week 39) | Participants with Jo-1 Ab levels ≥1.5 U/mL were to be discontinued from dosing of the study drug. |
| Number of Participants With a Clinical Laboratory Abnormality Leading to an AE | Up to End of Study (up to approximately Week 39) | Laboratory parameters included hematology (hematocrit, hemoglobin, red blood cell count, white blood cell count neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelet count); serum chemistries (blood urea nitrogen, creatinine, total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, total protein, sodium, potassium, bicarbonate, calcium, chloride, magnesium, inorganic phosphate, creatine kinase, lactate dehydrogenase, C-reactive protein, troponin, myoglobin, insulin-like growth factor 1, and cholesterol \[nonfasting\]); and urinalysis (color, pH, specific gravity, protein, glucose, ketones, and blood). Clinically significant laboratory abnormalities were based upon Investigator's discretion. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| Number of Participants With a Clinically Significant Pulmonary Function Event Resulting in a TEAE | Up to End of Study (up to approximately Week 39) | Pulmonary evaluations included pulmonary function tests and pulse oximetry. Clinically significant changes were to be reported as adverse events. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| Number of Participants With a Clinically Significant Electrocardiogram (ECG) Abnormality Leading to a TEAE | Up to End of Study (up to approximately Week 39) | ECG parameters that were evaluated included heart rate and PR, QR, and QT intervals. A clinically significant ECG abnormality was based upon the Investigator's discretion. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| Number of Participants With Vital Sign Abnormality Resulting in a TEAE | Up to End of Study (up to approximately Week 39) | The vital sign parameters that were evaluated included heart rate, systolic and diastolic blood pressure, and respiration rate as well as temperature. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
Secondary
| Measure | Time frame |
|---|---|
| Change From Baseline in Creatinine Kinase at Week 12 | Baseline, Week 12 |
Countries
Denmark, Italy, United States
Participant flow
Recruitment details
Participants who participated in and completed the treatment period and were considered to be compliant with the study drug by the Investigator in the parent studies (ATYR1940-C-003 \[NCT02603562\] or ATYR1940-C-004 \[NCT02579239\]) were eligible for participation in this study. Note that only data for this study are reported in this Results Record. Data for the parent studies (ATYR1940-C-003 \[NCT02603562\] and ATYR1940-C-004 \[NCT02579239\]) are reported in the respective Results Records.
Pre-assignment details
When a participant transferred from the parent study to this extension study, the duration between the last ATYR1940 dose in the parent study and first ATYR1940 dose in this extension study was to be 1 week; however, a maximum duration of 3 weeks was permissible.
Participants by arm
| Arm | Count |
|---|---|
| ATYR1940 Participants received ATYR1940 up to 3.0 mg/kg IV infusion once weekly until approval of ATYR1940, discontinuation of its development, the study was closed by the Sponsor, or a criterion for study drug discontinuation was met (up to a maximum of 34 weeks). | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | ATYR1940 |
|---|---|
| Age, Continuous | 30.0 years STANDARD_DEVIATION 15.94 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 8 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 7 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
Change From Baseline in Manual Muscle Testing (MMT) Score at Week 12
MMT (muscle strength) will be graded using a modified Medical Research Council scale. Scores were converted to 13-point scale (range from 0 \[on contraction palpable\] to 12 \[normal strength\]). An overall total score was calculated by summing all scores for a total possible score of 336. Decreased muscle strength was indicated by a decreased score. An overall total score was calculated as long as 24 of the 28 individual scores were non-missing.
Time frame: Baseline, Week 12
Population: Cumulative Safety population included all participants who received at least 1 full or partial dose of ATYR1940 in the current study (Study ATYR1940-C-006) and had a post-infusion safety observation since enrollment in parent studies, but with cumulative data from both the parent studies and the current study. Here, 'Number of Participants analyzed' signifies those who were evaluable for this outcome measure and number analyzed signifies those who were evaluable at specified time points only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ATYR1940 | Change From Baseline in Manual Muscle Testing (MMT) Score at Week 12 | Baseline | 229.1 score on a scale | Standard Deviation 82.56 |
| ATYR1940 | Change From Baseline in Manual Muscle Testing (MMT) Score at Week 12 | Change at Week 12 | 4.3 score on a scale | Standard Deviation 13.5 |
Primary
Number of Participants With a Clinical Laboratory Abnormality Leading to an AE
Laboratory parameters included hematology (hematocrit, hemoglobin, red blood cell count, white blood cell count neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelet count); serum chemistries (blood urea nitrogen, creatinine, total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, total protein, sodium, potassium, bicarbonate, calcium, chloride, magnesium, inorganic phosphate, creatine kinase, lactate dehydrogenase, C-reactive protein, troponin, myoglobin, insulin-like growth factor 1, and cholesterol \[nonfasting\]); and urinalysis (color, pH, specific gravity, protein, glucose, ketones, and blood). Clinically significant laboratory abnormalities were based upon Investigator's discretion. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time frame: Up to End of Study (up to approximately Week 39)
Population: Safety population was defined as all participants who received at least 1 full or partial dose of ATYR1940 in the current study (Study ATYR1940-C-006) and had a post-infusion safety observation since enrollment in parent studies.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ATYR1940 | Number of Participants With a Clinical Laboratory Abnormality Leading to an AE | 1 Participants |
Primary
Number of Participants With a Clinically Significant Electrocardiogram (ECG) Abnormality Leading to a TEAE
ECG parameters that were evaluated included heart rate and PR, QR, and QT intervals. A clinically significant ECG abnormality was based upon the Investigator's discretion. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time frame: Up to End of Study (up to approximately Week 39)
Population: Safety population was defined as all participants who received at least 1 full or partial dose of ATYR1940 in the current study (Study ATYR1940-C-006) and had a post-infusion safety observation since enrollment in parent studies.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ATYR1940 | Number of Participants With a Clinically Significant Electrocardiogram (ECG) Abnormality Leading to a TEAE | 2 Participants |
Primary
Number of Participants With a Clinically Significant Pulmonary Function Event Resulting in a TEAE
Pulmonary evaluations included pulmonary function tests and pulse oximetry. Clinically significant changes were to be reported as adverse events. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time frame: Up to End of Study (up to approximately Week 39)
Population: Safety population was defined as all participants who received at least 1 full or partial dose of ATYR1940 in the current study (Study ATYR1940-C-006) and had a post-infusion safety observation since enrollment in parent studies.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ATYR1940 | Number of Participants With a Clinically Significant Pulmonary Function Event Resulting in a TEAE | 0 Participants |
Primary
Number of Participants With a Jo-1 Antibody (Ab) Test Result ≥1.5 Units/Milliliter (U/mL)
Participants with Jo-1 Ab levels ≥1.5 U/mL were to be discontinued from dosing of the study drug.
Time frame: Up to End of Study (up to approximately Week 39)
Population: Cumulative Safety population included all participants who received at least 1 full or partial dose of ATYR1940 in the current study (Study ATYR1940-C-006) and had a post-infusion safety observation since enrollment in parent studies, but with cumulative data from both the parent studies and the current study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ATYR1940 | Number of Participants With a Jo-1 Antibody (Ab) Test Result ≥1.5 Units/Milliliter (U/mL) | 2 Participants |
Primary
Number of Participants With Positive Anti-Drug Antibodies (ADA)
Summarized titers are reported below.
Time frame: Up to End of Study (up to approximately Week 39)
Population: Cumulative Safety population included all participants who received at least 1 full or partial dose of ATYR1940 in the current study (Study ATYR1940-C-006) and had a post-infusion safety observation since enrollment in parent studies, but with cumulative data from both the parent studies and the current study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ATYR1940 | Number of Participants With Positive Anti-Drug Antibodies (ADA) | 3 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
TEAEs were defined as adverse events (AEs) with an onset following administration of the first dose of study drug. AEs were defined as any untoward medical occurrence in a participant administered study drug and that does not necessarily have a causal relationship with the study drug. Worsening of a pre-existing medical condition should have been considered an AE if there was either an increase in severity, frequency, or duration of the condition or an association with significantly worse outcomes. SAEs were defined as any AE that, in the view of either the Investigator or Sponsor, resulted in any of the following outcomes as fatal, life-threatening, required in-participant hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, an important medical event. A summary of all SAEs and Other AEs (nonserious) regardless of causality is located in 'Reported Adverse Events' Section.
Time frame: Up to End of Study (up to approximately Week 39)
Population: Safety population was defined as all participants who received at least 1 full or partial dose of ATYR1940 in the current study (Study ATYR1940-C-006) and had a post-infusion safety observation since enrollment in parent studies.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ATYR1940 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 7 Participants |
| ATYR1940 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
Primary
Number of Participants With Vital Sign Abnormality Resulting in a TEAE
The vital sign parameters that were evaluated included heart rate, systolic and diastolic blood pressure, and respiration rate as well as temperature. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time frame: Up to End of Study (up to approximately Week 39)
Population: Safety population was defined as all participants who received at least 1 full or partial dose of ATYR1940 in the current study (Study ATYR1940-C-006) and had a post-infusion safety observation since enrollment in parent studies.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ATYR1940 | Number of Participants With Vital Sign Abnormality Resulting in a TEAE | 0 Participants |
Secondary
Change From Baseline in Creatinine Kinase at Week 12
Time frame: Baseline, Week 12
Population: Cumulative Safety population included all participants who received at least 1 full or partial dose of ATYR1940 in the current study (Study ATYR1940-C-006) and had a post-infusion safety observation since enrollment in parent studies, but with cumulative data from both the parent studies and the current study. Here, 'Number of Participants analyzed' signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ATYR1940 | Change From Baseline in Creatinine Kinase at Week 12 | -82.3 Units/liter | Standard Deviation 164.98 |