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An Efficacy and Safety Study of ARGX-113 in Patients With Myasthenia Gravis Who Have Generalized Muscle Weakness (ADAPT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03669588
Recruitment Status : Completed
First Posted : September 13, 2018
Results First Posted : February 8, 2022
Last Update Posted : February 8, 2022
Sponsor:
Information provided by (Responsible Party):
argenx

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Generalized Myasthenia Gravis
Interventions Biological: ARGX-113
Biological: Placebo
Enrollment 167
Recruitment Details Study was conducted in generalized myasthenia gravis (gMG) patients at 56 sites worldwide. Patients were randomized 1:1 within each stratum (Japanese/non-Japanese, acetylcholine receptor-antibody [AChR-Ab] status and standard of care [SoC; ie, concomitant gMG treatment]) to receive ARGX-113 intravenous (IV) 10 milligrams/kilogram (mg/kg) or placebo, in addition to SoC. Patients completing the study were eligible to roll over into a follow-up study ARGX-113-1705.
Pre-assignment Details Total study duration was up to 28 weeks, including a 2-week screening period, an initial 8-week treatment cycle (TC) and intertreatment cycle (ITC) of variable length depending on the patient. Patients had to be on a stable dose of SoC and not have received immunoglobulins by IV, subcutaneous or intramuscular route, or plasma exchange, < 1 month prior to screening. The study included both AChR-Ab seropositive and seronegative patients; AChR-Ab detection in serum was performed during screening.
Arm/Group Title ARGX-113 Placebo
Hide Arm/Group Description

Patients received ARGX-113 IV 10 mg/kg administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.

Each 8-week TC comprised a 3-week treatment period and a 5-week follow-up period. At the end of each TC, patients entered the ITC period consisting of visits every 2 weeks. At each ITC visit, retreatment criteria were evaluated to determine if the patient was eligible to enter the next cycle for retreatment, based on clinical response as measured by the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale.

Patients received matching placebo administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.

Each 8-week TC comprised a 3-week treatment period and a 5-week follow-up period. At the end of each TC, patients entered the ITC period consisting of visits every 2 weeks. At each ITC visit, retreatment criteria were evaluated to determine if the patient was eligible to enter the next cycle for retreatment, based on clinical response as measured by the MG-ADL scale.

Period Title: Overall Study
Started 84 83
Completed 80 76
Not Completed 4 7
Reason Not Completed
Adverse Event             1             0
Physician Decision             0             1
Protocol Violation             1             0
Sponsor Decision             1             1
Withdrawal by Subject             1             4
Rescue Therapy Needed             0             1
Arm/Group Title ARGX-113 Placebo Total
Hide Arm/Group Description Patients received ARGX-113 IV 10 mg/kg administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle. Patients received matching placebo administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle. Total of all reporting groups
Overall Number of Baseline Participants 84 83 167
Hide Baseline Analysis Population Description
All patients in the randomized population who received at least a partial dose of investigational medicinal product (IMP) were included in the baseline analysis.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 84 participants 83 participants 167 participants
45.9  (14.41) 48.2  (14.97) 47.0  (14.69)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 84 participants 83 participants 167 participants
18 - <65 years
73
  86.9%
69
  83.1%
142
  85.0%
>= 65 years
11
  13.1%
14
  16.9%
25
  15.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 84 participants 83 participants 167 participants
Female
63
  75.0%
55
  66.3%
118
  70.7%
Male
21
  25.0%
28
  33.7%
49
  29.3%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 84 participants 83 participants 167 participants
American Indian or Alaska Native
2
   2.4%
0
   0.0%
2
   1.2%
Asian
9
  10.7%
7
   8.4%
16
   9.6%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
3
   3.6%
3
   3.6%
6
   3.6%
White
69
  82.1%
72
  86.7%
141
  84.4%
More than one race
1
   1.2%
0
   0.0%
1
   0.6%
Unknown or Not Reported
0
   0.0%
1
   1.2%
1
   0.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 84 participants 83 participants 167 participants
Japanese
8
   9.5%
7
   8.4%
15
   9.0%
Hispanic or Latino
7
   8.3%
2
   2.4%
9
   5.4%
Not Hispanic or Latino
69
  82.1%
73
  88.0%
142
  85.0%
Not Reported
0
   0.0%
1
   1.2%
1
   0.6%
Concomitant gMG treatment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 84 participants 83 participants 167 participants
Nonsteroidal Immunosuppressive Drugs (NSIDs)
51
  60.7%
51
  61.4%
102
  61.1%
No NSIDs
33
  39.3%
32
  38.6%
65
  38.9%
AChR-Ab status  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 84 participants 83 participants 167 participants
Positive
65
  77.4%
64
  77.1%
129
  77.2%
Negative
19
  22.6%
19
  22.9%
38
  22.8%
1.Primary Outcome
Title Percentage of MG-ADL Responders During Cycle 1 (C1); Analyzed in the AChR-Ab Seropositive Population
Hide Description The MG-ADL is an 8-item patient-reported scale to assess MG symptoms and their effects on daily activities. The scale comprises 2 items on daily life activities and 6 items on symptoms. The MG-ADL total score range is 0-24, with higher scores indicative of greater disease severity. A patient was considered an MG-ADL responder during C1 if there was a reduction of ≥2 points on the MG-ADL total score (compared to baseline of C1 [C1B]) for ≥4 consecutive weeks with the first reduction occurring no later than 1 week after the last infusion of IMP in C1.
Time Frame Baseline up to Day 63 (end of TC1)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed in the AChR-Ab seropositive population using the modified intention-to-treat (mITT) analysis set which included all randomized patients with a value for the MG-ADL total score at baseline and at least 1 postbaseline timepoint.
Arm/Group Title ARGX-113 Placebo
Hide Arm/Group Description:
Patients received ARGX-113 IV 10 mg/kg administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.
Patients received matching placebo administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.
Overall Number of Participants Analyzed 65 64
Measure Type: Number
Unit of Measure: percentage of patients
67.7 29.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ARGX-113, Placebo
Comments

Analysis with a 2-sided exact test (using logistic regression) at the 2-sided 5% significance level in the AChR-Ab seropositive population, stratified by Japanese versus (vs) non-Japanese and NSID vs no NSID as concomitant gMG treatment, with cycle baseline MG-ADL total score as covariate.

The treatment effect was presented as the odds ratio. An odds ratio of more than 1 represents a higher response rate for ARGX-113 compared to placebo.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.951
Confidence Interval (2-Sided) 95%
2.213 to 11.528
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Quantitative Myasthenia Gravis (QMG) Responders During C1; Analyzed in the AChR-Ab Seropositive Population
Hide Description The QMG scale quantifies disease severity based on impairments of body functions and structures as defined by the International Classification of Disability and Health. The QMG scale consists of 13 items that measure endurance or fatigability, and accounts for fluctuations in disease state. The QMG total score range is 0-39, with higher scores indicative of greater disease severity. A patient was considered a QMG responder during C1 if there was a reduction of ≥3-points on the QMG total score (compared to C1B) for ≥4 consecutive weeks with the first reduction occurring no later than 1 week after the last infusion of IMP in C1.
Time Frame Baseline up to Day 63 (end of TC1)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed in the AChR-Ab seropositive population using the mITT analysis set which included all randomized patients with a value for the MG-ADL total score at baseline and at least 1 postbaseline timepoint.
Arm/Group Title ARGX-113 Placebo
Hide Arm/Group Description:
Patients received ARGX-113 IV 10 mg/kg administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.
Patients received matching placebo administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.
Overall Number of Participants Analyzed 65 64
Measure Type: Number
Unit of Measure: percentage of patients
63.1 14.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ARGX-113, Placebo
Comments

Analysis with a 2-sided exact test (using logistic regression) at the 2-sided 5% significance level in the AChR-Ab seropositive population, stratified by Japanese vs non-Japanese and NSID vs no NSID as concomitant gMG treatment, with cycle baseline QMG total score as covariate.

The treatment effect was presented as the odds ratio. An odds ratio of more than 1 represents a higher response rate for ARGX-113 compared to placebo.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 10.842
Confidence Interval (2-Sided) 95%
4.179 to 31.200
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of MG-ADL Responders During C1; Analyzed in the Overall Population
Hide Description The percentage of MG-ADL responders during C1 in the overall population is reported for this secondary end point; percentage of MG-ADL responders during C1 in the AChR-Ab seropositive population is reported previously as a primary end point.
Time Frame Baseline up to Day 63 (end of TC1)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed in the overall population (including both AChR-Ab seropositive and seronegative patients) using the mITT analysis set which included all randomized patients with a value for the MG-ADL total score at baseline and at least 1 postbaseline timepoint.
Arm/Group Title ARGX-113 Placebo
Hide Arm/Group Description:
Patients received ARGX-113 IV 10 mg/kg administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.
Patients received matching placebo administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.
Overall Number of Participants Analyzed 84 83
Measure Type: Number
Unit of Measure: percentage of patients
67.9 37.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ARGX-113, Placebo
Comments

Analysis with a 2-sided exact test (using logistic regression) at the 2-sided 5% significance level in the overall population, stratified by AChR-Ab status (seropositive vs seronegative), Japanese vs non-Japanese and NSID vs no NSID as concomitant gMG treatment, with cycle baseline MG-ADL total score as covariate.

The treatment effect was presented as the odds ratio. An odds ratio of more than 1 represents a higher response rate for ARGX-113 compared to placebo.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.699
Confidence Interval (2-Sided) 95%
1.854 to 7.578
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Time That Patients Had a Clinically Meaningful Improvement (CMI) in MG-ADL Total Score up to and Including Day 126; Analyzed in the AChR-Ab Seropositive Population
Hide Description An MG-ADL CMI was defined as a reduction of ≥2 points on the total MG-ADL score compared to study entry baseline (SEB).
Time Frame Baseline up to Day 126
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed in the AChR-Ab seropositive population using the mITT analysis set which included all randomized patients with a value for the MG-ADL total score at baseline and at least 1 postbaseline timepoint.
Arm/Group Title ARGX-113 Placebo
Hide Arm/Group Description:
Patients received ARGX-113 IV 10 mg/kg administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.
Patients received matching placebo administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.
Overall Number of Participants Analyzed 65 64
Least Squares Mean (Standard Error)
Unit of Measure: percentage of time
48.714  (6.163) 26.649  (6.316)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ARGX-113, Placebo
Comments Analysis of covariance (ANCOVA) in the AChR-Ab seropositive population with treatment, baseline MG-ADL total score, Japanese vs non-Japanese, and NSID vs no NSID as concomitant gMG treatment as the covariates.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least square means difference
Estimated Value 22.065
Confidence Interval (2-Sided) 95%
10.949 to 33.181
Parameter Dispersion
Type: Standard Error of the Mean
Value: 5.616
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Time From Week 4 to Qualify for Retreatment; Analyzed in the AChR-Ab Seropositive Population
Hide Description Time to qualify for retreatment was defined as time from the Week 4 assessment until the first visit with a <2-point reduction compared to SEB in the MG-ADL total score and MG-ADL total score ≥5 points with >50% of the total score attributable to nonocular symptoms.
Time Frame Week 4 up to Day 182 (end of study [EoS])
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed in the AChR-Ab seropositive population using the mITT analysis set which included all randomized patients with a value for the MG-ADL total score at baseline and at least 1 postbaseline timepoint.
Arm/Group Title ARGX-113 Placebo
Hide Arm/Group Description:
Patients received ARGX-113 IV 10 mg/kg administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.
Patients received matching placebo administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.
Overall Number of Participants Analyzed 65 64
Median (95% Confidence Interval)
Unit of Measure: days
35.0
(29.0 to 43.0)
8.0
(1.0 to 30.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ARGX-113, Placebo
Comments Analysis was performed in the AChR-Ab seropositive population and the p-value was calculated using the log-rank test, stratified by Japanese vs non-Japanese and NSID vs no NSID as concomitant gMG treatment.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2604
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
6.Secondary Outcome
Title Percentage of Early MG-ADL Responders During C1; Analyzed in the AChR-Ab Seropositive Population
Hide Description A patient was considered an early MG-ADL responder during C1 if there was a reduction of ≥2 points on the MG-ADL total score (compared to C1B) for ≥4 consecutive weeks with the first reduction occurring no later than Week 2 (ie, after 1 or maximum 2 infusions of IMP in C1).
Time Frame Baseline up to Day 63 (end of TC1)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed in the AChR-Ab seropositive population using the mITT analysis set which included all randomized patients with a value for the MG-ADL total score at baseline and at least 1 postbaseline timepoint.
Arm/Group Title ARGX-113 Placebo
Hide Arm/Group Description:
Patients received ARGX-113 IV 10 mg/kg administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.
Patients received matching placebo administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.
Overall Number of Participants Analyzed 65 64
Measure Type: Number
Unit of Measure: percentage of patients
56.9 25.0
Time Frame Treatment-emergent adverse events were monitored from first administration of IMP on Day 1 until the EoS (up to a maximum of approximately 182 days).
Adverse Event Reporting Description The safety analysis set included patients in the randomized population who received at least a partial dose of IMP.
 
Arm/Group Title ARGX-113 Placebo
Hide Arm/Group Description Patients received ARGX-113 IV 10 mg/kg administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle. Patients received matching placebo administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle.
All-Cause Mortality
ARGX-113 Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/84 (0.00%)      0/83 (0.00%)    
Hide Serious Adverse Events
ARGX-113 Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/84 (4.76%)      7/83 (8.43%)    
Blood and lymphatic system disorders     
Thrombocytosis  1  1/84 (1.19%)  1 0/83 (0.00%)  0
Cardiac disorders     
Atrial fibrillation  1  0/84 (0.00%)  0 1/83 (1.20%)  1
Myocardial ischaemia  1  0/84 (0.00%)  0 1/83 (1.20%)  1
General disorders     
Therapeutic product ineffective  1  0/84 (0.00%)  0 1/83 (1.20%)  1
Infections and infestations     
Upper respiratory tract infection  1  0/84 (0.00%)  0 1/83 (1.20%)  1
Injury, poisoning and procedural complications     
Procedural pain  1  0/84 (0.00%)  0 1/83 (1.20%)  1
Spinal compression fracture  1  0/84 (0.00%)  0 1/83 (1.20%)  1
Musculoskeletal and connective tissue disorders     
Spinal ligament ossification  1  0/84 (0.00%)  0 1/83 (1.20%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Rectal adenocarcinoma  1  1/84 (1.19%)  1 0/83 (0.00%)  0
Nervous system disorders     
Myasthenia gravis  1  1/84 (1.19%)  1 2/83 (2.41%)  2
Myasthenia gravis crisis  1  0/84 (0.00%)  0 1/83 (1.20%)  1
Psychiatric disorders     
Depression  1  1/84 (1.19%)  1 0/83 (0.00%)  0
1
Term from vocabulary, MedDRA 23.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
ARGX-113 Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   49/84 (58.33%)      48/83 (57.83%)    
Gastrointestinal disorders     
Diarrhoea  1  6/84 (7.14%)  6 9/83 (10.84%)  14
Nausea  1  7/84 (8.33%)  7 9/83 (10.84%)  15
Infections and infestations     
Bronchitis  1  5/84 (5.95%)  6 2/83 (2.41%)  2
Nasopharyngitis  1  10/84 (11.90%)  12 15/83 (18.07%)  17
Upper respiratory tract infection  1  9/84 (10.71%)  11 4/83 (4.82%)  4
Urinary tract infection  1  8/84 (9.52%)  9 4/83 (4.82%)  4
Musculoskeletal and connective tissue disorders     
Myalgia  1  5/84 (5.95%)  6 1/83 (1.20%)  3
Nervous system disorders     
Dizziness  1  3/84 (3.57%)  5 5/83 (6.02%)  5
Headache  1  24/84 (28.57%)  40 23/83 (27.71%)  39
Respiratory, thoracic and mediastinal disorders     
Cough  1  3/84 (3.57%)  3 5/83 (6.02%)  5
Oropharyngeal pain  1  3/84 (3.57%)  3 7/83 (8.43%)  7
Vascular disorders     
Hypertension  1  3/84 (3.57%)  4 6/83 (7.23%)  6
1
Term from vocabulary, MedDRA 23.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Regulatory Manager
Organization: argenx BVBA
Phone: +32 93103400
EMail: regulatory@argenx.com
Layout table for additonal information
Responsible Party: argenx
ClinicalTrials.gov Identifier: NCT03669588    
Other Study ID Numbers: ARGX-113-1704
2018-002132-25 ( EudraCT Number )
First Submitted: September 6, 2018
First Posted: September 13, 2018
Results First Submitted: January 14, 2022
Results First Posted: February 8, 2022
Last Update Posted: February 8, 2022