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

• 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: argenx
• 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

Participant Flow

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
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

Baseline Characteristics

Arm/Group Title		ARGX-113	Placebo	Total
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
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%

Outcome Measures

1. Primary Outcome

Title	Percentage of MG-ADL Responders During Cycle 1 (C1); Analyzed in the AChR-Ab Seropositive Population
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)

Outcome Measure Data

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
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

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
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)

Outcome Measure Data

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
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

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
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)

Outcome Measure Data

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
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

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
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

Outcome Measure Data

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
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)

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
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])

Outcome Measure Data

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
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)

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
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)

Outcome Measure Data

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
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

Adverse Events

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
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%)
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
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

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Regulatory Manager
• Organization: argenx BVBA
• Phone: +32 93103400
• EMail: regulatory@argenx.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Howard JF Jr, Bril V, Vu T, Karam C, Peric S, Margania T, Murai H, Bilinska M, Shakarishvili R, Smilowski M, Guglietta A, Ulrichts P, Vangeneugden T, Utsugisawa K, Verschuuren J, Mantegazza R; ADAPT Investigator Study Group. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021 Jul;20(7):526-536. doi: 10.1016/S1474-4422(21)00159-9. Erratum In: Lancet Neurol. 2021 Aug;20(8):e5.

• 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