A Study Evaluating the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Crovalimab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibition (COMMODORE 3)

• ClinicalTrials.gov Identifier: NCT04654468
• Recruitment Status: Active, not recruiting
• First Posted: December 4, 2020
• Results First Posted: June 5, 2023
• Last Update Posted: March 5, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Paroxysmal Nocturnal Hemoglobinuria
• Intervention: Drug: Crovalimab
• Enrollment: 51

Participant Flow

Recruitment Details	Participants took part in the study at 5 investigative sites in China.
Pre-assignment Details	A total of 51 participants with a diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) were enrolled in the study and received at least 1 dose of crovalimab.

Arm/Group Title	Crovalimab
Arm/Group Description	Crovalimab was administered at an initial loading dose of 1000 milligrams (mg) (for participants with body weight between 40 and 100 kg) or 1500 mg (for participants with body weight >=100kg), as intravenous (IV) injection on Day 1 of Week 1 followed by four weekly subcutaneous (SC) injections of 340 mg starting on Day 2 of Week 1 and then once weekly (QW) at Weeks 2,3 and 4. Thereafter crovalimab was administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight >=100kg) once every 4 weeks (Q4W) from Week 5 for a total of 24 weeks of study treatment. Participants who derive benefit from the drug after 24 weeks of treatment may continue to receive crovalimab Q4W.
Period Title: Overall Study
Started	51
Completed	0
Not Completed	51
Reason Not Completed
Death	1
Ongoing in the Study	50

Baseline Characteristics

Arm/Group Title		Crovalimab
Arm/Group Description		Crovalimab was administered at an initial loading dose of 1000 mg (for participants with body weight between 40 and 100) kg or 1500 mg (for participants with body weight >=100kg), as IV injection on Day 1 of Week 1 followed by four weekly SC injections of 340 mg starting on Day 2 of Week 1 and then QW at Weeks 2,3 and 4. Thereafter crovalimab was administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight >=100kg) Q4W from Week 5 for a total of 24 weeks of study treatment. Participants who derive benefit from the drug after 24 weeks of treatment may continue to receive crovalimab.
Overall Number of Baseline Participants		51
Baseline Analysis Population Description		Safety population included all enrolled participants who received at least one dose of crovalimab.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	51 participants
		33.0 (9.4)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	51 participants
	Female	29 56.9%
	Male	22 43.1%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	51 participants
	Hispanic or Latino	0 0.0%
	Not Hispanic or Latino	51 100.0%
	Unknown or Not Reported	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	51 participants
	American Indian or Alaska Native	0 0.0%
	Asian	51 100.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	0 0.0%
	White	0 0.0%
	More than one race	0 0.0%
	Unknown or Not Reported	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Mean Percentage of Participants With Hemolysis Control
Description	A Generalized Estimating Equation (GEE) was used to estimate the population-average percentage of the participants with hemolysis control (measured by lactate dehydrogenase (LDH) ≤1.5 x upper limit of normal (ULN)) from Week 5 to Week 25 taking account of the intra-patient and inter-patient correlation between LDH control statuses across visits. The dependent variable was the binary indicator for hemolysis control. Independent variables are categorical effects of visits, continuous baseline LDH.
Time Frame	From Week 5 up to Week 25

Outcome Measure Data

Analysis Population Description

Primary Analysis Population (PAP) included all enrolled participants who received at least one dose of crovalimab and had at least one central LDH level assessment after the first IV infusion.

Arm/Group Title	Crovalimab
Arm/Group Description:	Crovalimab was administered at an initial loading dose of 1000 mg (for participants with body weight between 40 and 100) kg or 1500 mg (for participants with body weight >=100kg), as IV injection on Day 1 of Week 1 followed by four weekly SC injections of 340 mg starting on Day 2 of Week 1 and then QW at Weeks 2,3 and 4. Thereafter crovalimab was administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight >=100kg) Q4W from Week 5 for a total of 24 weeks of study treatment. Participants who derive benefit from the drug after 24 weeks of treatment may continue to receive crovalimab.
Overall Number of Participants Analyzed	51
Least Squares Mean (95% Confidence Interval); Unit of Measure: mean percentage of participants
	78.66; (67.78 to 86.59)

2. Primary Outcome

Title	Difference in Percentage of Participants With Transfusion Avoidance (TA) From Baseline Through Week 25 and Within 24 Weeks Prior to Screening
Description	TA was defined as participants who were packed red blood cell (pRBC) transfusion-free and did not require transfusion per protocol-specified guidelines. TA within 24 weeks prior to screening was based on the pRBC transfusion history in the medical records. Reported in this outcome measure is the difference in the percentage of participants between "baseline through Week 25" and "within 24 weeks prior to screening". 95% Confidence Interval (CI) for the difference between the percentage of participants with transfusion avoidance between Pre-screening and Post-baseline is calculated using the Newcombe method. Screening= Day -28 to Day -1 and Baseline= Day 1.
Time Frame	24 Weeks Prior to Screening, Baseline to Week 25

Outcome Measure Data

Analysis Population Description

PAP included all enrolled participants who received at least one dose of crovalimab and had at least one central LDH level assessment after the first IV infusion.

Arm/Group Title	Crovalimab
Arm/Group Description:	Crovalimab was administered at an initial loading dose of 1000 mg (for participants with body weight between 40 and 100) kg or 1500 mg (for participants with body weight >=100kg), as IV injection on Day 1 of Week 1 followed by four weekly SC injections of 340 mg starting on Day 2 of Week 1 and then QW at Weeks 2,3 and 4. Thereafter crovalimab was administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight >=100kg) Q4W from Week 5 for a total of 24 weeks of study treatment. Participants who derive benefit from the drug after 24 weeks of treatment may continue to receive crovalimab.
Overall Number of Participants Analyzed	51
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	50.98; (34.30 to 65.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Crovalimab
	Comments	Percentage of participants who achieved TA from baseline through Week 25 were compared with the percentage of participants who reported TA within 24 weeks prior to screening.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	Paired McNemar
	Comments	[Not Specified]

3. Secondary Outcome

Title	Percentage of Participants With Breakthrough Hemolysis (BTH)
Description	BTH was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin < 10 grams per deciliter (g/dL)], major adverse vascular event [MAVE, including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2xULN after a prior LDH reduction to ≤1.5xULN from the start of study treatment. As pre-specified in the SAP participants withdrawing before Week 25 were deemed to have experienced a BTH event. Percentages have been rounded off to the first decimal point.
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

PAP included all enrolled participants who received at least one dose of crovalimab and had at least one central LDH level assessment after the first IV infusion.

Arm/Group Title	Crovalimab
Arm/Group Description:	Crovalimab was administered at an initial loading dose of 1000 mg (for participants with body weight between 40 and 100) kg or 1500 mg (for participants with body weight >=100kg), as IV injection on Day 1 of Week 1 followed by four weekly SC injections of 340 mg starting on Day 2 of Week 1 and then QW at Weeks 2,3 and 4. Thereafter crovalimab was administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight >=100kg) Q4W from Week 5 for a total of 24 weeks of study treatment. Participants who derive benefit from the drug after 24 weeks of treatment may continue to receive crovalimab.
Overall Number of Participants Analyzed	51
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	3.9; (0.68 to 14.59)

4. Secondary Outcome

Title	Percentage of Participants With Stabilized Hemoglobin
Description	Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion. As pre-specified in the SAP participants withdrawing before Week 25 were deemed to not have hemoglobin stabilization.
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

PAP included all enrolled participants who received at least one dose of crovalimab and had at least one central LDH level assessment after the first IV infusion.

Arm/Group Title	Crovalimab
Arm/Group Description:	Crovalimab was administered at an initial loading dose of 1000 mg (for participants with body weight between 40 and 100) kg or 1500 mg (for participants with body weight >=100kg), as IV injection on Day 1 of Week 1 followed by four weekly SC injections of 340 mg starting on Day 2 of Week 1 and then QW at Weeks 2,3 and 4. Thereafter crovalimab was administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight >=100kg) Q4W from Week 5 for a total of 24 weeks of study treatment. Participants who derive benefit from the drug after 24 weeks of treatment may continue to receive crovalimab.
Overall Number of Participants Analyzed	51
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	51.0; (36.77 to 65.05)

5. Secondary Outcome

Title	Change From Baseline in Fatigue in Adults Aged >=18 Years
Description	Fatigue was assessed using functional assessment of chronic illness therapy-fatigue (FACIT-F) scale. FACIT-F is a self-assessment questionnaire with a 7-day recall period and 13 items evaluating fatigue and its impact on daily life activities. Items are scored on a response scale that ranges from 0 ("not at all") to 4 ("very much so"). Relevant items are reverse scored, and all the items are summed to create a total score range from 0 to 52, with 0 being the worst possible score and 52 being the best possible score. A higher score indicates low fatigue severity. A positive mean change indicates improvement. FACIT-F was assessed in adult participants only. FACIT-F assessment was unintentionally missed in the Schedule of Activities (SoA) table, which site used to guide the assessments at each timepoint. Therefore, data were not collected at Week 25.
Time Frame	Baseline, Week 2, Week 5, Week 9, Week 17, Week 25

Outcome Measure Data

Analysis Population Description

PAP included all enrolled participants who received at least one dose of crovalimab and had at least one central LDH level assessment after the first IV infusion. Overall number analyzed is the number of participants ≥18 years with data available for analysis.

Arm/Group Title		Crovalimab
Arm/Group Description:		Crovalimab was administered at an initial loading dose of 1000 mg (for participants with body weight between 40 and 100) kg or 1500 mg (for participants with body weight >=100kg), as IV injection on Day 1 of Week 1 followed by four weekly SC injections of 340 mg starting on Day 2 of Week 1 and then QW at Weeks 2,3 and 4. Thereafter crovalimab was administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight >=100kg) Q4W from Week 5 for a total of 24 weeks of study treatment. Participants who derive benefit from the drug after 24 weeks of treatment may continue to receive crovalimab.
Overall Number of Participants Analyzed		48
Mean (Standard Deviation); Unit of Measure: score on a scale
Baseline	Number Analyzed	48 participants
		31.77 (8.53)
Change from Baseline at Week 2	Number Analyzed	48 participants
		6.67 (8.02)
Change from Baseline at Week 5	Number Analyzed	48 participants
		8.08 (9.28)
Change from Baseline at Week 9	Number Analyzed	48 participants
		8.15 (10.61)
Change from Baseline at Week 17	Number Analyzed	48 participants
		8.77 (9.63)
Change from Baseline at Week 25	Number Analyzed	0 participants

6. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AEs)
Description	[Not Specified]
Time Frame	Up to 7 years

Outcome Measure Data Not Reported

7. Secondary Outcome

Title	Percentage of Participants With Injection-Site Reactions, Infusion-Related Reactions, Hypersensitivity, and Infections (Including Meningococcal Meningitis)
Description	[Not Specified]
Time Frame	Up to 7 years

Outcome Measure Data Not Reported

8. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AEs) Leading to Study Drug Discontinuation
Description	[Not Specified]
Time Frame	Up to 7 years

Outcome Measure Data Not Reported

9. Secondary Outcome

Title	Trough Serum Concentration of Crovalimab Over Time
Description	[Not Specified]
Time Frame	Up to 7 years

Outcome Measure Data Not Reported

10. Secondary Outcome

Title	Serum Concentrations of Crovalimab
Description	[Not Specified]
Time Frame	Up to 7 years

Outcome Measure Data Not Reported

11. Secondary Outcome

Title	Percentage of Participants With Anti-Drug Antibodies (ADAs) to Crovalimab
Description	[Not Specified]
Time Frame	Up to 7 years

Outcome Measure Data Not Reported

12. Secondary Outcome

Title	Terminal Complement Activity as Measured by Liposome Immunoassay (LIA)
Description	[Not Specified]
Time Frame	Up to 7 years

Outcome Measure Data Not Reported

13. Secondary Outcome

Title	Change Over Time in Total and Free C5 Concentration
Description	[Not Specified]
Time Frame	Up to 7 years

Outcome Measure Data Not Reported

14. Secondary Outcome

Title	Observed Value in Absolute Reticulocyte Count
Description	[Not Specified]
Time Frame	Up to 7 years

Outcome Measure Data Not Reported

15. Secondary Outcome

Title	Observed Value in Free Hemoglobin
Description	[Not Specified]
Time Frame	Up to 7 years

Outcome Measure Data Not Reported

16. Secondary Outcome

Title	Observed Value in Haptoglobin
Description	[Not Specified]
Time Frame	Up to 7 years

Outcome Measure Data Not Reported

17. Secondary Outcome

Title	Percent Change From Baseline in Absolute Reticulocyte Count
Description	[Not Specified]
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

Safety population included all enrolled participants who received at least one dose of crovalimab. Number of participants analyzed is the number of participants with data available for analysis at the specified timepoints.

Arm/Group Title	Crovalimab
Arm/Group Description:	Crovalimab was administered at an initial loading dose of 1000 mg (for participants with body weight between 40 and 100) kg or 1500 mg (for participants with body weight >=100kg), as IV injection on Day 1 of Week 1 followed by four weekly SC injections of 340 mg starting on Day 2 of Week 1 and then QW at Weeks 2,3 and 4. Thereafter crovalimab was administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight >=100kg) Q4W from Week 5 for a total of 24 weeks of study treatment. Participants who derive benefit from the drug after 24 weeks of treatment may continue to receive crovalimab.
Overall Number of Participants Analyzed	44
Mean (Standard Deviation); Unit of Measure: percent change
	40.9411 (66.0292)

18. Secondary Outcome

Title	Percent Change From Baseline in Free Hemoglobin
Description	[Not Specified]
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

Safety population included all enrolled participants who received at least one dose of crovalimab. Number of participants analyzed is the number of participants with data available for analysis at the specified timepoints.

Arm/Group Title	Crovalimab
Arm/Group Description:	Crovalimab was administered at an initial loading dose of 1000 mg (for participants with body weight between 40 and 100) kg or 1500 mg (for participants with body weight >=100kg), as IV injection on Day 1 of Week 1 followed by four weekly SC injections of 340 mg starting on Day 2 of Week 1 and then QW at Weeks 2,3 and 4. Thereafter crovalimab was administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight >=100kg) Q4W from Week 5 for a total of 24 weeks of study treatment. Participants who derive benefit from the drug after 24 weeks of treatment may continue to receive crovalimab.
Overall Number of Participants Analyzed	37
Mean (Standard Deviation); Unit of Measure: percent change
	-45.6180 (51.8421)

19. Secondary Outcome

Title	Percent Change From Baseline in Haptoglobin
Description	[Not Specified]
Time Frame	Baseline, Week 25

Outcome Measure Data

Analysis Population Description

Safety population included all enrolled participants who received at least one dose of crovalimab. Number of participants analyzed is the number of participants with data available for analysis at the specified timepoints.

Arm/Group Title	Crovalimab
Arm/Group Description:	Crovalimab was administered at an initial loading dose of 1000 mg (for participants with body weight between 40 and 100) kg or 1500 mg (for participants with body weight >=100kg), as IV injection on Day 1 of Week 1 followed by four weekly SC injections of 340 mg starting on Day 2 of Week 1 and then QW at Weeks 2,3 and 4. Thereafter crovalimab was administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight >=100kg) Q4W from Week 5 for a total of 24 weeks of study treatment. Participants who derive benefit from the drug after 24 weeks of treatment may continue to receive crovalimab.
Overall Number of Participants Analyzed	37
Mean (Standard Deviation); Unit of Measure: percent change
	295.1351 (1735.4180)

Adverse Events

Time Frame	From enrollment until primary completion date cutoff (up to approximately 25 weeks)
Adverse Event Reporting Description	Safety population included all enrolled participants who received at least one dose of crovalimab.
Arm/Group Title	CROVALIMAB
Arm/Group Description	Crovalimab was administered at an initial loading dose of 1000 mg (for participants with body weight between 40 and 100) kg or 1500 mg (for participants with body weight >=100kg), as IV injection on Day 1 of Week 1 followed by four weekly SC injections of 340 mg starting on Day 2 of Week 1 and then QW at Weeks 2,3 and 4. Thereafter crovalimab was administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100kg) or 1020 mg (for participants with body weight >=100kg) Q4W from Week 5 for a total of 24 weeks of study treatment. Participants who derive benefit from the drug after 24 weeks of treatment may continue to receive crovalimab.
All-Cause Mortality
	CROVALIMAB
	Affected / at Risk (%)
Total	1/51 (1.96%)
Serious Adverse Events
	CROVALIMAB
	Affected / at Risk (%)	# Events
Total	4/51 (7.84%)
Blood and lymphatic system disorders
Thrombocytopenia † 1	1/51 (1.96%)	1
Gastrointestinal disorders
Abdominal wall mass † 1	1/51 (1.96%)	1
Hepatobiliary disorders
Bile duct stone † 1	1/51 (1.96%)	1
Infections and infestations
Bacteraemia † 1	1/51 (1.96%)	1
Injury, poisoning and procedural complications
Subdural haematoma † 1	1/51 (1.96%)	1
Investigations
Platelet count decreased † 1	1/51 (1.96%)	1
1 Term from vocabulary, MedDRA version 24.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	CROVALIMAB
	Affected / at Risk (%)	# Events
Total	46/51 (90.20%)
Blood and lymphatic system disorders
Neutropenia † 1	7/51 (13.73%)	8
Gastrointestinal disorders
Gingival swelling † 1	3/51 (5.88%)	3
Infections and infestations
Upper respiratory tract infection † 1	24/51 (47.06%)	26
Urinary tract infection † 1	3/51 (5.88%)	4
Investigations
Alanine aminotransferase increased † 1	11/51 (21.57%)	15
Alpha hydroxybutyrate dehydrogenase increased † 1	8/51 (15.69%)	8
Bilirubin conjugated increased † 1	15/51 (29.41%)	27
Blood alkaline phosphatase increased † 1	9/51 (17.65%)	12
Blood bilirubin increased † 1	9/51 (17.65%)	10
Blood bilirubin unconjugated increased † 1	12/51 (23.53%)	13
Gamma-glutamyltransferase increased † 1	6/51 (11.76%)	9
Lymphocyte count decreased † 1	8/51 (15.69%)	15
Neutrophil count decreased † 1	13/51 (25.49%)	25
Platelet count decreased † 1	5/51 (9.80%)	10
Weight increased † 1	6/51 (11.76%)	6
White blood cell count decreased † 1	12/51 (23.53%)	29
Metabolism and nutrition disorders
Hypercholesterolaemia † 1	3/51 (5.88%)	5
Hypertriglyceridaemia † 1	5/51 (9.80%)	16
Hyperuricaemia † 1	5/51 (9.80%)	7
1 Term from vocabulary, MedDRA version 24.1; † 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.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

• Name/Title: Medical Communications
• Organization: Hoffmann-La Roche
• Phone: 800 821-8590
• EMail: genentech@druginfo.com

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT04654468
• Other Study ID Numbers: YO42311
• First Submitted: November 30, 2020
• First Posted: December 4, 2020
• Results First Submitted: February 6, 2023
• Results First Posted: June 5, 2023
• Last Update Posted: March 5, 2024