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ALXN1210 (Ravulizumab) Versus Eculizumab in Complement Inhibitor Treatment-Naïve Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)

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ClinicalTrials.gov Identifier: NCT02946463
Recruitment Status : Active, not recruiting
First Posted : October 27, 2016
Results First Posted : February 12, 2019
Last Update Posted : May 16, 2019
Sponsor:
Information provided by (Responsible Party):
Alexion Pharmaceuticals

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Paroxysmal Nocturnal Hemoglobinuria (PNH)
Interventions Biological: Ravulizumab
Biological: Eculizumab
Enrollment 246
Recruitment Details  
Pre-assignment Details Participants were stratified into 6 groups based on transfusion history and LDH screening levels. Stratified participants were then randomly assigned in a 1:1 ratio to receive either ravulizumab or eculizumab in the 26-week Primary Evaluation Period.
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description

Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.

After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 5 years.

Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.

After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 5 years.

Period Title: Primary Evaluation Period
Started 125 121
Received at Least 1 Dose of Study Drug 125 121
Completed 125 119
Not Completed 0 2
Reason Not Completed
Physician Decision             0             1
Withdrawal by Subject             0             1
Period Title: Extension Period
Started [1] 124 119
Received at Least 1 Dose of Ravulizumab 124 119
Completed [2] 0 0
Not Completed 124 119
[1]
1 participant did not enter the Extension Period.
[2]
The Extension Period is ongoing.
Arm/Group Title Ravulizumab Eculizumab Total
Hide Arm/Group Description Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks. Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks. Total of all reporting groups
Overall Number of Baseline Participants 125 121 246
Hide Baseline Analysis Population Description
All participants who received at least 1 dose of study drug.
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 125 participants 121 participants 246 participants
44.8  (15.16) 46.2  (16.24) 45.5  (15.69)
[1]
Measure Description: Age at first infusion of study drug
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 125 participants 121 participants 246 participants
Female
60
  48.0%
52
  43.0%
112
  45.5%
Male
65
  52.0%
69
  57.0%
134
  54.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 125 participants 121 participants 246 participants
Hispanic or Latino
5
   4.0%
13
  10.7%
18
   7.3%
Not Hispanic or Latino
116
  92.8%
102
  84.3%
218
  88.6%
Unknown or Not Reported
4
   3.2%
6
   5.0%
10
   4.1%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 125 participants 121 participants 246 participants
American Indian or Alaska Native
1
   0.8%
1
   0.8%
2
   0.8%
Asian
72
  57.6%
57
  47.1%
129
  52.4%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
2
   1.6%
4
   3.3%
6
   2.4%
White
43
  34.4%
51
  42.1%
94
  38.2%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
7
   5.6%
8
   6.6%
15
   6.1%
1.Primary Outcome
Title Proportion Of Participants With Normalization Of Lactate Dehydrogenase (LDH) Levels
Hide Description LDH is an indicator of intravascular hemolysis that occurs in patients with paroxysmal nocturnal hemoglobinuria (PNH). A decrease in LDH from above the upper limit of normal (ULN) to below the ULN indicates reduction (improvement) in hemolysis. Normalization of LDH levels (LDH-N) was LDH levels less than or equal to 1 x ULN, from Day 29 through Day 183. The ULN for LDH is 246 U/L.
Time Frame Day 29 through Day 183
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: All participants who received at least 1 dose of study drug (ravulizumab or eculizumab) and had at least 1 efficacy assessment after the first infusion of study drug.
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description:
Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.
Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.
Overall Number of Participants Analyzed 125 121
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of participants
0.536
(0.459 to 0.612)
0.494
(0.417 to 0.570)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ravulizumab, Eculizumab
Comments A minimum of 142 participants were estimated to provide 80% power to demonstrate noninferiority of ravulizumab to eculizumab.
Type of Statistical Test Non-Inferiority
Comments

LDH-N was analyzed using a generalized estimating equation (GEE) approach. The model included the following terms: treatment group, history of transfusion (as a categorical variable based on the stratification factor levels), and baseline LDH level (as a continuous variable).

Noninferiority margin was based on the lower bound of the 95% confidence interval (CI) for the odds ratio (OR) of ravulizumab versus eculizumab for LDH normalization being greater than an OR of 0.39.

Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.187
Confidence Interval (2-Sided) 95%
0.796 to 1.769
Estimation Comments [Not Specified]
2.Primary Outcome
Title Percentage Of Participants Who Achieved Transfusion Avoidance (TA)
Hide Description Transfusion avoidance was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines through Day 183.
Time Frame Baseline through Day 183
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: All participants who received at least 1 dose of study drug (ravulizumab or eculizumab) and had at least 1 efficacy assessment after the first infusion of study drug.
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description:
Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.
Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.
Overall Number of Participants Analyzed 125 121
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
73.6
(65.87 to 81.33)
66.1
(57.68 to 74.55)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ravulizumab, Eculizumab
Comments A minimum of 193 participants were estimated to provide 80% power to demonstrate noninferiority of ravulizumab to eculizumab. The difference of percentages were calculated using stratified Newcombe CI method. Stratification factors were: observed stratification groups of packed red blood cells (pRBC)/whole blood units transfused in the 1 year prior to first dose of study drug and screening LDH levels.
Type of Statistical Test Non-Inferiority
Comments Noninferiority margin was based on the lower bound of the 95% CI. Noninferiority margin was -20%.
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 6.8
Confidence Interval (2-Sided) 95%
-4.66 to 18.14
Estimation Comments Treatment difference was estimated for ravulizumab - eculizumab.
3.Secondary Outcome
Title Percentage Of Participants With Breakthrough Hemolysis (BTH)
Hide Description Breakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 gram/deciliter (g/dL)], major adverse vascular event [MAVE, including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 × ULN, after prior LDH reduction to <1.5 × ULN on therapy.
Time Frame Baseline through Day 183
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: All participants who received at least 1 dose of study drug (ravulizumab or eculizumab) and had at least 1 efficacy assessment after the first infusion of study drug.
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description:
Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.
Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.
Overall Number of Participants Analyzed 125 121
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
4.0
(0.56 to 7.44)
10.7
(5.23 to 16.26)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ravulizumab, Eculizumab
Comments The difference of percentages was calculated using stratified Newcombe CI method. The stratification factors were: observed stratification groups of pRBC units transfused in the 1 year prior to first dose of study drug and screening LDH levels.
Type of Statistical Test Non-Inferiority
Comments Noninferiority margin was based on the upper bound of the 95% CI. Noninferiority margin was 20%.
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -6.7
Confidence Interval (2-Sided) 95%
-14.21 to 0.18
Estimation Comments Treatment difference was estimated for ravulizumab - eculizumab.
4.Secondary Outcome
Title Percent Change From Baseline In Lactate Dehydrogenase (LDH) Levels
Hide Description Baseline is defined as the average of all available assessments of LDH levels prior to first study drug dose. Estimates are based on Mixed Model for Repeated Measures (MMRM) that includes treatment group, history of transfusion (as a categorical variable based on the stratification factor levels) and baseline LDH level (as a continuous variable), study visit and study visit by treatment group interaction. An unstructured covariance structure was used.
Time Frame Baseline, Day 183
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: All participants who received at least 1 dose of study drug (ravulizumab or eculizumab) and had at least 1 efficacy assessment after the first infusion of study drug.
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description:
Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.
Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.
Overall Number of Participants Analyzed 125 121
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
-76.84
(-79.96 to -73.73)
-76.02
(-79.20 to -72.83)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ravulizumab, Eculizumab
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Noninferiority margin was based on the upper bound of the 95% CI. Noninferiority margin was 20%.
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -0.83
Confidence Interval (2-Sided) 95%
-5.21 to 3.56
Estimation Comments Treatment difference was estimated for ravulizumab - eculizumab.
5.Secondary Outcome
Title Change From Baseline In Quality Of Life As Assessed By The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue
Hide Description FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline is defined as the last non-missing value prior to first dose of study drug. Estimates are based on MMRM that includes treatment group, the observed stratification randomization indicators (history of transfusion and LDH) and baseline FACIT-Fatigue level, study visit, and study visit by treatment group interaction. An unstructured covariance structure was used.
Time Frame Baseline, Day 183
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: All participants who received at least 1 dose of study drug (ravulizumab or eculizumab) and had at least 1 efficacy assessment after the first infusion of study drug.
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description:
Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.
Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.
Overall Number of Participants Analyzed 125 121
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
7.07
(5.55 to 8.60)
6.40
(4.85 to 7.96)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ravulizumab, Eculizumab
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments Noninferiority margin was based on the lower bound of the 95% CI. Noninferiority margin was -5%.
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.67
Confidence Interval (2-Sided) 95%
-1.21 to 2.55
Estimation Comments Treatment difference was estimated for ravulizumab - eculizumab.
6.Secondary Outcome
Title Percentage Of Participants With Stabilized Hemoglobin Levels
Hide Description Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion through Day 183.
Time Frame Baseline through Day 183
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: All participants who received at least 1 dose of study drug (ravulizumab or eculizumab) and had at least 1 efficacy assessment after the first infusion of study drug.
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description:
Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks.
Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.
Overall Number of Participants Analyzed 125 121
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
68.0
(59.82 to 76.18)
64.5
(55.93 to 72.99)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ravulizumab, Eculizumab
Comments The difference of percentages was calculated using stratified Newcombe CI method. The stratification factors were: observed stratification groups of pRBC units transfused in the 1 year prior to first dose of study drug and screening LDH levels.
Type of Statistical Test Non-Inferiority
Comments Noninferiority margin was based on the lower bound of the 95% CI. Noninferiority margin was -20%.
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 2.9
Confidence Interval (2-Sided) 95%
-8.80 to 14.64
Estimation Comments Treatment difference was estimated for ravulizumab - eculizumab.
Time Frame From Day 1 (after first dose) through Day 183 (before dosing)
Adverse Event Reporting Description Treatment-emergent adverse events (TEAEs) reported below include TEAEs that occurred during the Primary Evaluation Period, which was defined as events that started during or after the first infusion of study treatment up to before dosing on Day 183. Adverse events that occurred during or after dosing on Day 183 were considered as part of the Extension Period and were not reported.
 
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description Participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg on Day 1. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Day 15 and every 8 weeks thereafter for 26 weeks. Participants received 600 mg of eculizumab on Days 1, 8, 15, and 22, followed by 900 mg of eculizumab on Day 29 and every 2 weeks thereafter for 26 weeks.
All-Cause Mortality
Ravulizumab Eculizumab
Affected / at Risk (%) Affected / at Risk (%)
Total   0/125 (0.00%)   0/121 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Ravulizumab Eculizumab
Affected / at Risk (%) Affected / at Risk (%)
Total   11/125 (8.80%)   9/121 (7.44%) 
Blood and lymphatic system disorders     
Anaemia  1  1/125 (0.80%)  0/121 (0.00%) 
Aplastic anaemia  1  1/125 (0.80%)  0/121 (0.00%) 
Neutropenia  1  1/125 (0.80%)  0/121 (0.00%) 
Thrombocytopenia  1  1/125 (0.80%)  0/121 (0.00%) 
Cardiac disorders     
Left ventricular failure  1  1/125 (0.80%)  0/121 (0.00%) 
Myocardial ischaemia  1  1/125 (0.80%)  0/121 (0.00%) 
Gastrointestinal disorders     
Ileus  1  0/125 (0.00%)  1/121 (0.83%) 
Neutropenic colitis  1  0/125 (0.00%)  1/121 (0.83%) 
General disorders     
Pyrexia  1  1/125 (0.80%)  2/121 (1.65%) 
Infections and infestations     
Abscess limb  1  0/125 (0.00%)  1/121 (0.83%) 
Cellulitis  1  0/125 (0.00%)  1/121 (0.83%) 
Infection  1  0/125 (0.00%)  1/121 (0.83%) 
Leptospirosis  1  1/125 (0.80%)  0/121 (0.00%) 
Pneumonia  1  0/125 (0.00%)  1/121 (0.83%) 
Systemic infection  1  1/125 (0.80%)  0/121 (0.00%) 
Viral upper respiratory tract infection  1  0/125 (0.00%)  1/121 (0.83%) 
Injury, poisoning and procedural complications     
Laceration  1  1/125 (0.80%)  0/121 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Adenocarcinoma of colon  1  0/125 (0.00%)  1/121 (0.83%) 
Lung adenocarcinoma  1  0/125 (0.00%)  1/121 (0.83%) 
Uterine leiomyoma  1 [1]  1/60 (1.67%)  0/52 (0.00%) 
Renal and urinary disorders     
Paroxysmal nocturnal haemoglobinuria  1  0/125 (0.00%)  1/121 (0.83%) 
Renal colic  1  1/125 (0.80%)  0/121 (0.00%) 
Vascular disorders     
Deep vein thrombosis  1  1/125 (0.80%)  0/121 (0.00%) 
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
[1]
This is a sex-specific adverse event that only affects female participants.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Ravulizumab Eculizumab
Affected / at Risk (%) Affected / at Risk (%)
Total   109/125 (87.20%)   104/121 (85.95%) 
Gastrointestinal disorders     
Abdominal pain  1  7/125 (5.60%)  7/121 (5.79%) 
Diarrhoea  1  10/125 (8.00%)  5/121 (4.13%) 
Nausea  1  11/125 (8.80%)  10/121 (8.26%) 
General disorders     
Pyrexia  1  6/125 (4.80%)  11/121 (9.09%) 
Infections and infestations     
Nasopharyngitis  1  11/125 (8.80%)  18/121 (14.88%) 
Upper respiratory tract infection  1  13/125 (10.40%)  7/121 (5.79%) 
Viral upper respiratory tract infection  1  9/125 (7.20%)  9/121 (7.44%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  8/125 (6.40%)  8/121 (6.61%) 
Back pain  1  7/125 (5.60%)  6/121 (4.96%) 
Myalgia  1  7/125 (5.60%)  9/121 (7.44%) 
Pain in extremity  1  9/125 (7.20%)  7/121 (5.79%) 
Nervous system disorders     
Dizziness  1  9/125 (7.20%)  7/121 (5.79%) 
Headache  1  45/125 (36.00%)  40/121 (33.06%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  4/125 (3.20%)  8/121 (6.61%) 
Oropharyngeal pain  1  8/125 (6.40%)  6/121 (4.96%) 
1
Term from vocabulary, MedDRA 20.1
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: Alexion Pharmaceuticals Inc.
Organization: Alexion Pharmaceuticals Inc.
Phone: 855-752-2356
EMail: clinicaltrials@alexion.com
Layout table for additonal information
Responsible Party: Alexion Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02946463     History of Changes
Other Study ID Numbers: ALXN1210-PNH-301
2016-002025-11 ( EudraCT Number )
First Submitted: October 25, 2016
First Posted: October 27, 2016
Results First Submitted: January 24, 2019
Results First Posted: February 12, 2019
Last Update Posted: May 16, 2019