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Trial record 13 of 73 for:    "Paroxysmal Nocturnal Hemoglobinuria"

ALXN1210 Versus Eculizumab in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab

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ClinicalTrials.gov Identifier: NCT03056040
Recruitment Status : Active, not recruiting
First Posted : February 16, 2017
Results First Posted : March 21, 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 195
Recruitment Details  
Pre-assignment Details Participants were stratified into 1 of 2 groups based on their transfusion history. Stratified participants were randomly assigned in a 1:1 ratio to receive ravulizumab or eculizumab.
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description

On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.

After completion of the 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 3 years.

Participants received 900 mg of eculizumab q2w for 26 weeks.

After completion of the 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 3 years.

Period Title: Primary Evaluation Period
Started 97 98
Received at Least 1 Dose of Study Drug 97 98
Completed 96 95
Not Completed 1 3
Reason Not Completed
Withdrawal by Subject             1             1
Lack of Efficacy             0             1
Pregnancy             0             1
Period Title: Extension Period
Started 96 95
Received at Least 1 Dose of Ravulizumab 96 95
Completed [1] 0 0
Not Completed 96 95
[1]
The Extension Period is ongoing.
Arm/Group Title Ravulizumab Eculizumab Total
Hide Arm/Group Description On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127. Participants received 900 mg of eculizumab q2w for 26 weeks. Total of all reporting groups
Overall Number of Baseline Participants 97 98 195
Hide Baseline Analysis Population Description
All participants who received at least 1 dose of study treatment (ravulizumab or eculizumab).
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 97 participants 98 participants 195 participants
46.6  (14.41) 48.8  (13.97) 47.7  (14.19)
[1]
Measure Description: Age at first infusion of study drug
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 97 participants 98 participants 195 participants
Female
47
  48.5%
50
  51.0%
97
  49.7%
Male
50
  51.5%
48
  49.0%
98
  50.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 97 participants 98 participants 195 participants
Hispanic or Latino
3
   3.1%
4
   4.1%
7
   3.6%
Not Hispanic or Latino
76
  78.4%
77
  78.6%
153
  78.5%
Unknown or Not Reported
18
  18.6%
17
  17.3%
35
  17.9%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 97 participants 98 participants 195 participants
White
50
  51.5%
61
  62.2%
111
  56.9%
Asian
23
  23.7%
19
  19.4%
42
  21.5%
Not Reported
13
  13.4%
13
  13.3%
26
  13.3%
Black or African American
5
   5.2%
3
   3.1%
8
   4.1%
Unknown
3
   3.1%
1
   1.0%
4
   2.1%
Other
2
   2.1%
1
   1.0%
3
   1.5%
Multiple
1
   1.0%
0
   0.0%
1
   0.5%
1.Primary Outcome
Title Percent Change In Lactate Dehydrogenase Levels From Baseline To Day 183
Hide Description Lactate dehydrogenase (LDH) is an indicator of intravascular hemolysis that occurs in participants with paroxysmal nocturnal hemoglobinuria. A decrease in LDH indicates reduction (improvement) in hemolysis. Baseline was defined as the average of all available on-study assessments prior to the first study drug infusion. The percent change in LDH was analyzed using a mixed-effect model for repeated measures (MMRM) with the fixed, categorical effects of treatment, study visit, and study visit by treatment group interaction, as well as the continuous, fixed covariate of baseline LDH and the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1).
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 randomized treatment (ravulizumab or eculizumab).
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description:
On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.
Participants received 900 mg of eculizumab q2w for 26 weeks.
Overall Number of Participants Analyzed 97 98
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
-0.82
(-7.75 to 6.11)
8.39
(1.47 to 15.32)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ravulizumab, Eculizumab
Comments Adjusting for a possible 10% dropout rate, a minimum of 192 participants were estimated to provide 90% power to demonstrate noninferiority of ravulizumab to eculizumab.
Type of Statistical Test Non-Inferiority
Comments

A difference in percent change in LDH between the ravulizumab and eculizumab treatment groups at Day 183 along with a 2-sided 95% confidence interval (CI) was calculated.

Noninferiority margin (NIM) was based on the upper bound of the 95% CI. NIM was 15%.

Method of Estimation Estimation Parameter Treatment Difference
Estimated Value -9.21
Confidence Interval (2-Sided) 95%
-18.84 to 0.42
Estimation Comments Treatment difference was estimated for ravulizumab - eculizumab.
2.Secondary Outcome
Title Percentage Of Participants With Breakthrough Hemolysis
Hide Description Breakthrough hemolysis (BTH) was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 grams (g)/deciliter (dL)], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 times the upper limit of normal (ULN).
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 randomized treatment (ravulizumab or eculizumab).
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description:
On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.
Participants received 900 mg of eculizumab q2w for 26 weeks.
Overall Number of Participants Analyzed 97 98
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
0.0
(0.00 to 3.73)
5.1
(1.68 to 11.51)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ravulizumab, Eculizumab
Comments A difference in the percentages of participants with BTH was calculated between the ravulizumab and eculizumab treatment groups, along with a 95% CI for the difference using the stratified Newcombe CI method. The stratification factor observed was transfusion history within 1 year prior to first dose of study drug.
Type of Statistical Test Non-Inferiority
Comments NIM was based on the upper bound of the 95% CI. NIM was 20%.
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value -5.1
Confidence Interval (2-Sided) 95%
-18.99 to 8.89
Estimation Comments Treatment difference was estimated for ravulizumab - eculizumab.
3.Secondary Outcome
Title Change From Baseline To Day 183 In Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Scores
Hide Description FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline was defined as the last non-missing assessment value prior to first study drug dose. Change in FACIT-Fatigue score from Baseline to Day 183 was analyzed using an MMRM with the fixed, categorical effects of treatment, the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1), study visit, and study visit by treatment group interaction, as well as the continuous fixed covariate of Baseline FACIT-Fatigue score.
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 randomized treatment (ravulizumab or eculizumab).
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description:
On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.
Participants received 900 mg of eculizumab q2w for 26 weeks.
Overall Number of Participants Analyzed 97 98
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
2.01
(0.64 to 3.39)
0.54
(-0.84 to 1.93)
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 NIM was based on the lower bound of the 95% CI. NIM margin was -3.
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value 1.47
Confidence Interval (2-Sided) 95%
-0.21 to 3.15
Estimation Comments Treatment difference was estimated for ravulizumab - eculizumab.
4.Secondary Outcome
Title Percentage Of Participants Who Achieved Transfusion Avoidance
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 (hemoglobin value of ≤9 g/dL with signs or symptoms of sufficient severity to warrant a transfusion, or a hemoglobin value of ≤7 g/dL regardless of presence of clinical signs or symptoms) 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 randomized treatment (ravulizumab or eculizumab).
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description:
On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.
Participants received 900 mg of eculizumab q2w for 26 weeks.
Overall Number of Participants Analyzed 97 98
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
87.6
(81.08 to 94.18)
82.7
(75.16 to 90.15)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ravulizumab, Eculizumab
Comments A difference in the percentages of participants achieving transfusion avoidance was calculated between the ravulizumab and eculizumab treatment groups, along with a 95% CI for the difference using the stratified Newcombe CI method. The stratification factor observed was transfusion history within 1 year prior to first dose of study drug
Type of Statistical Test Non-Inferiority
Comments NIM was based on the lower bound of the 95% CI. NIM was -20%.
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value 5.5
Confidence Interval (2-Sided) 95%
-4.27 to 15.68
Estimation Comments Treatment difference was estimated for ravulizumab - eculizumab.
5.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 randomized treatment (ravulizumab or eculizumab).
Arm/Group Title Ravulizumab Eculizumab
Hide Arm/Group Description:
On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.
Participants received 900 mg of eculizumab q2w for 26 weeks.
Overall Number of Participants Analyzed 97 98
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
76.3
(67.82 to 84.75)
75.5
(67.00 to 84.02)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ravulizumab, Eculizumab
Comments A difference in the percentages of participants with stabilized hemoglobin was calculated between the ravulizumab and eculizumab treatment groups, along with a 95% CI for the difference using the stratified Newcombe CI method. The stratification factor observed was transfusion history within 1 year prior to first dose of study drug.
Type of Statistical Test Non-Inferiority
Comments NIM was based on the lower bound of the 95% CI. NIM was -20%.
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value 1.4
Confidence Interval (2-Sided) 95%
-10.41 to 13.31
Estimation Comments Treatment difference was estimated for ravulizumab - eculizumab.
Time Frame From Baseline (after first dose) to 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 On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127. Participants received 900 mg of eculizumab q2w for 26 weeks.
All-Cause Mortality
Ravulizumab Eculizumab
Affected / at Risk (%) Affected / at Risk (%)
Total   0/97 (0.00%)   0/98 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Ravulizumab Eculizumab
Affected / at Risk (%) Affected / at Risk (%)
Total   4/97 (4.12%)   8/98 (8.16%) 
Blood and lymphatic system disorders     
Haemolysis  1  0/97 (0.00%)  2/98 (2.04%) 
Cardiac disorders     
Palpitations  1  0/97 (0.00%)  1/98 (1.02%) 
Gastrointestinal disorders     
Colitis  1  1/97 (1.03%)  0/98 (0.00%) 
General disorders     
Hyperthermia  1  1/97 (1.03%)  0/98 (0.00%) 
Pyrexia  1  0/97 (0.00%)  3/98 (3.06%) 
Hepatobiliary disorders     
Cholelithiasis  1  0/97 (0.00%)  1/98 (1.02%) 
Infections and infestations     
Influenza  1  1/97 (1.03%)  0/98 (0.00%) 
Lower respiratory tract infection  1  1/97 (1.03%)  0/98 (0.00%) 
Pyelonephritis acute  1  0/97 (0.00%)  1/98 (1.02%) 
Nervous system disorders     
Epilepsy  1  1/97 (1.03%)  0/98 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Respiratory failure  1  1/97 (1.03%)  0/98 (0.00%) 
1
Term from vocabulary, MedDRA (20.1)
Indicates events were collected by systematic assessment
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   84/97 (86.60%)   85/98 (86.73%) 
Blood and lymphatic system disorders     
Anaemia  1  6/97 (6.19%)  3/98 (3.06%) 
Gastrointestinal disorders     
Abdominal pain  1  6/97 (6.19%)  9/98 (9.18%) 
Constipation  1  7/97 (7.22%)  5/98 (5.10%) 
Diarrhoea  1  9/97 (9.28%)  7/98 (7.14%) 
Nausea  1  8/97 (8.25%)  9/98 (9.18%) 
Vomiting  1  6/97 (6.19%)  4/98 (4.08%) 
General disorders     
Chest pain  1  3/97 (3.09%)  9/98 (9.18%) 
Fatigue  1  6/97 (6.19%)  6/98 (6.12%) 
Influenza like illness  1  7/97 (7.22%)  8/98 (8.16%) 
Pyrexia  1  9/97 (9.28%)  2/98 (2.04%) 
Infections and infestations     
Nasopharyngitis  1  21/97 (21.65%)  20/98 (20.41%) 
Rhinitis  1  5/97 (5.15%)  4/98 (4.08%) 
Upper respiratory tract infection  1  18/97 (18.56%)  10/98 (10.20%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal pain  1  2/97 (2.06%)  5/98 (5.10%) 
Pain in extremity  1  5/97 (5.15%)  4/98 (4.08%) 
Nervous system disorders     
Dizziness  1  3/97 (3.09%)  7/98 (7.14%) 
Headache  1  26/97 (26.80%)  17/98 (17.35%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  5/97 (5.15%)  10/98 (10.20%) 
Dyspnoea  1  0/97 (0.00%)  6/98 (6.12%) 
Oropharyngeal pain  1  4/97 (4.12%)  9/98 (9.18%) 
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
Name/Title: Alexion Pharmaceuticals Inc.
Organization: Alexion Pharmaceuticals Inc.
Phone: 855-752-2356
Responsible Party: Alexion Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03056040     History of Changes
Other Study ID Numbers: ALXN1210-PNH-302
2016-002026-36 ( EudraCT Number )
First Submitted: February 14, 2017
First Posted: February 16, 2017
Results First Submitted: February 15, 2019
Results First Posted: March 21, 2019
Last Update Posted: May 16, 2019